Heather Wakelee
Winston Chen and Phyllis Huang Professor
Medicine - Oncology
Bio
Dr. Heather Wakelee specializes in the treatment of lung cancer, thymoma and mesothelioma. She completed all post-graduate training at Stanford University and joined the faculty in 2003. For many years she was the physician lead for the thoracic malignancies clinical research group and has developed research programs related to lung cancer and thymoma across multiple areas including clinical trials, translation work and population sciences. She is the Principal Investigator on numerous clinical trials. In 2021 Dr. Wakelee took on the role of Deputy Director of the Stanford Cancer Institute and is the Division Chief of Medical Oncology. She is also active in many national and international organizations related to lung cancer and thymoma including leadership roles in the International Association for the Study of Lung Cancer (IASLC).
Clinical Focus
- Cancer > Thoracic Oncology
- Lung Cancer - Medical Oncology
- Investigational Therapeutics
- Medical Oncology
- thymoma
- Mesothelioma
- thymic carcinoma
- Thoracic Cancers - Medical Oncology
- Mesothelioma - Medical Oncology
- Oncology (Cancer)
- Thoracic Cancers
Academic Appointments
-
Professor - University Medical Line, Medicine - Oncology
-
Member, Stanford Cancer Institute
Honors & Awards
-
Merit Award, American Society of Clinical Oncology (05/2003)
-
Alpha Omega Alpha, Johns Hopkins University (06/1996)
-
Teaching Award, Stanford University Division of Oncology (2007, 2008, 2009, 2011)
-
Young Investigator Award, ECOG-ACRIN (2015)
Professional Education
-
Fellowship: Stanford University Division of Oncology (2003) CA
-
Residency: Stanford University Internal Medicine Residency (1999) CA
-
Board Certification: American Board of Internal Medicine, Medical Oncology (2003)
-
Medical Education: Johns Hopkins University School of Medicine (1996) MD
-
M. D., Johns Hopkins University, Medicine (1996)
-
A.B., Princeton University, Molecular Biology (1992)
Current Research and Scholarly Interests
Dr. Wakelee is a clinical investigator with a focus in lung cancer and other thoracic malignancies. Along with her other colleagues in thoracic medical oncology at Stanford she is focused on clinical trials with agents that are specifically targeted to known mutations in lung cancer such as EGFR, ALK and other "driver" mutations with a particular focus on resistance mechanisms. Earlier work on anti-angiogenesis agents continues as well. The treatment of NSCLC revolves increasingly around the use of immune modulatory agents, particularly PD-(L)1 checkpoint inhibitors and the majority of current trials utilize these drugs including bringing them to patients with earlier stages of disease with a hope to improve cure rates.
Dr. Wakelee is an active member of the Eastern Cooperative Oncology Group (ECOG-ACRIN). Stanford University actively participates in trial design and recruitment of patients to ECOG-ACRIN trials. Dr. Wakelee also plays a leadership role in the International Association for the Study of Lung Cancer (IASLC) having served on the board of directors from 2015-2019) and was elected to the role of President-Elect in 2019 and her tenure as President stared in 2021.
Thymic malignancies are an understudied rare disease and Dr. Wakelee has developed 2 clinical trials in this patient population and is involved in translational efforts with the disease.
Dr. Wakelee is also involved in several collaborative efforts with her colleagues in thoracic surgery, radiation oncology, pulmonary medicine, basic science and population sciences. Work with Max Diehn on circulating tumor DNA is leading towards the potential to improve surveillance and early detection of NSCLC amongst other applications.
Clinical Trials
-
Crizotinib in Treating Patients With Stage IB-IIIA Non-small Cell Lung Cancer That Has Been Removed by Surgery and ALK Fusion Mutations (An ALCHEMIST Treatment Trial)
Recruiting
This randomized phase III trial studies how well crizotinib works in treating patients with stage IB-IIIA non-small cell lung cancer that has been removed by surgery and has a mutation in a protein called anaplastic lymphoma kinase (ALK). Mutations, or changes, in ALK can make it very active and important for tumor cell growth and progression. Crizotinib may stop the growth of tumor cells by blocking the ALK protein from working. Crizotinib may be an effective treatment for patients with non-small cell lung cancer and an ALK fusion mutation.
-
Efficacy and Safety Study of Tisotumab Vedotin for Patients With Solid Tumors
Recruiting
This trial will study tisotumab vedotin to find out whether it is an effective treatment alone or with other anticancer drugs for certain solid tumors and what side effects (unwanted effects) may occur. There are seven parts to this study. * In Part A, the treatment will be given to participants every 3 weeks (3-week cycles). * In Part B, participants will receive tisotumab vedotin on Days 1, 8, and 15 every 4-week cycle. * In Part C, participants will receive tisotumab vedotin on Days 1 and 15 of every 4-week cycle. * In Part D, participants will be given treatment on Day 1 of every 3-week cycle. Participants in Part D will get tisotumab vedotin with either: * Pembrolizumab or, * Pembrolizumab and carboplatin, or * Pembrolizumab and cisplatin * In Part E, participants will receive tisotumab vedotin on Days 1 and 15 of every 4-week cycle. * In Part F, participants will receive tisotumab vedotin on Days 1, 15, and 29 of every 6-week cycle. Participants in Part F will get tisotumab vedotin with pembrolizumab. * In Part G, participants will receive tisotumab vedotin on Days 1, 15, and 29 of every 6-week cycle. Participants in Part G will get tisotumab vedotin with pembrolizumab and carboplatin.
-
Genetic Testing in Screening Patients With Stage IB-IIIA Non-small Cell Lung Cancer That Has Been or Will Be Removed by Surgery (The ALCHEMIST Screening Trial)
Recruiting
This ALCHEMIST trial studies genetic testing in screening patients with stage IB-IIIA non-small cell lung cancer that has been or will be removed by surgery. Studying the genes in a patient's tumor cells may help doctors select the best treatment for patients that have certain genetic changes.
-
Phase II Randomized Trial of Carboplatin+Pemetrexed+Bevacizumab+/- Atezolizumab in Stage IV NSCLC
Recruiting
While cigarette smoking remains the primary cause of most lung cancer cases, lung carcinoma in never smokers account for nearly 20 percent of cases. Never smokers with lung cancer typically present with different molecular profiles from that of smokers, which results in prognostic and therapeutic implications. Molecular changes in NSCLC that have therapeutic significance include mutations in the epidermal growth factor receptor (EGFR) and rearrangements in the anaplastic lymphoma kinase (ALK) gene. These driver mutations typically are present in lung tumors found in never or light smokers. The addition of bevacizumab to carboplatin and paclitaxel in first-line treatment of non-squamous NSCLC showed improved survival compared to carboplatin and paclitaxel alone, 12.3 vs. 10.3 months respectively. Results from the POINTBREAK trial demonstrated that carboplatin + pemetrexed + bevacizumab is an alternative option to carboplatin + paclitaxel + bevacizumab, with comparable survival but less toxicity. In recent years, immunotherapy has emerged as a form of treatment that can lead to robust responses in a subset of patients. The PD-1 inhibitor nivolumab and the PD-L1 inhibitor atezolizumab have shown prolonged survival in comparison to docetaxel in patients who previously progressed with chemotherapy, irrespective of PD-L1 expression. Thus, this study combines immunotherapeutic agent atezolozumab with an ant-angiogenic agent, bevacizumab, and double platinum therapy (carboplatin and pemetrexed).
-
Screening Protocol for Tumor Antigen Expression Profiling and HLA Typing for Eligibility Determination
Recruiting
This screening study is intended for men and women ≥ 18 to ≤ 75 years of age who have advanced solid or hematologic malignancy. The study will assess a subject's human leukocyte antigen (HLA) subtype and tumor antigen expression profile. Based on the results, it will be determined if a subject is eligible to be considered for Adaptimmune sponsored clinical trials testing the safety and efficacy of genetically changed T cells targeting specific tumor antigens. No treatment intervention will occur as part of this screening study. Upon enrollment, subjects will be required to provide a blood sample for HLA subtype analysis. If the results of the analysis match the HLA-A subtypes noted in the inclusion criteria and do not express the HLA subtypes that are exclusionary for the available interventional clinical trial(s), then the subject will be required to provide either an archival tumor specimen or fresh tumor tissue biopsy. The tumor specimen will be screened at a central laboratory for the expression (protein or gene) of multiple antigens which may include, but are not limited to MAGE-A4. Based upon the results of these diagnostic analyses, if eligible, subjects will be referred to an appropriate available interventional clinical trial(s) at the discretion of the Investigator. Following screening, tumor samples will be retained by Adaptimmune for the purpose of developing and validating in vitro diagnostic (IVD) assay(s) for antigen expression profiling which is required for regulatory approval of a new therapeutic product indication.
-
Study of RET Inhibitor TAS0953/HM06 in Patients With Advanced Solid Tumors With RET Gene Abnormalities
Recruiting
Phase 1 and 2 trial to study the safety, pharmacokinetics, and efficacy of TAS0953/HM06 in patients with advanced solid tumors with RET gene abnormalities. Phase 1 aims to determine the Maximum Tolerated Dose (MTD) and identify the Recommended Phase 2 Dose (RP2D) to be used in phase 2.
-
To Evaluate the Efficacy/Safety of Osimertinib Prior to CRT and Maintenance of it With Stage III, Unresectable NSCLC With EGFR Mutations
Recruiting
The purpose of this study is to measure efficacy and safety of osimertinib as induction therapy prior to curative intent CRT and maintenance osimertinib in adult patients with Stage III, unresectable NSCLC with common EGFR mutations (exon 19 deletion or L858R).
-
18F-FPPRGD2 PET/CT or PET/MRI in Predicting Early Response in Patients With Cancer Receiving Anti-Angiogenesis Therapy
Not Recruiting
The purpose of the study is to conduct research of a new PET radiopharmaceutical in cancer patients. The uptake of the novel radiopharmaceutical 18F-FPPRGD2 will be assessed in study participants with glioblastoma multiforme (GBM), gynecological cancers, and renal cell carcinoma (RCC) who are receiving antiangiogenesis treatment.
Stanford is currently not accepting patients for this trial. For more information, please contact CCTO, 650-498-7061.
-
4D-CT-based Ventilation Imaging for Adaptive Functional Guidance in Radiotherapy
Not Recruiting
To develop and investigate a novel radiotherapy technique for preserving lung function based on a map of lung function.
Stanford is currently not accepting patients for this trial. For more information, please contact Laura Gable, 650-736-0798.
-
A 3rd/4th Line Placebo-controlled Trial of Sorafenib in Patients With Predominantly Non Squamous Non-Small Cell Lung Cancer (NSCLC).
Not Recruiting
The purpose of the study is to see if sorafenib plus best supportive care (i.e. in addition to the non-cancer treatments patients would normally receive) is an effective treatment for lung cancer compared to best supportive care alone. The safety and tolerability of the two treatment groups will also be compared. The goal of the study is to test the ability of sorafenib to improve survival compared to best supportive care alone.
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.
-
A Dose Escalation and Cohort Expansion Study of NKTR-214 in Combination With Nivolumab and Other Anti-Cancer Therapies in Patients With Select Advanced Solid Tumors
Not Recruiting
In this four-part study, NKTR-214 was administered in combination with nivolumab and with/without other anticancer therapies. Part 1 considered escalating doublet (NKTR 214 + nivolumab) doses to determine the RP2D. Part 2 considered dose expansion cohorts for the doublet (NKTR 214 + nivolumab ± chemotherapy). Part 3 was schedule-finding for a triplet therapy (NKTR 214 + nivolumab + ipilimumab). Part 4 dose expansion for the triplet (NKTR 214 + nivolumab + ipilimumab) was planned to further assess the efficacy of the RP2D triplet combination at dosing schedules from Part 3.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
-
A Multi-Center Study of Ibrutinib in Combination With MEDI4736 in Subjects With Relapsed or Refractory Solid Tumors
Not Recruiting
This is a Phase 1b/2, multi-center study to assess the safety and efficacy of ibrutinib in combination with durvalumab (MEDI4736) in participants with relapsed or refractory solid tumors.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
-
A Phase 1 Dose Escalation Study of OMP-21M18 in Subjects With Solid Tumors
Not Recruiting
A phase 1 open-label dose escalation study of OMP-21M18 in subjects with previously treated solid tumour for which there is no remaining standard curative therapy and no therapy with a demonstrated survival benefit.
Stanford is currently not accepting patients for this trial. For more information, please contact Dana Supan, (650) 736 - 1694.
-
A Phase 1/2 Study to Evaluate MEDI4736
Not Recruiting
This is a multicenter, open-label, first-time-in-human study with a standard 3+3 dose-escalation phase in participants with advanced solid tumors followed by an expansion phase in participants with advanced solid tumors. An exploration cohort has been added to determine the safety using every 4 weeks (Q4W) dosing.
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, 650-724-1388.
-
A Phase 2 Study of Amrubicin in Relapsed or Refractory Thymic Malignancies
Not Recruiting
A research study of the drug amrubicin in patients with cancer of the thymus (thymoma or thymic carcinoma). We hope to learn whether this drug is an effective and safe treatment for thymic cancers.
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, 650-724-1388.
-
A Phase I/II Study of Bexarotene in Combination With ZD1839 (IRESSA®) in the Treatment of Non-Small Cell Lung Cancer
Not Recruiting
The purpose of Phase 1 of this study is to evaluate the safety of the combination regimen, bexarotene and ZD1839. Phase II will evaluate the median survival, time to disease progression, and toxicity.
Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, (650) 736 - 4112.
-
A Phase II Study to Evaluate the Efficacy and Safety of Oral Ceritinib in Patients With ALK-positive NSCLC Metastatic to the Brain and/or to Leptomeninges
Not Recruiting
This was a phase II, multi-center, open-label, five-arm study in which the efficacy and safety of oral ceritinib treatment was assessed in patients with NSCLC metastatic to the brain and/or to leptomeninges harboring a confirmed ALK rearrangement, using the FDA approved Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular Inc.) test and scoring algorithm (including positivity criteria). If documentation of ALK rearrangement as described above was not locally available, a test to confirm ALK rearrangement was performed by a Novartis designated central laboratory. Patients waited for the central laboratory result of the ALK rearrangement status before initiating treatment with ceritinib.
Stanford is currently not accepting patients for this trial. For more information, please contact Richard A Quick, 650-724-1388.
-
A Study of Aflibercept Administered in Combination With Pemetrexed and Cisplatin in Participants With Advanced Carcinoma
Not Recruiting
The purpose of the study was to determine whether the combination of aflibercept, pemetrexed and cisplatin is safe and effective in treating non-small cell lung cancer (NSCLC).
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.
-
A Study of ASA404 or Placebo in Combination With Docetaxel in Second-line Treatment for (Stage IIIb/IV) Non-small Cell Lung Cancer
Not Recruiting
The purpose of this study is to determine if adding ASA404 to docetaxel chemotherapy makes the cancer treatment more effective in patients with locally advanced or metastatic non-small cell lung cancer
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.
-
A Study of Atezolizumab (an Engineered Anti-Programmed Death-Ligand 1 [PDL1] Antibody) to Evaluate Safety, Tolerability and Pharmacokinetics in Participants With Locally Advanced or Metastatic Solid Tumors
Not Recruiting
This Phase I, multicenter, first-in-human, open-label, dose-escalation study will evaluate the safety, tolerability, and pharmacokinetics of atezolizumab (MPDL3280A) administered as single agent to participants with locally advanced or metastatic solid malignancies or hematologic malignancies. The study will be conducted in two cohorts: Dose-escalation cohort and Expansion cohort.
Stanford is currently not accepting patients for this trial. For more information, please contact Maria Pitsiouni, 650-721-6977.
-
A Study of Atezolizumab and Tiragolumab Compared With Durvalumab in Participants With Locally Advanced, Unresectable Stage III Non-Small Cell Lung Cancer (NSCLC)
Not Recruiting
The purpose of this study is to evaluate the efficacy and safety of atezolizumab in combination with tiragolumab compared with durvalumab in participants with locally advanced, unresectable Stage III non-small cell lung cancer (NSCLC) who have received at least two cycles of concurrent platinum-based chemoradiotherapy (CRT) and have not had radiographic disease progression.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
-
A Study of Atezolizumab in Participants With Programmed Death - Ligand 1 (PD-L1) Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer
Not Recruiting
This multicenter, single-arm study will evaluate the efficacy and safety of Atezolizumab in participants with PD-L1-positive locally advanced or metastatic non-small cell lung cancer (NSCLC). Participants will receive Atezolizumab 1200 milligrams (mg) intravenously every 3 weeks as long as participants are experiencing clinical benefit as assessed by the investigator, that is , in the absence of unacceptable toxicity or symptomatic deterioration attributed to disease progression.
Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, 650-736-4112.
-
A Study of Atezolizumab in Participants With Programmed Death-Ligand 1 (PD-L1) Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) [FIR]
Not Recruiting
This multicenter, single-arm study will evaluate the efficacy and safety of atezolizumab (MPDL3280A) in participants with PD-L1-positive locally advanced or metastatic NSCLC. Participants will receive an intravenous (IV) dose of 1200 milligrams (mg) atezolizumab (MPDL3280A) on Day 1 of 21-day cycles until disease progression. Eligible participants will be categorized in to three groups as follows: 1. Participants with no prior chemotherapy for advanced disease; 2. Participants who progress during or following a prior-platinum based chemotherapy regimen for advanced disease (2L+participants); 3. Participants who are 2L+ and previously treated for brain metastases.
Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, 650-736-4112.
-
A Study of CDX-1127 (Varlilumab) in Patients With Select Solid Tumor Types or Hematologic Cancers
Not Recruiting
This is a study of CDX-1127, a therapy that targets the immune system and may act to promote anti-cancer effects. The study enrolls patients with hematologic cancers (certain leukemias and lymphomas), as well as patients with select types of solid tumors.
Stanford is currently not accepting patients for this trial. For more information, please contact Jennifer Vargas, 650-723-0371.
-
A Study of Enzastaurin and Erlotinib in Participants With Solid Tumors and Lung Cancer
Not Recruiting
Phase I: A study to see what doses of Enzastaurin and Erlotinib are best tolerated by participants with solid tumor cancer. Phase II: A study to see how long participants with non-small cell lung cancer (NSCLC) treated with Enzastaurin and Erlotinib live.
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.
-
A Study of HGS1029 (AEG40826-2HCl) in Subjects With Advanced Solid Tumors
Not Recruiting
The purpose of this study is to evaluate the safety and tolerability of HGS1029 in subjects with advanced solid tumors and to determine a phase 2 dose.
Stanford is currently not accepting patients for this trial. For more information, please contact Dana Supan, (650) 736 - 1694.
-
A Study of HGS1036 in Combination With Chemotherapy in Subjects With Advanced Solid Malignancies
Not Recruiting
The primary purpose of this study is to determine the maximally tolerated dose (MTD) of HGS1036 when used in combination with the standard chemotherapeutic regimens paclitaxel plus carboplatin, cisplatin plus etoposide, or docetaxel.
Stanford is currently not accepting patients for this trial. For more information, please contact Jennifer Vargas, 650-723-0371 .
-
A Study of Onartuzumab (MetMAb) in Combination With Bevacizumab (Avastin) Plus Platinum And Paclitaxel or With Pemetrexed Plus Platinum in Patients With Non-Squamous Non-Small Cell Lung Cancer
Not Recruiting
This multicenter, randomized, double-blind, placebo-controlled study will evaluate the efficacy and safety of RO5490258 (MetMab) in combination with either of two backbone chemotherapy regimens in the first-line setting in patients with incurable Stage IIIB or IV non-squamous non-small cell lung cancer. In Cohort 1, patients will be randomized to receive 4 cycles of bevacizumab (Avastin) 15 mg/kg iv, paclitaxel 200 mg/m2 iv, platinum (cisplatin/carboplatin) iv plus either MetMab 15 mg/kg iv or placebo on Day 1 of each 21-day cycle. In Cohort 2, patients will be randomized to receive pemetrexed 500 mg/m2 iv, platinum (cisplatin/carboplatin) iv plus either MetMAb 15 mg/m2 iv or placebo on Day 1 of each 21-day cycle. Patients who have not progressed after 4 cycles will be offered maintenance therapy with their assigned treatment of bevacizumab plus either MetMAb or placebo (Cohort 1) or pemetrexed plus either MetMAb or placebo (Cohort 2). Anticipated time on study treatment is until disease progression or unacceptable toxicity occurs.
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie SanPedro-Salcedo, (650) 724 - 1388.
-
A Study of Onartuzumab (MetMAb) Versus Placebo in Combination With Paclitaxel Plus Platinum in Patients With Squamous Non-Small Cell Lung Cancer
Not Recruiting
This multicenter, randomized, double-blind, placebo-controlled study will evaluate the efficacy and safety of onartuzumab (MetMAb) in combination with paclitaxel plus platinum in patients with incurable Stage IIIB or Stage IV squamous non-small cell lung cancer (NSCLC). Patients will be randomized to receive either onartuzumab (MetMAb) 15 mg/kg iv or placebo on Day 1 of each 21-day cycle in combination with 4 cycles of paclitaxel 200 mg/m2 iv and platinum (carboplatin/cisplatin) iv on Day 1 of each 21-day cycle. Patients who have not progressed after 4 cycles will continue with either onartuzumab (MetMAb) or placebo as maintenance therapy until disease progression or unacceptable toxicity occurs.
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.
-
A Study Of PF-06647020 For Adult Patients With Advanced Solid Tumors
Not Recruiting
To assess the safety and tolerability at increasing dose levels of PF-06647020 in patients with advanced solid tumors in order to determine the maximum tolerated dose and select the recommended Phase 2 dose.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
-
A Study of Pharmacokinetic Drug Interaction Study of the Hedgehog Pathway Inhibitor GDC-0449 in Combination With Rosiglitazone or Combined Oral Contraceptive in Patients With Locally Advanced or Metastatic Solid Tumors That Are Refractory to Standard Therapy or for Whom No Standard Therapy Exists
Not Recruiting
This is a single-arm, multicenter, Phase Ib study designed to describe the effect of GDC-0449 on the pharmacokinetics of rosiglitazone and oral contraceptives in patients with advanced solid tumors who are refractory to treatment or for whom no standard therapy exists.
Stanford is currently not accepting patients for this trial. For more information, please contact Ruth Lira, (650) 723 - 1367.
-
A Study of TAK-788 in Adults With Non-Small Cell Lung Cancer
Not Recruiting
This study is about a medicine called TAK-788, also known as mobocertinib, given to adults with non-small cell lung cancer. The main aims of this study are to check if there are any side effects from TAK-788, to learn how TAK-788 is processed by the body, and to determine the best dose of TAK-788 to treat this condition. Participants will take TAK-788 capsules with chemotherapy. Participants will continue to take TAK-788 unless they or their doctor decide they should stop this treatment. Participants will take TAK-788 capsules with or without chemotherapy under antidiarrhea prevention to determine the safety of TAK-788 treatment. Non-Asian, non-White participants will take TAK-788 to determine the safety and tolerability of TAK-788 treatment.
Stanford is currently not accepting patients for this trial. For more information, please contact Joel W Neal, MD, PhD, 650-725-3081.
-
A Study of Weekly Tisotumab Vedotin for Patients With Platinum-Resistant Ovarian Cancer With Safety Run-in (innovaTV 208)
Not Recruiting
This trial will study tisotumab vedotin to find out what its side effects are and to see if it works for platinum-resistant ovarian cancer (PROC). It will test different doses of tisotumab vedotin that are given at different times. It will also compare the side effects and ability to treat tumors of these different doses and schedules. In this study, there will be a safety run-in group of approximately 12 patients that will look at a dose-dense treatment schedule. In a dose-dense schedule, smaller doses are given more frequently. In addition to the safety run-in patients, there will be three groups in the study. One group will get tisotumab vedotin once every 3 weeks (21-day cycles). The two other groups will get tisotumab vedotin once a week for 3 weeks followed by 1 week off (28-day cycles).
Stanford is currently not accepting patients for this trial. For more information, please contact Ann Moffat, 669-233-2816.
-
A Study of XL184 (Cabozantinib) With or Without Erlotinib in Adults With Non-Small Cell Lung Cancer
Not Recruiting
In Phase 1 of this study, the purpose is to evaluate the safety, tolerability, and highest safe dose of the multiple receptor tyrosine kinase inhibitor (including VEGFR2, MET, and RET) XL184 in combination with the EGFR inhibitor erlotinib administered to adults with Non-Small-Cell Lung Cancer (NSCLC). In Phase 2 of this study, the purpose is to evaluate the objective response rate of daily oral administration of XL184 with or without erlotinib in subjects with NSCLC who have progressed after responding to treatment with erlotinib.
Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, (650) 736 - 4112.
-
Adjuvant Afatinib in Stage I-III NSCLC With EGFR Mutation
Not Recruiting
This research study is a Phase II clinical trial, which tests the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific cancer. "Investigational" means that the drug is still being studied. It also means that the FDA has not yet approved afatinib for use in patients. In this research study the investigators are looking to see if taking afatinib after surgery works better when taken over a short period of time, compared to a long period of time.
Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, 650-736-4112.
-
An Investigational Drug, PF-02341066 Is Being Studied Versus Standard Of Care In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene
Not Recruiting
This is a Phase 3 trial comparing the safety and anti-tumor activity of PF-02341066 versus pemetrexed or docetaxel in patients with advanced non-small cell lung cancer with specific gene profile involving the ALK gene after failure of one previous chemotherapy regimen that included one platinum drug.
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.
-
An Investigational Drug, PF-02341066, Is Being Studied In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene
Not Recruiting
This is a Phase 2 trial that will evaluate the safety and efficacy of PF-02341066 in patients with advanced non-small cell lung cancer with a specific gene profile involving the ALK gene. This trial will also allow patients from a Phase 3 trial who received standard of care chemotherapy (Study A8081007) to receive PF-02341066.
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.
-
An Observational Study of the Ethnic Impact of Patients Undergoing Second (2nd) Line Treatment for Non-Small Cell Lung Cancer Using Pemetrexed
Not Recruiting
This large, non-randomized observational study is being conducted to provide data about the impact of ethnic origin on outcomes and resource utilization during the 2nd line treatment of non-small cell lung cancer (NSCLC) in a routine medical care setting.
Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, (650) 736 - 4112.
-
An Open-Label, Randomized, Phase 3 Trial of Nivolumab Versus Investigator's Choice Chemotherapy as First-Line Therapy for Stage IV or Recurrent PD-L1+ Non-Small Cell Lung Cancer (CheckMate 026)
Not Recruiting
The purpose of this study is to show that Nivolumab will improve progression free survival in subjects with strongly Stage IV or Recurrent PD-L1+ non-small cell lung cancer when compared to chemotherapy
Stanford is currently not accepting patients for this trial. For more information, please contact Smriti Rai, 650-723-0270.
-
Bendamustine Hydrochloride and Rituximab With or Without Bortezomib Followed by Rituximab With or Without Lenalidomide in Treating Patients With High-Risk Stage II, Stage III, or Stage IV Follicular Lymphoma
Not Recruiting
RATIONALE: Drugs used in chemotherapy, such as bendamustine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. It is not yet known whether giving bendamustine hydrochloride and rituximab together alone is more effective than giving bendamustine hydrochloride and rituximab together with bortezomib or lenalidomide in treating follicular lymphoma. PURPOSE: This randomized phase II trial is studying giving bendamustine hydrochloride and rituximab together with or without bortezomib followed by rituximab with or without lenalidomide to see how well they work in treating patients with high-risk stage II, stage III, or stage IV follicular lymphoma.
Stanford is currently not accepting patients for this trial. For more information, please contact Ekaterina Dib, 650-723-0503.
-
Bevacizumab or Pemetrexed Disodium Alone or In Combination After Induction Therapy in Treating Patients With Advanced Non-Squamous Non-Small Cell Lung Cancer
Not Recruiting
RATIONALE: Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of non-small cell lung cancer by blocking blood flow to the tumor. Pemetrexed disodium may stop the growth of tumor cells by blocking some enzymes needed for cell growth. It is not yet known whether giving bevacizumab or pemetrexed disodium alone or in combination is more effective in treating non-squamous non-small cell lung cancer. PURPOSE: This randomized phase III trial is studying bevacizumab and pemetrexed disodium alone or in combination after induction therapy to see how well they work in treating patients with advanced non-squamous non-small cell lung cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, (650) 736 - 4112.
-
BLP25 Liposome Vaccine and Bevacizumab After Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Stage IIIA or Stage IIIB Non-Small Cell Lung Cancer That Cannot Be Removed by Surgery
Not Recruiting
RATIONALE: Vaccines may help the body build an effective immune response to kill tumor cells. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving vaccine therapy together with bevacizumab after chemotherapy and radiation therapy may kill more tumor cells. PURPOSE: This phase II trial is studying the side effects of giving BLP25 liposome vaccine together with bevacizumab after chemotherapy and radiation therapy in treating patients with newly diagnosed stage IIIA or stage IIIB non-small cell lung cancer that cannot be removed by surgery.
Stanford is currently not accepting patients for this trial. For more information, please contact Maria Pitsiouni, 650-721-6977.
-
Brentuximab Vedotin and Nivolumab With or Without Ipilimumab in Treating Patients With Relapsed or Refractory Hodgkin Lymphoma
Not Recruiting
This phase I/II trial studies the side effects and best dose of ipilimumab and nivolumab when given together with brentuximab vedotin, and how well they work in treating patients with Hodgkin lymphoma that has returned after a period of improvement (recurrent) or has not responded to previous treatment (refractory). Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of cancer cells to grow and spread. Brentuximab vedotin is a monoclonal antibody, brentuximab, linked to a toxic agent called vedotin. Brentuximab attaches to CD30 positive cancer cells in a targeted way and delivers vedotin to kill them. It is not known whether giving brentuximab vedotin and nivolumab with or without ipilimumab may kill more cancer cells.
Stanford is currently not accepting patients for this trial. For more information, please contact Caitlin Plahn, 650-723-3046.
-
Carboplatin and Paclitaxel Combined With Cetuximab and/or IMC-A12 in Patients With Advanced Non-Small Cell Lung Cancer
Not Recruiting
This randomized phase II trial is studying how well giving carboplatin and paclitaxel together with cetuximab and/or cixutumumab (IMC-A12) works in treating patients with stage IIIB or stage IV non-small cell lung cancer. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab and cixutumumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving chemotherapy together with monoclonal antibody therapy may kill more tumor cells. It is not yet known whether carboplatin and paclitaxel are more effective when given with cetuximab and/or cixutumumab in treating non-small cell lung cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Lauren Pernicka, (650) 721 - 6977.
-
Cetuximab, Cisplatin, Fluorouracil, and Radiation Therapy in Treating Patients With Anal Cancer
Not Recruiting
RATIONALE: Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some find tumor cells and kill them or carry tumor-killing substances to them. Others interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cisplatin and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Cetuximab may help cisplatin and fluorouracil work better by making tumor cells more sensitive to the drugs. It may also make tumor cells more sensitive to radiation therapy. Giving cetuximab together with chemotherapy and radiation therapy may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving cetuximab together with cisplatin, fluorouracil, and radiation therapy works in treating immunocompetent patients with stage I (closed to accrual as of 11/3/2008), stage II, (some stage II closed to accrual as of 11/3/2008) or stage III anal cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Deryn Warner, (650) 723 - 2876.
-
Chemotherapy and Radiation Therapy With or Without Panitumumab in Treating Patients With Stage IIIA Non-Small Cell Lung Cancer
Not Recruiting
RATIONALE: Drugs used in chemotherapy (CT), such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy (RT) uses high-energy x-rays to kill tumor cells. Monoclonal antibodies, such as panitumumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving these treatments before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. It is not yet known whether chemotherapy and radiation therapy are more effective when given with or without panitumumab in treating patients with non-small cell lung cancer. PURPOSE: This randomized phase II trial is studying chemotherapy and radiation therapy to see how well they work when given with or without panitumumab in treating patients with stage IIIA non-small cell lung cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Laura Gable, (650) 736 - 0798.
-
Chemotherapy With or Without Bevacizumab in Treating Patients With Stage IB, Stage II, or Stage IIIA Non-small Cell Lung Cancer That Was Removed By Surgery
Not Recruiting
This randomized phase III trial studies chemotherapy and bevacizumab to see how well they work compared to chemotherapy alone in treating patients with stage IB, stage II, or stage IIIA non-small cell lung cancer that was removed by surgery. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Bevacizumab also may stop the growth of non-small cell lung cancer by blocking the growth of new blood vessels necessary for tumor growth. It is not yet known whether chemotherapy is more effective with or without bevacizumab in treating non-small cell lung cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Maria Pitsiouni, 650-721-6977.
-
Cisplatin and Etoposide With or Without Veliparib in Treating Patients With Extensive Stage Small Cell Lung Cancer
Not Recruiting
This randomized phase I/II trial studies the side effects and best dose of veliparib when given together with or without cisplatin and etoposide and to see how well they work in treating patients with extensive stage small cell lung cancer or large cell neuroendocrine non-small cell lung cancer that has spread to other parts of the body. Drugs used in chemotherapy, such as cisplatin and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving cisplatin and etoposide with or without veliparib may work better in treating patients with extensive stage small cell lung cancer or metastatic large cell neuroendocrine non-small cell lung cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Maria Pitsiouni, 650-721-6977.
-
Clinical and Pathologic Studies of Patients Undergoing Treatment With EGFR Inhibitors
Not Recruiting
Cetuximab, erlotinib, and panitumumab are all recently FDA approved epidermal growth factor receptor (EGFR) inhibitors that treat a wide variety of tumor types, such as colon, lung, and head and neck. Blockade of the EGFR results in inhibition of multiple downstream pathways, leading to slowed tumor growth. In addition, these inhibitors may enhance anti-tumor immune responses through uncharacterized mechanisms. While producing significant responses in many settings, EGFR inhibitors also result in significant skin toxicity (rash) in a high percentage of patients. Multiple studies have correlated the presence and severity of rash with clinical response. Unfortunately, severe rash can often lead to dose delays, reductions, or even discontinuation of EGFR inhibitors, thus limiting their efficacy. The mechanism of both the rash and its correlation with tumor response is poorly understood. Skin biopsies display a robust leukocyte infiltrate, but a systematic analysis of the type of infiltrating leukocytes, activation state, or homing receptor expression has not been performed. Chemokines and chemokine receptors control leukocyte trafficking to the skin and other tissue sites, and defined receptor profiles for skin-, gut-, and lung-homing leukocytes are well established. In this study, the investigators propose to evaluate the homing phenotype of leukocytes from peripheral blood and skin biopsies of patients receiving EGFR inhibitors. The investigators will use RNA microarrays to evaluate the expression of chemokines and other key genes regulated in skin during treatment. The investigators will utilize in vitro methods to investigate effects of EGFR inhibitors on imprinting of T cell tissue-specific homing receptors. The investigators will examine correlations among the pathologic data, clinical findings, and tumor response. If validated, peripheral blood evaluation could potentially be used as a predictive indicator for patients receiving EGFR inhibitors. This study may also identify novel targets for limiting skin toxicity while receiving EGFR inhibitors, thus allowing maximal dosing and clinical response from these agents.
Stanford is currently not accepting patients for this trial. For more information, please contact Russell Pachynski, (650) 906 - 6530.
-
Clinical Study of BYM338 for the Treatment of Unintentional Weight Loss in Patients With Cancer of the Lung or the Pancreas
Not Recruiting
A safety \& efficacy clinical study of the investigational medicinal product BYM338 for the treatment of unintentional weight loss in patients with cancer of the lung or the pancreas
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.
-
CT-2103/Carboplatin vs Paclitaxel/Carboplatin for NSCLC in Women With Estradiol > 25 pg/mL
Not Recruiting
This study is designed to test whether CT-2103/carboplatin provides improved overall survival compared to paclitaxel/carboplatin in women with NSCLC who have estradiol levels \>30 pg/ml.
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.
-
CyberKnife Radiosurgical Treatment of Inoperable Early Stage Non-Small Cell Lung Cancer
Not Recruiting
The purpose of this study is to assess the short and long-term outcomes after CyberKnife stereotactic radiosurgery for early stage non-small cell lung cancer (NSCLC) in patients who are medically inoperable.
Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, (650) 736 - 4112.
-
Efficacy and Safety of Pembrolizumab (MK-3475) With Platinum Doublet Chemotherapy as Neoadjuvant/Adjuvant Therapy for Participants With Resectable Stage II, IIIA, and Resectable IIIB (T3-4N2) Non-small Cell Lung Cancer (MK-3475-671/KEYNOTE-671)
Not Recruiting
This trial will evaluate the safety and efficacy of pembrolizumab (MK-3475) in combination with platinum doublet neoadjuvant chemotherapy (NAC) before surgery \[neoadjuvant phase\], followed by pembrolizumab alone after surgery \[adjuvant phase\] in participants with resectable stage II, IIIA, and resectable IIIB (T3-4N2) non-small cell lung cancer (NSCLC). The primary hypotheses of this study are that neoadjuvant pembrolizumab (vs. placebo) in combination with NAC, followed by surgery and adjuvant pembrolizumab (vs. placebo) will improve: 1) event free survival (EFS) by biopsy assessed by local pathologist or by investigator-assessed imaging using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1); and 2) overall survival (OS).
Stanford is currently not accepting patients for this trial. For more information, please contact Study Coordinator, 650-736-7221.
-
Erlotinib and Momelotinib for the Treatment of Epidermal Growth Factor Receptor (EGFR) Mutated EGFR Tyrosine Kinase Inhibitor (TKI) Naive Metastatic Non-Small Cell Lung Cancer (NSCLC)
Not Recruiting
This study will evaluate the safety, preliminary efficacy, and pharmacokinetics (PK) of momelotinib (MMB) and erlotinib, as well as define the maximum tolerated dose (MTD) of momelotinib (MMB) combined with erlotinib in adults with epidermal growth factor receptor (EGFR)-mutated, EGFR tyrosine kinase inhibitor (TKI) naive metastatic non-small cell lung cancer (NSCLC). Participants will be sequentially enrolled to receive progressively increasing doses of momelotinib (MMB) in combination with erlotinib. Escalation of momelotinib (MMB) doses will proceed to the MTD, defined as the highest tested dose associated with dose-limiting toxicities (DLT) during the first 28 days of combined erlotinib and momelotinib (MMB) treatment. There will be four dose levels and each treatment cycle will consist of 28 days.
Stanford is currently not accepting patients for this trial. For more information, please contact Smriti Rai, 650-723-0270.
-
Erlotinib Hydrochloride and Cabozantinib-s-Malate Alone or in Combination as Second or Third Line Therapy in Treating Patients With Stage IV Non-small Cell Lung Cancer
Not Recruiting
This randomized phase II trial studies how well giving erlotinib hydrochloride and cabozantinib-s-malate alone or in combination works as second or third line therapy in treating patient with stage IV non-small cell lung cancer. Erlotinib hydrochloride and cabozantinib-s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving erlotinib hydrochloride together with cabozantinib-s-malate is more effective than erlotinib hydrochloride or cabozantinib-s-malate alone in treating non-small cell lung cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Maria Pitsiouni, 650-721-6977.
-
Erlotinib Hydrochloride in Treating Patients With Stage IB-IIIA Non-small Cell Lung Cancer That Has Been Completely Removed by Surgery (An ALCHEMIST Treatment Trial)
Not Recruiting
This phase III ALCHEMIST trial studies how well erlotinib hydrochloride compared to observation works in treating patients with stage IB-IIIA non-small cell lung cancer that has been completely removed by surgery (resected). Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Stanford is currently not accepting patients for this trial. For more information, please contact Heather A. Wakelee, 650-724-3697.
-
Erlotinib Hydrochloride or Crizotinib and Chemoradiation Therapy in Treating Patients With Stage III Non-small Cell Lung Cancer
Not Recruiting
This randomized phase II trial studies how well erlotinib hydrochloride or crizotinib with chemoradiation therapy works in treating patients with stage III non-small cell lung cancer. Radiation therapy uses high energy x rays to kill tumor cells. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs used in chemotherapy, such as cisplatin, etoposide, paclitaxel, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving erlotinib hydrochloride is more effective than crizotinib with chemoradiation therapy in treating patients with non-small cell lung cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Katie Brown, 650-723-1423.
-
Erlotinib in Patients With Resected, Early Stage NSCLC With Confirmed Mutations in the EGFR
Not Recruiting
In this research study erlotinib will be given to eligible participants whose lung cancer has been removed by surgery. Eligible patients have adenocarcinoma, a type of non-small lung cancer, and must have 1 or more of the following characteristics: be female, be of Asian or Pacific Rim descent and/or be a never smoker. The potential participant's tumor will be examined for Epidermal growth factor (EGFR) mutations. EGFR is a protein that is overexpressed in most non-small cell lung cancers. Some EGFR has been found to have specific mutations and the participant must have one of these mutations in his tumor. Erlotinib blocks this protein and may control tumor growth and increase survival. Previous research has shown that erlotinib is most effective for people who have these specific mutations in the EGFR.
Stanford is currently not accepting patients for this trial. For more information, please contact Lei Shura, 650-723-2312.
-
Erlotinib Plus Tivantinib (ARQ 197) Versus Single Agent Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer
Not Recruiting
The purpose of this study is to evaluate progression-free survival among subjects with KRAS mutation positive Non-Small Cell Lung Cancer (NSCLC) treated with erlotinib plus tivantinib (ARQ 197) compared to single agent chemotherapy.
Stanford is currently not accepting patients for this trial. For more information, please contact Lei Shura, 650-723-2312.
-
Erlotinib With or Without Hydroxychloroquine in Chemo-Naive Advanced NSCLC and (EGFR) Mutations
Not Recruiting
The purpose of this research study is to learn if adding hydroxychloroquine (HCQ) to erlotinib helps treat non-small cell lung cancer (NSCLC). Another goal of this research study is to learn more about NSCLC and how it may respond to study treatment. Erlotinib (Tarceva) is a type of drug called a tyrosine kinase inhibitor (TKI). TKIs block a protein called the epidermal growth factor receptor (EGFR). EGFR may control tumor growth and tumor cell survival. However, although TKI drugs can work for some lung cancer patients for a period of time, eventually the tumor finds a way to resist or counteract the TKI treatment and it begins to grow again. Hydroxychloroquine (HCQ) is a drug approved by the FDA for treating malaria, rheumatoid arthritis, and several other diseases. Laboratory research suggests that when HCQ is given with a TKI, it may help delay or prevent TKI resistance from developing.
Stanford is currently not accepting patients for this trial. For more information, please contact Zeina Babetty, (650) 723 - 2983.
-
Evaluation of Cyberknife Precision Radiation Delivery System for Unresectable Malignant Lung Cancer
Not Recruiting
This study has two primary objectives. The first objective is to determine the maximal tolerated dose (MTD) that can be delivered with stereotactic radiosurgery in patients with inoperable malignant lung tumors. Once the MTD is established, the second objective is to determine the efficacy of radiosurgical ablation of lung tumors in terms of symptoms and radiographic responses.
Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, (650) 736 - 4112.
-
ExAblate (MRgFUS) Treatment of Metastatic Bone Tumors for the Palliation of Pain
Not Recruiting
A Pivotal Study to Evaluate the Effectiveness and Safety of ExAblate Treatment of Metastatic Bone and Multiple Myeloma Tumors for the Palliation of Pain in Patients Who are not Candidates for Radiation Therapy
Stanford is currently not accepting patients for this trial. For more information, please contact Kamil Unver, (650) 725 - 9810.
-
ExAblate Conformal Bone System Treatment of Metastatic Bone Tumors for the Palliation of Pain
Not Recruiting
A study to evaluate the safety and initial effectiveness of the ExAblate 2100 Conformal Bone System in the treatment of pain resulting from metastatic bone tumors.
Stanford is currently not accepting patients for this trial. For more information, please contact Fizaa Ahmed, 650-725-6409.
-
Expanded Access to Ensartinib for Participants With ALK+ NSCLC
Not Recruiting
This is an open-label, multicenter, intermediate-sized expanded access treatment protocol to the existing IND 111,695 for ensartinib (X-396). The treatment plan is designed to provide ensartinib to participants with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC).
Stanford is currently not accepting patients for this trial. For more information, please contact Richard Quick, 650-723-2983.
-
Expanded Treatment Protocol With LDK378 in ALK(+) NSCLC
Not Recruiting
Novartis-sponsored, open-label, multi-center, interventional ETP to provide LDK378 to patients with ALK (+)NSCLC, who have been pre-treated with an ALK inhibitor; except in countries where ALK inhibitors are not approved or available. The protocol will further evaluate the safety of LDK378 in patients with ALK(+) NSCLC.
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, 650-724-1388.
-
Grapiprant (ARY-007) and Pembrolizumab in Patients With Advanced or Metastatic Post-PD-1/L1 NSCLC Adenocarcinoma
Not Recruiting
This study will be conducted in adult participants diagnosed with NSCLC who have been previously treated for a minimum of 12 weeks with any PD-1 or PD-L1 checkpoint inhibitor. This is a phase 1b/2, multi-center, open label study designed to assess safety and tolerability of grapiprant in combination with pembrolizumab, to determine the recommended phase 2 dose (RP2D) with pembrolizumab, and to evaluate disease response with grapiprant based on investigator assessments. Pharmacokinetics, pharmacodynamics and response biomarkers will also be assessed.
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro, 650-724-1388.
-
Identification of Circulating Tumor Cells in the Peripheral Blood of Lung Cancer Patients
Not Recruiting
The primary aim of this study is to determine whether we can identify human lung cancer tumor cells in the peripheral blood of lung cancer patients.
Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, 650-736-4112.
-
Imaging and Biomarkers of Hypoxia in Solid Tumors
Not Recruiting
Hypoxia, meaning a lack of oxygen, has been associated strongly with a wide range of human cancers. Hypoxia occurs when tumor growth exceeds the ability of blood vessels to supply the tumor with oxygenated blood. It is currently understood that hypoxic tumors are more aggressive. Current methods for measuring hypoxia include invasive procedures such as tissue biopsy, or insertion of an electrode into the tumor. EF5-PET may be a non-invasive way to measure tumor hypoxia.
Stanford is currently not accepting patients for this trial. For more information, please contact Justin Carter, 650-725-4796.
-
Immunobiology of Cancer
Not Recruiting
To learn whether or not an Interferon defect in cell signaling, recently discovered in immune cells from melanoma patients as well as breast cancer patients, is common to all cancers.
Stanford is currently not accepting patients for this trial. For more information, please contact Diana Simons, (650) 498 - 7943.
-
LDK378 in Adult Patients With ALK-activated NSCLC Previously Treated With Chemotherapy and Crizotinib
Not Recruiting
A single-arm, open-label, multicenter, phase II study. Treatment with LDK378 750 mg qd continued until the patient experienced unacceptable toxicity that precluded further treatment, discontinued treatment at the discretion of the investigator or patient, started a new anti-cancer therapy and/or died. LDK378 could be continued beyond RECIST-defined progressive disease (PD) as assessed by the investigator if, in the judgment of the investigator, there was evidence of clinical benefit. In these patients tumor assessment would continue as per the schedule of assessments until treatment with LDK378 was permanently discontinued. Patients who discontinued the study medication in the absence of progression continued to be followed for tumor assessment until the time of PD as assessed by the investigator
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo , 650-724-1388.
-
Lung-MAP: Biomarker-Targeted Second-Line Therapy in Treating Patients With Recurrent Stage IV Squamous Cell Lung Cancer
Not Recruiting
This screening and multi-sub-study randomized phase II/III trial will establish a method for genomic screening of similar large cancer populations followed by assigning and accruing simultaneously to a multi-sub-study hybrid ?Master Protocol? (S1400). The type of cancer trait (biomarker) will determine to which sub-study, within this protocol, a participant will be assigned to compare new targeted cancer therapy, designed to block the growth and spread of cancer, or combinations to standard of care therapy with the ultimate goal of being able to approve new targeted therapies in this setting. In addition, the protocol includes a ?non-match? sub-study which will include all screened patients not eligible for any of the biomarker-driven sub-studies. This sub-study will compare a non-match therapy to standard of care also with the goal of approval.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
-
Lung-MAP: Nivolumab With or Without Ipilimumab as Second-Line Therapy in Treating Patients With Recurrent Stage IV Squamous Cell Lung Cancer and No Matching Biomarkers
Not Recruiting
This randomized phase III trial compares nivolumab with ipilimumab and nivolumab alone in treating patients with stage IV squamous cell lung cancer that has come back after previous treatment. This is a "non-match" sub-study that includes all screened patients not eligible for a biomarker-driven sub-study. Monoclonal antibodies, such as nivolumab and ipilimumab, may be able to shrink tumors. It is not yet known whether nivolumab works better with or without ipilimumab in treating patients with squamous cell lung cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Heather A. Wakelee, 650-498-7061.
-
MAGE A10ᶜ⁷⁹⁶T for Advanced NSCLC
Not Recruiting
This first time in human study is intended for men and women at least 18 years of age who have advanced lung cancer which has grown or returned after being treated. In particular, it is a study for subjects who have a blood test positive for HLA-A\*02:01 and/or HLA-A\*02:06 and a tumor test positive for MAGE A10 protein expression (protein or gene). This trial is a dose escalation trial that will evaluate 3 doses of transduced cells administered after a lymphodepleting chemotherapy regimen using a 3+3 dose escalation design .The study will take the subject's T cells, which are a natural type of immune cell in the blood, and send them to a laboratory to be modified. The changed T cells used in this study will be the subject's own T cells that have been genetically changed with the aim of attacking and destroying cancer cells. When the MAGE A10ᶜ⁷⁹⁶T cells are available, subjects will receive lymphodepleting chemotherapy with cyclophosphamide and fludarabine, followed by the T cell infusion. The purpose of this study is to test the safety of genetically changed T cells and find out what effects, if any, they have in subjects with lung cancer. The study will evaluate three different cell dose levels in order to find out the target cell dose. Once the target cell dose is determined, additional subjects will be enrolled to further test the safety and effects at this cell dose. Subjects will be seen frequently by the Study Physician right after receiving their T cells back and up to first 6 months. After that, subjects will be seen every three months. Subjects will be seen every 6 months by their Study Physician for the first 5 years after the T cell infusion. If the T cells are found in the blood at five years, then the subjects will continue to be seen once a year until the T cells are no longer found in the blood for a maximum of 15 years. If the T cells are no longer found in the blood at 5 years, then the subject will be contacted by the Study Physician for the next 10 years. Subjects who have a confirmed response or clinical benefit ≥4 weeks after the first T-cell infusion and whose tumor continues to express the appropriate antigen target may be eligible for a second infusion. All subjects, completing or withdrawing from the Interventional Phase of the study, will enter a 15-year long-term follow-up phase for observation of delayed adverse events. All subjects will continue to be followed for overall survival during the long-term follow-up phase.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
-
Manuka Honey in Preventing Esophagitis-Related Pain in Patients Receiving Chemotherapy and Radiation Therapy For Lung Cancer
Not Recruiting
RATIONALE: Manuka honey may prevent or reduce esophagitis-related pain caused by chemotherapy and radiation therapy. It is not yet known whether Manuka honey is more effective than standard care in preventing pain. PURPOSE: This randomized phase II clinical trial is studying Manuka honey to see how well it works in preventing esophagitis-related pain in patients receiving chemotherapy and radiation therapy for lung cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Laura Gable, (650) 736 - 0798.
-
Microarray Analysis of Gene Expression and Identification of Progenitor Cells in Lung Carcinoma
Not Recruiting
This study will help us understand the gene expression profiles of lung cancer. We will identify genes related to lung cancer development, their growth and metastasis to the lung. In addition, we will examine the role nicotine in the development and progression of lung tumors of smokers, ex-smokers, non-smokers on supplemental nicotine and non smokers with no exposure to nicotine.
Stanford is currently not accepting patients for this trial. For more information, please contact Susan Jacobs, RN, 650-725-8082.
-
Molecular Analysis of Thoracic Malignancies
Not Recruiting
A research study to learn about the biologic features of cancer development, growth, and spread. We are studying components of blood, tumor tissue, normal tissue, and other fluids, such as urine, cerebrospinal fluid, abdominal or chest fluid in patients with cancer. Our analyses of blood, tissue, and/or fluids may lead to improved diagnosis and treatment of cancer by the identification of markers that predict clinical outcome, markers that predict response to specific therapies, and the identification of targets for new therapies.
Stanford is currently not accepting patients for this trial. For more information, please contact Jordan Preiss, 650-723-1002.
-
Nexavar® Versus Placebo in Locally Advanced/Metastatic RAI-Refractory Differentiated Thyroid Cancer
Not Recruiting
Trial of sorafenib versus placebo in the treatment of locally advanced or metastatic differentiated thyroid cancer refractory to radioiodine
Stanford is currently not accepting patients for this trial. For more information, please contact Ruth Lira, (650) 723 - 1367.
-
Nivolumab After Surgery and Chemotherapy in Treating Patients With Stage IB-IIIA Non-small Cell Lung Cancer (An ALCHEMIST Treatment Trial)
Not Recruiting
This phase III ALCHEMIST treatment trial studies how well nivolumab after surgery and chemotherapy work in treating patients with stage IB-IIIA non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
-
Octreotide Acetate and Recombinant Interferon Alfa-2b or Bevacizumab in Treating Patients With Metastatic or Locally Advanced, High-Risk Neuroendocrine Tumor
Not Recruiting
This randomized phase III trial studies octreotide acetate and recombinant interferon alfa-2b to see how well it works compared to octreotide acetate and bevacizumab in treating patients with high-risk neuroendocrine tumors that have spread to other places in the body (metastatic) or spread from where it started to nearby tissue or lymph nodes (locally advanced). Octreotide acetate and recombinant interferon alfa-2b may interfere with the growth of tumor cells and slow the growth of cancer. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving octreotide acetate together with recombinant interferon alfa-2b is more effective than giving octreotide acetate together with bevacizumab in treating patients with neuroendocrine tumor.
Stanford is currently not accepting patients for this trial. For more information, please contact Deryn Warner, (650) 723 - 2876.
-
Osimertinib and Necitumumab in Treating Patients With EGFR-Mutant Stage IV or Recurrent Non-small Cell Lung Cancer Who Have Progressed on a Previous EGFR Tyrosine Kinase Inhibitor
Not Recruiting
This phase I trial studies the safety, side effects and best dose of necitumumab when given together with osimertinib in treating patients with EGFR-mutant non-small cell lung cancer that is stage IV or has come back after a period of improvement (recurrent) and who have progressed on a previous EGFR tyrosine kinase inhibitor. Immunotherapy with monoclonal antibodies, such as necitumumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving necitumumab with osimertinib may be safe, tolerable in treating patients with EGFR-mutant non-small cell lung cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Sukhmani K. Padda, 650-498-7061.
-
Oxaliplatin, Leucovorin Calcium, and Fluorouracil With or Without Celecoxib in Treating Patients With Stage III Colon Cancer Previously Treated With Surgery
Not Recruiting
PURPOSE: This randomized phase III trial is studying giving oxaliplatin, leucovorin calcium, and fluorouracil together to compare how well they work when given together with or without celecoxib in treating patients with stage III colon cancer previously treated with surgery. RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Celecoxib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving oxaliplatin, leucovorin calcium, and fluorouracil is more effective with or without celecoxib in treating colon cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Ben Priestley, 650-723-2990 (Palo Alto and South Bay locations).
-
Paclitaxel With or Without Cixutumumab as Second-Line Therapy in Treating Patients With Metastatic Esophageal Cancer or Gastroesophageal Junction Cancer
Not Recruiting
This randomized phase II trial studies how well paclitaxel with or without cixutumumab works in treating patients with esophageal cancer or gastroesophageal junction cancer that has spread to other places in the body (metastatic). Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Cixutumumab may kill cancer cells by blocking the action of a protein needed for cancer cell growth. Giving paclitaxel with or without cixutumumab may kill more tumor cells.
Stanford is currently not accepting patients for this trial. For more information, please contact Deryn Warner, (650) 723 - 2876.
-
Pazopanib Hydrochloride in Treating Patients With Progressive Carcinoid Tumors
Not Recruiting
This randomized phase II trial studies how well pazopanib hydrochloride works in treating patients with carcinoid tumors that are growing, spreading, or getting worse. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Stanford is currently not accepting patients for this trial. For more information, please contact Ben Priestley, 650-723-2990.
-
PDR001 in Combination With Platinum-doublet Chemotherapy and Other Immunology Agents in PD-L1 Unselected, Metastatic NSCLC Patients
Not Recruiting
The primary purpose of this study is to establish the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of PDR001 when administered in combination with platinum-doublet chemotherapy and other immunooncology agent(s) in treatment naive patients with PD-L1 unselected, advanced NSCLC, and to estimate the preliminary anti-tumor activity in this patient population.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
-
Pembrolizumab in Patients With Metastatic Non-squamous Non-small Cell Lung Cancer
Not Recruiting
This phase II trial studies how well pembrolizumab works in treating patients with non-squamous non-small cell lung cancer which has spread to other places in the body. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread.
Stanford is currently not accepting patients for this trial. For more information, please contact Richard Quick, 650-723-2983.
-
Pemetrexed Disodium/Observation in Treating Patients W/ Malignant Pleural Mesothelioma w/Out Progressive Disease After 1st Line Chemotherapy
Not Recruiting
RATIONALE: Pemetrexed disodium may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. PURPOSE: This randomized phase II trial is studying how well pemetrexed disodium or observation works in treating patients with malignant pleural mesothelioma without progressive disease after first-line chemotherapy.
Stanford is currently not accepting patients for this trial. For more information, please contact Ekaterina Dib, 650-723-0503.
-
Phase 1 Erlotinib and Dovitinib (TKI258) in Advanced Non-small Cell Lung Cancer (NSCLC)
Not Recruiting
This phase I trial studies the side effects and best dose of giving erlotinib and dovitinib together to treat patients with metastatic non-small cell lung cancer. Erlotinib blocks the epidermal growth factor receptor (EGFR) and has known activity in non-small cell lung cancer and dovitinib blocks the fibroblast growth factor receptor (FGFR) and other targets which may be important to treat lung cancer. The combination of both drugs may work better than either drug alone, but may also have increased side effects. This trial will look at the side effects of combining the drugs and look for how effective the combination may be.
Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, (650) 736 - 4112.
-
Phase 1 Trial of Hu5F9-G4, a CD47-targeting Antibody
Not Recruiting
The purpose of this study is to assess the safety and tolerability of Hu5F9-G4 in participants with solid tumors.
Stanford is currently not accepting patients for this trial. For more information, please contact Contact, 650-498-4331.
-
Phase 1 Trial of Oral Ixabepilone
Not Recruiting
This Phase 1 study of oral ixabepilone given every 6 hours for 3 doses on Day 1, every 21 days, was a dose-finding study designed to determine the maximum tolerated dose (MTD) and safety of this dosing schedule in participants with advanced cancer
Stanford is currently not accepting patients for this trial. For more information, please contact Dana Supan, (650) 736 - 1694.
-
Phase 1-2 of Temozolomide and Hypofractionated Radiotherapy in Tx of Supratentorial Glioblastoma Multiform
Not Recruiting
The purpose of this study is to investigate the safety and effectiveness of a combination treatment for glioblastoma multiforme utilizing radiotherapy plus the FDA-approved chemotherapy drug temozolomide
Stanford is currently not accepting patients for this trial. For more information, please contact Polly Young, 650-497-7499.
-
Phase 1/1b Study to Evaluate the Safety and Tolerability of Ciforadenant Alone and in Combination With Atezolizumab in Advanced Cancers
Not Recruiting
This is a phase 1/1b open-label, multicenter, dose-selection study of ciforadenant, an oral small molecule targeting the adenosine-A2A receptor on T-lymphocytes and other cells of the immune system. This trial will study the safety, tolerability, and anti-tumor activity of ciforadenant as a single agent and in combination with atezolizumab, a PD-L1 inhibitor against various solid tumors. Ciforadenant blocks adenosine from binding to the A2A receptor. Adenosine suppresses the anti-tumor activity of T cells and other immune cells.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
-
Phase 1/2 Study of X-396, an Oral ALK Inhibitor, in Patients With ALK-positive Non-Small Cell Lung Cancer
Not Recruiting
This is the first human study to use X-396 (ensartinib), a drug being developed for treatment of advanced cancers. The initial purpose of the study is to determine the largest amount of X-396 that can be safely given to humans (the maximum tolerated dose). Once the recommended Phase 2 dose has been determined, an expansion phase will assess the preliminary anti-tumor activity of X-396 in ALK-positive non-small cell lung cancer. The study will also provide early information on how the body handles the drug (pharmacokinetics) and on the efficacy of X-396.
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, 650-724-1388.
-
Phase 2 Etirinotecan Pegol in Refractory Brain Metastases & Advanced Lung Cancer / Metastatic Breast Cancer
Not Recruiting
This phase 2 trial evaluates how well pegylated irinotecan (NKTR-102) works in treating patients with non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), or breast cancer (mBC) that has spread to the brain and does not respond to treatment. Pegylated irinotecan may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Stanford is currently not accepting patients for this trial. For more information, please contact Sophie Bertrand, 650-723-4467.
-
Phase 2 Trial of Bevacizumab in Combination With Pemetrexed
Not Recruiting
This trial evaluated the safety of combining bevacizumab and pemetrexed in non-small cell lung cancer (NSCLC) patients with stable brain metastases as second-line chemotherapy, while evaluating progression-free survival (PFS) and overall survival (OS).
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.
-
Phase 2a Desipramine in Small Cell Lung Cancer and Other High-Grade Neuroendocrine Tumors
Not Recruiting
Intrapatient dose escalation study of desipramine in subjects with small cell lung cancer (SCLC) and other high-grade neuroendocrine tumors.
Stanford is currently not accepting patients for this trial. For more information, please contact CCTO, 650-498-7061.
-
Phase I Vorinostat Concurrent With Stereotactic Radiosurgery (SRS) in Brain Metastases From Non-Small Cell Lung Cancer
Not Recruiting
The purpose of this study is to determine the maximum tolerated dose (MTD) of vorinostat given concurrently with stereotactic radiosurgery (SRS) to treat non-small cell lung cancer (NSCLCA) brain metastases in patient with 1-4 lesions.
Stanford is currently not accepting patients for this trial. For more information, please contact Maria Coburn, (650) 736 - 9551.
-
Phase I/II Eval Safety & Prelim Activity Nivolumab Comb W/Vorolanib Pts W/Refractory Thoracic Tumors
Not Recruiting
This is a two-agent, open-label, non-randomized, Phase 1/2 dose escalation and dose expansion study of combinatorial oral vorolanib plus infusional nivolumab in patients with Non-Small Cell Lung Cancer naïve to checkpoint inhibitor therapy, Non-Small Cell Lung Cancer who have progressed on checkpoint inhibitor therapy, Small Cell Lung Cancer ( who have progressed on platinum-based chemotherapy, and thymic carcinoma.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
-
Phase II Bevacizumab, Gemcitabine and Carboplatin in Newly Diagnosed Non-Small Cell Lung Cancer
Not Recruiting
A multi-center study of bevacizumab in combination with gemcitabine and carboplatin as treatment for newly-diagnosed advanced non-small cell lung cancer (NSCLC).
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.
-
Phase II Docetaxel / Carboplatin / XRT + Surgical Resection in Stage III NSCLC
Not Recruiting
The purpose of this study is to assess how well this particular combination of chemotherapy, radiation and surgery works to help people with locally advanced lung cancer, how well PET scans indicates whether someone has responded to chemotherapy and radiation, and gene expression patterns related to outcomes in patients with locally advanced lung cancer who receive this treatment regimen.
Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, (650) 736 - 4112.
-
PROSPECT: Chemotherapy Alone or Chemotherapy Plus Radiation Therapy in Treating Patients With Locally Advanced Rectal Cancer Undergoing Surgery
Not Recruiting
The standard treatment for locally advanced rectal cancer involves chemotherapy and radiation, known as 5FUCMT, (the chemotherapy drugs 5-fluorouracil/capecitabine and radiation therapy) prior to surgery. Although radiation therapy to the pelvis has been a standard and important part of treatment for rectal cancer and has been shown to decrease the risk of the cancer coming back in the same area in the pelvis, some patients experience undesirable side effects from the radiation and there have been important advances in chemotherapy, surgery, and radiation which may be of benefit. The purpose of this study is to compare the effects, both good and bad, of the standard treatment of chemotherapy and radiation to chemotherapy using a combination regimen known as FOLFOX, (the drugs 5-fluorouracil (5-FU), oxaliplatin and leucovorin) and selective use of the standard treatment, depending on response to the FOLFOX. The drugs in the FOLFOX regimen are all FDA (Food and Drug Administration) approved and have been used routinely to treat patients with advanced colorectal cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Ben Priestley, 650-723-2990.
-
Pulmonary Interstitial Lymphography in Early Stage Lung Cancer
Not Recruiting
The stereotactic body radiation therapy (SBRT) procedure is an emerging alternative to the standard treatment for early stage non-small cell lung cancer (NSCLC), typically lobectomy with lymphadenectomy. This procedure (lobectomy) does not fulfill the medical need as many patients are poor operative candidates or decline surgery. This study assesses the feasibility of stereotactic body radiation therapy (SBRT) as a tool to produce therapeutically useful computed tomography (CT) scans, using standard water-soluble iodinated compounds as the contrast agents.
Stanford is currently not accepting patients for this trial. For more information, please contact Laura Gable, (650) 736 - 0798.
-
QUILT-3.026: AMG 655 in Combination With AMG 479 in Advanced, Refractory Solid Tumors
Not Recruiting
This is a multi-center, 2-part phase 1b/2 study of AMG 655 in combination with AMG 479 to be conducted in the United States and Spain. Part 1 is a dose escalation segment to identify a dose of AMG 655 in combination with AMG 479 that is safe and tolerable. Part 2 will evaluate the safety and estimate the efficacy of AMG 655 at the dose selected in Part 1 in combination with AMG 479 for the treatment of patients with advanced NSCLC (non-squamous histology; squamous histology), CRC, pancreatic cancer, ovarian cancer, and sarcoma.
Stanford is currently not accepting patients for this trial. For more information, please contact Dana Supan, (650) 736 - 1694.
-
Radiation Therapy in Preventing Central Nervous System (CNS) Metastases in Patients With Non-Small Cell Lung Cancer
Not Recruiting
RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. It is not yet known if giving radiation therapy to the head is effective in preventing CNS metastases in patients who have stage III non-small cell lung cancer. PURPOSE: This randomized phase III trial is studying how well radiation therapy to the head works in preventing CNS metastases in patients who have been previously treated for stage III non-small cell lung cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Derek Huang, (650) 725 - 0203.
-
Radiation Therapy in Treating Patients With Extensive Stage Small Cell Lung Cancer
Not Recruiting
RATIONALE: Radiation therapy uses high energy x-rays to kill tumor cells. This may be an effective treatment for extensive stage small cell lung cancer. PURPOSE: This randomized phase II trial is comparing how well radiation therapy to the brain works when given with or without radiation therapy to other areas of the body in treating patients with extensive stage small cell lung cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Laura Gable, (650) 736 - 0798.
-
Radiation Therapy in Treating Patients With Stage I Non-Small Cell Lung Cancer
Not Recruiting
RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. It is not yet known which regimen of stereotactic body radiation therapy is more effective in treating patients with non-small cell lung cancer. PURPOSE: This randomized phase II trial is studying the side effects of two radiation therapy regimens and to see how well they work in treating patients with stage I non-small cell lung cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact laura gable, (650) 736 - 0798.
-
Radiation Therapy Regimens in Treating Patients With Limited-Stage Small Cell Lung Cancer Receiving Cisplatin and Etoposide
Not Recruiting
Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as etoposide, carboplatin and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known which radiation therapy regimen is more effective when given together with chemotherapy in treating patients with limited-stage small cell lung cancer. This randomized phase III trial is comparing different chest radiation therapy regimens to see how well they work in treating patients with limited-stage small cell lung cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Katie Brown, 650-723-1423.
-
Radical-Dose Image Guided Radiation Therapy in Treating Patients With Metastatic Non-small Cell Lung Cancer Undergoing Immunotherapy
Not Recruiting
This phase II trial studies how well radical-dose image guided radiation therapy works in treating patients with non-small cell lung cancer that has spread to other places in the body who are undergoing immunotherapy. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving radical-dose image guided radiation therapy to patients with non-small cell lung cancer may help to improve response to immunotherapy anti-cancer treatment.
Stanford is currently not accepting patients for this trial. For more information, please contact Kim Nguyen, 650-497-8966.
-
Randomized Study to Compare CyberKnife to Surgical Resection In Stage I Non-small Cell Lung Cancer
Not Recruiting
Lung cancer remains the most frequent cause of cancer death in both men and women in the world. Surgical resection using lobectomy with mediastinal lymph node dissection or sampling has been a standard of care for operable early stage NSCLC. Several studies have reported high local control and survival using SBRT in stage I NSCLC patients. SBRT is now an accepted treatment for medically inoperable patients with stage I NSCLC and patients with operable stage I lung cancer are entered on clinical protocols. The purpose of this study is to conduct a phase III randomized study to compare CyberKnife SBRT with surgery, the current standard of care for stage I operable NSCLC.
Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, (650) 736 - 4112.
-
Recombinant Interleukin-15 in Treating Patients With Advanced Melanoma, Kidney Cancer, Non-small Cell Lung Cancer, or Squamous Cell Head and Neck Cancer
Not Recruiting
This phase I trial studies the side effects and best dose of recombinant interleukin-15 in treating patients with melanoma, kidney cancer, non-small cell lung cancer, or head and neck cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment. Recombinant interleukin-(IL)15 is a biological product, a protein, made naturally in the body and when made in the laboratory may help stimulate the immune system in different ways and stop tumor cells from growing.
Stanford is currently not accepting patients for this trial. For more information, please contact Brenda Hann, 650-723-0966.
-
Regorafenib and Methotrexate in Treating Participants With Recurrent or Metastatic KRAS Mutated Non-Small Cell Lung Cancer
Not Recruiting
This phase II trial studies how well regorafenib works together with methotrexate in treating participants with metastatic non-squamous non-small cell lung cancer with tumors that harbor a KRAS mutation. Regorafenib is a targeted therapy that works on different cancer pathways to stop the growth of tumor cells and stop them from spreading. Methotrexate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving regorafenib and methotrexate together may work in treating participants with KRAS mutated non-small cell lung cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Grace Hwang, 650-723-0437.
-
Safety and Efficacy Clinical Study of SNS-595 in Patients With Advanced Small Cell Lung Cancer
Not Recruiting
The purpose of this study is to evaluate the objective tumor response rate to SNS-595 in patients with small cell lung cancer (SCLC).
Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, (650) 736 - 4112.
-
Safety and Tolerability Study of SNS-314 for Advanced Solid Tumors
Not Recruiting
This is a study to assess the safety and tolerability of SNS-314 in advanced solid tumors in humans.
Stanford is currently not accepting patients for this trial. For more information, please contact Sipra Choudhury, (650) 736 - 2563.
-
Safety, Pharmacokinetic and Preliminary Efficacy Study of AC0010MA in Advanced Non Small Cell Lung Cancer
Not Recruiting
AC0010MA is a new, irreversible, Epidermal Growth Factor Receptor (EGFR) mutation selective Tyrosine Kinase Inhibitor. Aim at local advanced or metastatic non-small cell lung cancer patients with EGFR mutation or T790M drug-resistant mutation. The molecular mechanism: by irreversible combining the EGFR-RTKs ATP binding site of cell, selectively suppress the activities of EGFR tyrosine kinase phosphorylation, block the signal transduction pathway of EGFR and inhibit the function of ras/raf/MAPK downstream, thus block the tumor cell growth by EGFR induction, and promotes apoptosis. AC0010MA Maleate Capsules has three characters: 1. Irreversible binding to EGFR; 2. Effectively suppresses the tumor cell with EGFR mutant while has no suppression to EGFR wild-type cell; 3. Efficient suppress the tumor cell with EGFR T790M drug-resistant mutation.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
-
Saracatinib in Treating Patients With Relapsed or Refractory Thymoma or Thymic Cancer
Not Recruiting
This phase II trial is studying how well saracatinib works in treating patients with relapsed or refractory thymoma or thymic cancer. Saracatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.
-
Sorafenib in Treating Patients With Refractory Non-Small Cell Lung Cancer
Not Recruiting
RATIONALE: Preclinical studies indicate that sorafenib is a potent inhibitor of Raf kinase in vitro and in vivo, with significant dose-dependent, anti-tumor activity in four different human tumor types including colon, pancreatic, lung, and ovarian. This activity was cytostatic in nature and was maintained if dosing was continued. That is, tumor growth is suspended while the drug is administered but returns to baseline rates when the agent is withdrawn. Therefore, the optimal schedule will be an uninterrupted one. To assess the activity of sorafenib in a timely manner and with a meaningful interpretation, a randomized discontinuation design was adopted in the present trial, conducted in a population who were potentially sensitive to sorafenib. PURPOSE: This randomized phase II trial is studying sorafenib to see how well it works compared to placebo in treating patients with refractory non-small cell lung cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, (650) 736 - 4112.
-
Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients With Relapsed or Refractory Germ Cell Tumors
Not Recruiting
This randomized phase III trial studies how well standard-dose combination chemotherapy works compared to high-dose combination chemotherapy and stem cell transplant in treating patients with germ cell tumors that have returned after a period of improvement or did not respond to treatment. Drugs used in chemotherapy, such as paclitaxel, ifosfamide, cisplatin, carboplatin, and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. Giving colony-stimulating factors, such as filgrastim or pegfilgrastim, and certain chemotherapy drugs, helps stem cells move from the bone marrow to the blood so they can be collected and stored. Chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. It is not yet known whether high-dose combination chemotherapy and stem cell transplant are more effective than standard-dose combination chemotherapy in treating patients with refractory or relapsed germ cell tumors.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
-
Study of Atezolizumab in Combination With Cobimetinib in Participants With Locally Advanced or Metastatic Solid Tumors
Not Recruiting
This is a Phase Ib, open-label, multicenter study designed to assess the safety, tolerability, and pharmacokinetics of coadministration of intravenous (IV) dosing of atezolizumab (an engineered anti-programmed death-ligand 1 \[anti-PD-L1\] antibody) and oral dosing of cobimetinib in participants with metastatic or locally advanced cancer for which no standard therapy exists.
Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, 650-736-4112.
-
Study of Cabozantinib (XL184) in Adults With Advanced Malignancies
Not Recruiting
This is a Phase 2 study to evaluate the efficacy and safety of cabozantinib (XL184) in subjects with selected advanced tumor types.
Stanford is currently not accepting patients for this trial. For more information, please contact Dana Supan, (650) 736 - 1694.
-
Study of Cobimetinib in Participants With Solid Tumors
Not Recruiting
This non-randomized, open-label, study will determine the highest safe dose of cobimetinib, how often it should be taken, how well participants with cancer tolerate cobimetinib and will assess the pharmacokinetic effect of midazolam and dextromethorphan on the study drug.
Stanford is currently not accepting patients for this trial. For more information, please contact Dana Supan, (650) 736 - 1694.
-
Study of Positron Emission Tomography and Computed Tomography in Guiding Radiation Therapy in Patients With Stage III Non-small Cell Lung Cancer
Not Recruiting
This randomized phase II trial studies how well positron emission tomography (PET)/computed tomography (CT)-guided radiation therapy works compared to standard radiation therapy in treating patients with stage III non-small cell lung cancer. Radiation therapy uses high-energy x-rays to kill tumor cells. Using imaging procedures, such as PET and CT scans, to guide the radiation therapy, may help doctors deliver higher doses directly to the tumor and cause less damage to healthy tissue.
Stanford is currently not accepting patients for this trial. For more information, please contact Laura Gable, 650-736-0798.
-
Study of the Glutaminase Inhibitor CB-839 in Solid Tumors
Not Recruiting
Many tumor cells, in contrast to normal cells, have been shown to require the amino acid glutamine to produce energy for growth and survival. To exploit the dependence of tumors on glutamine, CB-839, a potent and selective inhibitor of the first enzyme in glutamine utilization, glutaminase, will be tested in this Phase 1 study in patients with solid tumors. This study is an open-label Phase 1 evaluation of CB-839 in patients with advanced solid tumors. The study will be conducted in 2 parts. Part 1 is a dose escalation study enrolling patients with locally-advanced, metastatic and/or refractory solid tumors to receive CB-839 capsules orally twice or three times daily. In Part 2, patients with each of the following diseases will be enrolled: A) Triple-Negative Breast Cancer, B) Non-Small Cell Lung Cancer (adenocarcinoma), C) Renal Cell Cancer, D) Mesothelioma, E) Fumarate hydratase (FH)-deficient tumors, F) Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GIST), G) SDH-deficient non-GIST tumors, H) tumors harboring mutations in isocitrate dehydrogenase-1 (IDH1) or IDH2, and I) cMyc mutation tumors. As an extension of Parts 1 \& 2, patients will be treated with CB-839 in combination with standard chemotherapy. Combination groups include: Pac-CB, CBE, CB-Erl, CBD, and CB-Cabo. Pac-CB: patients with locally-advanced or metastatic TNBC will be treated with paclitaxel and CB-839. CBE: patients with advanced clear cell RCC or papillary RCC will be treated with everolimus in combination with CB-839. CB-Erl: patients with advanced NSCLC lacking the T790M EGFR mutation will be treated with erlotinib and CB-839. CBD: patients with NSCLC harboring KRAS mutation will be treated with docetaxel and CB-839. CB-Cabo: patients with histologically confirmed diagnosis of locally-advanced, inoperable or metastatic RCC treated with cabozantinib in combination with CB-839. All patients will be assessed for safety, pharmacokinetics (plasma concentration of drug), pharmacodynamics (inhibition of glutaminase), biomarkers (biochemical markers that may predict responsiveness in later studies), and tumor response.
Stanford is currently not accepting patients for this trial. For more information, please contact Pei-Jen Chang, 650-725-0866.
-
Study of XL647 Administered Orally Daily to Patients With Solid Tumors
Not Recruiting
The purpose of this study is to assess the safety and tolerability of the multiple receptor tyrosine kinase (RTK) inhibitor (including EGFR, VEGFR2, ErbB2, and EphB4) XL647 when given orally daily to adults with advanced solid tumors.
Stanford is currently not accepting patients for this trial. For more information, please contact Joanne Fehling, (650) 736 - 1694.
-
Study of XL647 in Subjects With NSCLC Who Have Progressed After Responding to Treatment With Gefitinib or Erlotinib
Not Recruiting
The purpose of this study is to determine the best confirmed response rate of daily administration of the multiple receptor tyrosine kinase (RTK) inhibitor (including EGFR and VEGFR2) XL647 in subjects with NSCLC who have progressed after responding to treatment with either erlotinib or gefitinib.
Stanford is currently not accepting patients for this trial. For more information, please contact Lisa Zhou, (650) 736 - 4112.
-
Study to Assess Safety and Efficacy of Atezolizumab (MPDL3280A) Compared to Best Supportive Care Following Chemotherapy in Patients With Lung Cancer [IMpower010]
Not Recruiting
This is a Phase III, global, multicenter, open-label, randomized study to compare the efficacy and safety of 16 cycles (1 cycle duration=21 days) of atezolizumab (MPDL3280A) treatment compared with best supportive care (BSC) in participants with Stage IB-Stage IIIA non-small cell lung cancer (NSCLC) following resection and adjuvant chemotherapy, as measured by disease-free survival (DFS) as assessed by the investigator and overall survival (OS). Participants, after completing up to 4 cycles of adjuvant cisplatin-based chemotherapy, will be randomized in a 1:1 ratio to receive atezolizumab for 16 cycles or BSC.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
-
Study to Evaluate Safety, Pharmacokinetics, and Efficacy of Rociletinib (CO-1686) in Previously Treated Mutant Epidermal Growth Factor Receptor (EGFR) in Non-Small Cell Lung Cancer (NSCLC) Patients
Not Recruiting
Rociletinib is a novel, potent, small molecule irreversible tyrosine kinase inhibitor (TKI) that selectively targets mutant forms of the epidermal growth factor receptor (EGFR) while sparing wild-type (WT) EGFR. The purpose of the study is to evaluate the pharmacokinetic (PK) and safety profile of oral rociletinib; to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of oral rociletinib; to assess the safety and efficacy of rociletinib in previously treated NSCLC patients known to have the T790M EGFR mutation.
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro Salcedo, 650-724-1388.
-
Talactoferrin in Treating Patients With Relapsed or Refractory Non-Small Cell Lung Cancer or Squamous Cell Head and Neck Cancer
Not Recruiting
This phase I trial studies how well talactoferrin works in treating patients with relapsed or refractory non-small cell lung cancer (NSCLC) or squamous cell head and neck cancer. Biological therapies, such as talactoferrin, may stimulate the immune system in different ways and stop tumor cells from growing
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, (650) 724 - 1388.
-
TIGER-3: Open Label, Multicenter Study of Rociletinib (CO-1686) Mono Therapy Versus Single-agent Cytotoxic Chemotherapy in Patients With Mutant EGFR NSCLC Who Have Failed at Least One Previous EGFR-Directed TKI and Platinum-doublet Chemotherapy
Not Recruiting
The purpose of this study is to compare the anti-tumor efficacy of oral single-agent rociletinib, as measured by investigator assessment of the PFS, with that of single-agent cytotoxic chemotherapy in patients with EGFR-mutated, advanced/metastatic NSCLC after failure of at least 1 previous EGFR-directed TKI and at least 1 line of platinum-containing doublet chemotherapy.
Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, 650-724-1388.
-
Tivantinib With or Without Erlotinib Hydrochloride in Treating Patients With Metastatic or Locally Advanced Kidney Cancer That Cannot Be Removed by Surgery
Not Recruiting
This randomized phase II trial studies how well tivantinib with or without erlotinib hydrochloride works in treating patients with metastatic or locally advanced kidney cancer that cannot be removed by surgery. Tivantinib and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Stanford is currently not accepting patients for this trial. For more information, please contact Preeti Chavan, 650-725-0426.
-
Transoral Surgery Followed By Low-Dose or Standard-Dose Radiation Therapy With or Without Chemotherapy in Treating Patients With HPV Positive Stage III-IVA Oropharyngeal Cancer
Not Recruiting
This randomized phase II trial studies how well transoral surgery followed by low-dose or standard-dose radiation therapy works in treating patients with human papilloma virus (HPV) positive stage III-IVA oropharyngeal cancer. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving radiation therapy with chemotherapy may kill any tumor cells that remain after surgery. It is not yet known how much extra treatment needs to be given after surgery.
Stanford is currently not accepting patients for this trial. For more information, please contact Ekaterina Dib, 650-723-0503.
-
Trial of Nivolumab vs Therapy of Investigator's Choice in Recurrent or Metastatic Head and Neck Carcinoma (CheckMate 141)
Not Recruiting
The purpose of this study is to find out whether Nivolumab will significantly improve overall survival as compared to therapy of investigator's choice in patients with recurrent or metastatic head and neck carcinoma.
Stanford is currently not accepting patients for this trial. For more information, please contact Risa Jiron, 650-736-1598.
2024-25 Courses
-
Independent Studies (5)
- Directed Reading in Medicine
MED 299 (Aut, Win, Spr, Sum) - Early Clinical Experience in Medicine
MED 280 (Aut, Win, Spr, Sum) - Graduate Research
MED 399 (Aut, Win, Spr, Sum) - Medical Scholars Research
MED 370 (Aut, Win, Spr, Sum) - Undergraduate Research
MED 199 (Aut, Win, Spr, Sum)
- Directed Reading in Medicine
All Publications
-
Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone in patients with early-stage non-small-cell lung cancer (KEYNOTE-671): a randomised, double-blind, placebo-controlled, phase 3 trial.
Lancet (London, England)
2024
Abstract
BACKGROUND: At the first interim analysis of the KEYNOTE-671 trial, adding perioperative pembrolizumab to neoadjuvant chemotherapy significantly improved event-free survival in participants with early-stage non-small-cell lung cancer (NSCLC). We report overall survival and health-related quality of life outcomes from the second interim analysis.METHODS: KEYNOTE-671 was a global phase 3 trial done at 189 medical centres. Eligible participants (aged ≥18 years) with resectable stage II, IIIA, or IIIB (N2) NSCLC were randomly assigned (1:1) to four cycles of neoadjuvant pembrolizumab (200 mg administered intravenously every 3 weeks) plus cisplatin-based chemotherapy followed by surgery and 13 cycles of adjuvant pembrolizumab (200 mg administered intravenously every 3 weeks) or to four cycles of neoadjuvant placebo (administered intravenously every 3 weeks) plus cisplatin-based chemotherapy followed by surgery and 13 cycles of adjuvant placebo (administered intravenously every 3 weeks). Randomisation was done centrally using an interactive response technology system and was stratified by disease stage, PD-L1 expression, histology, and geographical region in blocks of four. Participants, investigators, and sponsor personnel were masked to treatment assignments; local pharmacists were unmasked to support treatment preparation. The dual primary endpoints were overall survival and event-free survival evaluated in the intention-to-treat population. This study is registered at ClinicalTrials.gov, NCT03425643, and is ongoing but closed to enrolment.FINDINGS: Between May 11, 2018, and Dec 15, 2021, 797 participants were randomly assigned to the pembrolizumab group (n=397) or the placebo group (n=400). Median study follow-up at the second interim analysis was 36·6 months (IQR 27·6-47·8). 36-month overall survival estimates were 71% (95% CI 66-76) in the pembrolizumab group and 64% (58-69) in the placebo group (hazard ratio 0·72 [95% CI 0·56-0·93]; one-sided p=0·0052; threshold, one-sided p=0·0054). Median event-free survival was 47·2 months (95% CI 32·9 to not reached) in the pembrolizumab group and 18·3 months (14·8-22·1) in the placebo group (hazard ratio 0·59 [95% CI 0·48-0·72]). In the as-treated population, grade 3-5 treatment-related adverse events occurred in 179 (45%) of 396 participants in the pembrolizumab group and in 151 (38%) of 399 participants in the placebo group. Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group and three (1%) participants in the placebo group.INTERPRETATION: The significant overall survival benefit of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone coupled with a manageable safety profile support the use of perioperative pembrolizumab in patients with resectable, early-stage NSCLC.FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.
View details for DOI 10.1016/S0140-6736(24)01756-2
View details for PubMedID 39288781
-
IMpower010: Final disease-free survival (DFS) and second overall survival (OS) interim results after ≥5 years of follow up of a phase III study of adjuvant atezolizumab vs best supportive care in resected stage IB-IIIA non-small cell lung cancer (NSCLC).
JOURNAL OF CLINICAL ONCOLOGY
2024; 42 (17_SUPPL): LBA8035
View details for DOI 10.1200/JCO.2024.42.17_suppl.LBA8035
View details for Web of Science ID 001244441000035
-
Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial.
Annals of oncology : official journal of the European Society for Medical Oncology
2023
Abstract
IMpower010 (NCT02486718) demonstrated significantly improved disease-free survival (DFS) with adjuvant atezolizumab vs best supportive care (BSC) following platinum-based chemotherapy in the PD-L1-positive and all stage II-IIIA non-small cell lung cancer (NSCLC) populations, at the DFS interim analysis. Results of the first interim analysis of overall survival (OS) are here reported.The design, participants, and primary-endpoint DFS outcomes have been reported for this phase 3, open-label, 1:1 randomised study of atezolizumab (1200 mg q3w; 16 cycles) vs BSC after adjuvant platinum-based chemotherapy (1-4 cycles) in adults with completely resected stage IB (≥4 cm)-IIIA NSCLC. Key secondary endpoints included OS in the stage IB-IIIA intent-to-treat (ITT) population and safety in randomised treated patients. The first pre-specified interim analysis of OS was conducted after 251 deaths in the ITT population. Exploratory analyses included OS by baseline PD-L1 expression level (SP263 assay).At a median 45.3 months' follow-up on April 18, 2022, 127 of 507 patients (25%) in the atezolizumab arm and 124 of 498 (24.9%) in the BSC arm had died. The median OS in the ITT population was not estimable; the stratified HR was 0.995 (95% CI 0.78-1.28). The stratified OS HRs (95% CI) were 0.95 (0.74-1.24) in the stage II-IIIA (n=882), 0.71 (0.49-1.03) in the stage II-IIIA PD-L1 TC ≥1% (n=476), and 0.43 (95% CI 0.24-0.78) in the stage II-IIIA PD-L1 TC ≥50% (n=229) populations. Atezolizumab-related adverse event incidences remained unchanged since the previous analysis (grade 3/4 in 53 [10.7%] and grade 5 in 4 [0.8%] of 495 patients, respectively).Although OS remains immature for the ITT population, these data indicate a positive trend favouring atezolizumab in PD-L1 subgroup analyses, primarily driven by the PD-L1 TC ≥50% stage II-IIIA subgroup. No new safety signals were observed after 13 months' additional follow-up. Together, these findings support the positive benefit-risk profile of adjuvant atezolizumab in this setting.
View details for DOI 10.1016/j.annonc.2023.07.001
View details for PubMedID 37467930
-
KEYNOTE-671: Randomized, double-blind, phase 3 study of pembrolizumab or placebo plus platinum-based chemotherapy followed by resection and pembrolizumab or placebo for early stage NSCLC
JOURNAL OF CLINICAL ONCOLOGY
2023; 41 (17_SUPPL): LBA100
View details for DOI 10.1200/JCO.2023.41.17_suppl.LBA100
View details for Web of Science ID 001182783300019
-
KEYNOTE-671: Randomized, double-blind, phase 3 study of pembrolizumab or placebo plus platinum-based chemotherapy followed by resection and pembrolizumab or placebo for early stage NSCLC.
LIPPINCOTT WILLIAMS & WILKINS. 2023
View details for Web of Science ID 001043181100006
-
Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer.
The New England journal of medicine
2023
Abstract
Among patients with resectable early-stage non-small-cell lung cancer (NSCLC), a perioperative approach that includes both neoadjuvant and adjuvant immune checkpoint inhibition may provide benefit beyond either approach alone.We conducted a randomized, double-blind, phase 3 trial to evaluate perioperative pembrolizumab in patients with early-stage NSCLC. Participants with resectable stage II, IIIA, or IIIB (N2 stage) NSCLC were assigned in a 1:1 ratio to receive neoadjuvant pembrolizumab (200 mg) or placebo once every 3 weeks, each of which was given with cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant pembrolizumab (200 mg) or placebo once every 3 weeks for up to 13 cycles. The dual primary end points were event-free survival (the time from randomization to the first occurrence of local progression that precluded the planned surgery, unresectable tumor, progression or recurrence, or death) and overall survival. Secondary end points included major pathological response, pathological complete response, and safety.A total of 397 participants were assigned to the pembrolizumab group, and 400 to the placebo group. At the prespecified first interim analysis, the median follow-up was 25.2 months. Event-free survival at 24 months was 62.4% in the pembrolizumab group and 40.6% in the placebo group (hazard ratio for progression, recurrence, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.72; P<0.001). The estimated 24-month overall survival was 80.9% in the pembrolizumab group and 77.6% in the placebo group (P = 0.02, which did not meet the significance criterion). A major pathological response occurred in 30.2% of the participants in the pembrolizumab group and in 11.0% of those in the placebo group (difference, 19.2 percentage points; 95% CI, 13.9 to 24.7; P<0.0001; threshold, P = 0.0001), and a pathological complete response occurred in 18.1% and 4.0%, respectively (difference, 14.2 percentage points; 95% CI, 10.1 to 18.7; P<0.0001; threshold, P = 0.0001). Across all treatment phases, 44.9% of the participants in the pembrolizumab group and 37.3% of those in the placebo group had treatment-related adverse events of grade 3 or higher, including 1.0% and 0.8%, respectively, who had grade 5 events.Among patients with resectable, early-stage NSCLC, neoadjuvant pembrolizumab plus chemotherapy followed by resection and adjuvant pembrolizumab significantly improved event-free survival, major pathological response, and pathological complete response as compared with neoadjuvant chemotherapy alone followed by surgery. Overall survival did not differ significantly between the groups in this analysis. (Funded by Merck Sharp and Dohme; KEYNOTE-671 ClinicalTrials.gov number, NCT03425643.).
View details for DOI 10.1056/NEJMoa2302983
View details for PubMedID 37272513
-
Women in cancer research and oncology
CANCER CELL
2021; 39 (3): 285–87
Abstract
March 8 is International Women's Day. Women, particularly women of color, are still underrepresented in science and medical careers and face severe health disparities. To commemorate this day, we asked female cancer researchers and oncologists to talk about their work experiences and their efforts to improve equity, representation, and leadership.
View details for Web of Science ID 000627120300001
View details for PubMedID 33689700
-
Integrating genomic features for non-invasive early lung cancer detection
NATURE
2020
View details for DOI 10.1038/s41586-020-2140-0
View details for Web of Science ID 000521531000011
-
COVID-19 in patients with thoracic malignancies (TERAVOLT): first results of an international, registry-based, cohort study.
The Lancet. Oncology
2020
Abstract
Early reports on patients with cancer and COVID-19 have suggested a high mortality rate compared with the general population. Patients with thoracic malignancies are thought to be particularly susceptible to COVID-19 given their older age, smoking habits, and pre-existing cardiopulmonary comorbidities, in addition to cancer treatments. We aimed to study the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with thoracic malignancies.The Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) registry is a multicentre observational study composed of a cross-sectional component and a longitudinal cohort component. Eligibility criteria were the presence of any thoracic cancer (non-small-cell lung cancer [NSCLC], small-cell lung cancer, mesothelioma, thymic epithelial tumours, and other pulmonary neuroendocrine neoplasms) and a COVID-19 diagnosis, either laboratory confirmed with RT-PCR, suspected with symptoms and contacts, or radiologically suspected cases with lung imaging features consistent with COVID-19 pneumonia and symptoms. Patients of any age, sex, histology, or stage were considered eligible, including those in active treatment and clinical follow-up. Clinical data were extracted from medical records of consecutive patients from Jan 1, 2020, and will be collected until the end of pandemic declared by WHO. Data on demographics, oncological history and comorbidities, COVID-19 diagnosis, and course of illness and clinical outcomes were collected. Associations between demographic or clinical characteristics and outcomes were measured with odds ratios (ORs) with 95% CIs using univariable and multivariable logistic regression, with sex, age, smoking status, hypertension, and chronic obstructive pulmonary disease included in multivariable analysis. This is a preliminary analysis of the first 200 patients. The registry continues to accept new sites and patient data.Between March 26 and April 12, 2020, 200 patients with COVID-19 and thoracic cancers from eight countries were identified and included in the TERAVOLT registry; median age was 68·0 years (61·8-75·0) and the majority had an Eastern Cooperative Oncology Group performance status of 0-1 (142 [72%] of 196 patients), were current or former smokers (159 [81%] of 196), had non-small-cell lung cancer (151 [76%] of 200), and were on therapy at the time of COVID-19 diagnosis (147 [74%] of 199), with 112 (57%) of 197 on first-line treatment. 152 (76%) patients were hospitalised and 66 (33%) died. 13 (10%) of 134 patients who met criteria for ICU admission were admitted to ICU; the remaining 121 were hospitalised, but were not admitted to ICU. Univariable analyses revealed that being older than 65 years (OR 1·88, 95% 1·00-3·62), being a current or former smoker (4·24, 1·70-12·95), receiving treatment with chemotherapy alone (2·54, 1·09-6·11), and the presence of any comorbidities (2·65, 1·09-7·46) were associated with increased risk of death. However, in multivariable analysis, only smoking history (OR 3·18, 95% CI 1·11-9·06) was associated with increased risk of death.With an ongoing global pandemic of COVID-19, our data suggest high mortality and low admission to intensive care in patients with thoracic cancer. Whether mortality could be reduced with treatment in intensive care remains to be determined. With improved cancer therapeutic options, access to intensive care should be discussed in a multidisciplinary setting based on cancer specific mortality and patients' preference.None.
View details for DOI 10.1016/S1470-2045(20)30314-4
View details for PubMedID 32539942
-
Circulating Tumor DNA Changes During Chemoradiation for Lung Cancer Predict Patient Outcomes
ELSEVIER SCIENCE INC. 2019: S113
View details for DOI 10.1016/j.ijrobp.2019.06.610
View details for Web of Science ID 000485671502643
-
Role of KEAP1/NFE2L2 mutations in the chemotherapeutic response of non-small cell lung cancer patients.
Clinical cancer research : an official journal of the American Association for Cancer Research
2019
Abstract
Activation of NFE2L2 has been linked to chemoresistance in cell line models. Recently, somatic mutations which activate NFE2L2, including mutations in NFE2L2,KEAP1, or CUL3,have been found to be associated with poor outcomes in patients with non-small cell lung cancer (NSCLC). However, the impact of these mutations on chemoresistance remains incompletely explored.We investigated the effect of Keap1 deletion on chemoresistance in cell lines from Trp53-based mouse models of lung squamous cell carcinoma (LSCC) and lung adenocarcinoma (LUAD). Separately, we identified 51 stage IV NSCLC patients with KEAP1, NFE2L2, or CUL3mutations and a matched cohort of 52 wildtype patients. Time to treatment failure after front line platinum doublet chemotherapy and overall survival was compared between the two groups.Deletion of Keap1 in Trp53-null murine LUAD and LSCC resulted in increased clonogenic survival upon treatment with diverse cytotoxic chemotherapies. In NSCLC patients, median time to treatment failure (TTF) after first line chemotherapy for the KEAP1/NFE2L2/CUL3-mutant cohort was 2.8 months compared to 8.3 months in the control group (p < 0.0001) Median overall survival (OS) was 11.2 months in the KEAP1/NFE2L2/CUL3-mutant group and 36.8 months in the control group (p = 0.006). Conclusions: Keap1 deletion confers chemoresistance in murine lung cancer cells. Patients with metastatic NSCLC with mutations in KEAP1, NFE2L2, or CUL3 have shorter time to treatment failure and overall survival after first line platinum doublet chemotherapy compared with matched controls. Novel approaches for improving outcomes in this subset of NSCLC patients are therefore needed.
View details for DOI 10.1158/1078-0432.CCR-19-1237
View details for PubMedID 31548347
-
Phase II trial of single agent amrubicin in patients with previously treated advanced thymic malignancies.
Lung cancer (Amsterdam, Netherlands)
2019; 137: 71–75
Abstract
There are limited treatment options for patients with thymic malignancies. Here we present data supporting treatment with single agent amrubicin, a third generation anthracycline and topoisomerase II inhibitor.This was a phase 2 open-label, single arm trial of amrubicin in patients with thymoma (T) or thymic carcinoma (TC), conducted at two academic institutions. Patients were included if they had received at least one prior chemotherapy regimen. The first 18 patients received amrubicin at 40 mg/m2 IV days 1-3 repeated every 3-weeks. Due to the high incidence of febrile neutropenia, dosing was subsequently amended to 35 mg/m2 for the final 15 patients.A total of 33 patients (14 T/19 TC) were enrolled from 2011 to 2014. Median number of prior therapies was 2. Best response included 6 partial responses, 21 stable disease, and 6 progressive disease (all TC). Objective response rate was 18% (90% exact binomial CI 8.2%-32.8%; T = 4/14 (29%), TC = 2/19 (11%)). Median progression-free survival was 7.7 months (T: 8.3 months; TC: 7.3) and median overall survival was 29.7 months (T: 54.1 months; TC: 18 months). There was a high rate of febrile neutropenia (7 patients) that occurred despite a reduction in amrubicin dose and one related death. Five patients had reduction in LVEF below 50% during the course of treatment resulting in treatment discontinuation in one patient.Amrubicin shows promise as a single agent in heavily pre-treated patients with thymic malignancies. Notable side effects include febrile neutropenia and the use of growth factor support is essential. Further investigation of this agent is warranted.
View details for DOI 10.1016/j.lungcan.2019.09.015
View details for PubMedID 31557562
-
Keynote Address: When Breath Becomes Air-As Physician Becomes Patient
JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK
2017; 15 (5.5): 696–98
Abstract
As part of the NCCN 22nd Annual Conference: Improving the Quality, Effectiveness, and Efficiency of Cancer Care, Lucy Kalanithi, MD, wife of now-deceased best-selling author Paul Kalanithi (When Breath Becomes Air), and Heather Wakelee, MD, Paul's oncologist, discussed-for the first time together in a public forum-Paul's experience of going from a neurosurgery resident to a patient with cancer with a terminal diagnosis. Robert Carlson, MD, moderated the discussion.
View details for DOI 10.6004/jnccn.2017.0076
View details for Web of Science ID 000402785200010
View details for PubMedID 28515247
-
Erlotinib, cabozantinib, or erlotinib plus cabozantinib as second-line or third-line treatment of patients with EGFR wild-type advanced non-small-cell lung cancer (ECOG-ACRIN 1512): a randomised, controlled, open-label, multicentre, phase 2 trial
LANCET ONCOLOGY
2016; 17 (12): 1661-1671
Abstract
Erlotinib is approved for the treatment of all patients with advanced non-small-cell lung cancer (NSCLC), but is most active in the treatment of EGFR mutant NSCLC. Cabozantinib, a small molecule tyrosine kinase inhibitor, targets MET, VEGFR, RET, ROS1, and AXL, which are implicated in lung cancer tumorigenesis. We compared the efficacy of cabozantinib alone or in combination with erlotinib versus erlotinib alone in patients with EGFR wild-type NSCLC.This three group, randomised, controlled, open-label, multicentre, phase 2 trial was done in 37 academic and community oncology practices in the USA. Patients were eligible if they had received one or two previous treatments for advanced non-squamous, EGFR wild-type, NSCLC. Patients were stratified by performance status and line of therapy, and randomly assigned using permuted blocks within strata to receive open-label oral daily dosing of erlotinib (150 mg), cabozantinib (60 mg), or erlotinib (150 mg) and cabozantinib (40 mg). Imaging was done every 8 weeks. At the time of radiographic progression, there was optional crossover for patients in either single-drug group to receive combination treatment. The primary endpoint was to compare progression-free survival in patients given erlotinib alone versus cabozantinib alone, and in patients given erlotinib alone versus the combination of erlotinib plus cabozantinib. We assessed the primary endpoint in the per-protocol population, which was defined as all patients who were eligible, randomly assigned, and received at least one dose of treatment. The safety analysis population included all patients who received study treatment irrespective of eligibility. This trial is registered with ClinicalTrials.gov, number NCT01708954.Between Feb 7, 2013, and July 1, 2014, we enrolled and randomly assigned 42 patients to erlotinib treatment, 40 patients to cabozantinib treatment, and 43 patients to erlotinib plus cabozantinib treatment, of whom 111 (89%) in total were included in the primary analysis (erlotinib [n=38], cabozantinib [n=38], erlotinib plus cabozantinib [n=35]). Compared with erlotinib alone (median 1·8 months [95% CI 1·7-2·2]), progression-free survival was significantly improved in the cabozantinib group (4·3 months [3·6-7·4]; hazard ratio [HR] 0·39, 80% CI 0·27-0·55; one-sided p=0·0003) and in the erlotinib plus cabozantinib group (4·7 months [2·4-7·4]; HR 0·37, 0·25-0·53; one-sided p=0·0003). Among participants included in the safety analysis of the erlotinib (n=40), cabozantinib (n=40), and erlotinib plus cabozantinib (n=39) groups, the most common grade 3 or 4 adverse events were diarrhoea (three [8%] cases in the erlotinib group vs three [8%] in the cabozantinib group vs 11 [28%] in the erlotinib plus cabozantinib group), hypertension (none vs ten [25%] vs one [3%]), fatigue (five [13%] vs six [15%] vs six [15%]), oral mucositis (none vs four [10%] vs one [3%]), and thromboembolic event (none vs three [8%] vs two [5%]). One death due to respiratory failure occurred in the cabozantinib group, deemed possibly related to either drug, and one death due to pneumonitis occurred in the erlotinib plus cabozantinib group, deemed related to either drug or the combination.Despite its small sample size, this trial showed that, in patients with EGFR wild-type NSCLC, cabozantinib alone or combined with erlotinib has clinically meaningful, superior efficacy to that of erlotinib alone, with additional toxicity that was generally manageable. Cabozantinib-based regimens are promising for further investigation in this patient population.ECOG-ACRIN Cancer Research Group, National Cancer Institute of the National Institutes of Health.
View details for DOI 10.1016/S1470-2045(16)30561-7
View details for Web of Science ID 000389537700035
View details for PubMedID 27825638
View details for PubMedCentralID PMC5154681
-
Integrated digital error suppression for improved detection of circulating tumor DNA
NATURE BIOTECHNOLOGY
2016; 34 (5): 547-555
Abstract
High-throughput sequencing of circulating tumor DNA (ctDNA) promises to facilitate personalized cancer therapy. However, low quantities of cell-free DNA (cfDNA) in the blood and sequencing artifacts currently limit analytical sensitivity. To overcome these limitations, we introduce an approach for integrated digital error suppression (iDES). Our method combines in silico elimination of highly stereotypical background artifacts with a molecular barcoding strategy for the efficient recovery of cfDNA molecules. Individually, these two methods each improve the sensitivity of cancer personalized profiling by deep sequencing (CAPP-Seq) by about threefold, and synergize when combined to yield ∼15-fold improvements. As a result, iDES-enhanced CAPP-Seq facilitates noninvasive variant detection across hundreds of kilobases. Applied to non-small cell lung cancer (NSCLC) patients, our method enabled biopsy-free profiling of EGFR kinase domain mutations with 92% sensitivity and >99.99% specificity at the variant level, and with 90% sensitivity and 96% specificity at the patient level. In addition, our approach allowed monitoring of NSCLC ctDNA down to 4 in 10(5) cfDNA molecules. We anticipate that iDES will aid the noninvasive genotyping and detection of ctDNA in research and clinical settings.
View details for DOI 10.1038/nbt.3520
View details for PubMedID 27018799
-
Racial and Ethnic Variations in Lung Cancer Incidence and Mortality: Results From the Women's Health Initiative.
Journal of clinical oncology
2016; 34 (4): 360-368
Abstract
This study aimed to evaluate racial/ethnic differences in lung cancer incidence and mortality in the Women's Health Initiative Study, a longitudinal prospective cohort evaluation of postmenopausal women recruited from 40 clinical centers.Lung cancer diagnoses were centrally adjudicated by pathology review. Baseline survey questionnaires collected sociodemographic and health information. Logistic regression models estimated incidence and mortality odds by race/ethnicity adjusted for age, education, calcium/vitamin D, body mass index, smoking (status, age at start, duration, and pack-years), alcohol, family history, oral contraceptive, hormones, physical activity, and diet.The cohort included 129,951 women--108,487 (83%) non-Hispanic white (NHW); 10,892 (8%) non-Hispanic black (NHB); 4,882 (4%) Hispanic; 3,696 (3%) Asian/Pacific Islander (API); 534 (< 1%) American Indian/Alaskan Native; and 1,994 (1%) other. In unadjusted models, Hispanics had 66% lower odds of lung cancer compared with NHW (odds ratio [OR], 0.34; 95% CI, 0.2 to 0.5), followed by API (OR, 0.45; 95% CI, 0.27 to 0.75) and NHB (OR, 0.75; 95% CI, 0.59 to 0.95). In fully adjusted multivariable models, the decreased lung cancer risk for Hispanic compared with NHW women attenuated to the null (OR, 0.59; 95% CI, 0.35 to 0.99). In unadjusted models Hispanic and API women had decreased risk of death compared with NHW women (OR, 0.30 [95% CI, 0.15 to 0.62] and 0.34 [95% CI, 0.16 to 0.75, respectively); however, no racial/ethnic differences were found in risk of lung cancer death in fully adjusted models.Differences in lung cancer incidence and mortality are associated with sociodemographic, clinical, and behavioral factors. These findings suggest modifiable exposures and behaviors may contribute to differences in incidence of and mortality by race/ethnicity for postmenopausal women. Interventions focused on these factors may reduce racial/ethnic differences in lung cancer incidence and mortality.
View details for DOI 10.1200/JCO.2015.63.5789
View details for PubMedID 26700122
-
Diffuse High Intensity PD-L1 Staining in Thymic Epithelial Tumors.
Journal of thoracic oncology
2015; 10 (3): 500-508
Abstract
Blockade of the immune checkpoint programmed death receptor ligand-1 (PD-L1)/PD-1 pathway has well-established clinical activity across many tumor types. PD-L1 protein expression by immunohistochemistry is emerging as a predictive biomarker of response to these therapies. Here, we examine PD-L1 expression in a thymic epithelial tumor (TET) tissue microarray (TMA).The TMA contained 69 TETs and 17 thymic controls, with each case represented by triplicate cores. The TMA was stained with rabbit monoclonal antibody (clone 15; Sino Biological, Beijing, China) to human PD-L1. PD-L1 staining was scored based on intensity as follows: 0 = none, 1 = equivocal/uninterpretable, 2 = weak, and 3 = intermediate-strong. Those cases with all cores scoring three in the epithelial component were categorized as PD-L1 and the remaining as PD-L1.PD-L1 scores were more frequent in TETs than in controls (68.1% versus 17.6%; p = 0.0036). PD-L1 scores and histology were significantly correlated, with higher intensity staining in World Health Organization (WHO). B2/B3/C TETs. Only 14.8% of TETs had PD-L1 staining of associated lymphocytes. In an adjusted analysis (age/sex), PD-L1 TETs had a significantly worse overall survival (hazard ratio: 5.40, 95% confidence interval: 1.13-25.89; p = 0.035) and a trend for worse event-free survival (hazard ratio: 2.94, 95% confidence interval: 0.94-9.24; p = 0.064).PD-L1 expression was present in all cases of TETs within the epithelial component but only in a minority in the lymphocytic component. TETs stained more intensely for PD-L1 than in controls, and PD-L1 TETs were associated with more aggressive histology and worse prognosis. This study lends rationale to a clinical trial with anti-PD-1/PD-L1 therapy in this rare tumor type.
View details for DOI 10.1097/JTO.0000000000000429
View details for PubMedID 25402569
-
Lung cancer incidence in never smokers
JOURNAL OF CLINICAL ONCOLOGY
2007; 25 (5): 472–78
View details for DOI 10.1200/JCO.2006.07.2983
View details for Web of Science ID 000244176000003
-
A phase 2 single-arm trial of high-dose precision targeted radiotherapy added to immunotherapy for patients with metastatic non-small cell lung cancer.
International journal of radiation oncology, biology, physics
2024
Abstract
For metastatic non-small cell lung cancer (NSCLC), the addition of radiotherapy (RT) to immune checkpoint inhibitor (ICI) therapy could have synergistic anti-cancer effects and address the most threatening tumors. We posited that the addition of high-dose RT to ICI could prolong progression-free survival (PFS).In this single arm phase 2 trial, 45 patients with metastatic NSCLC who had received an anti-PD-1/anti-PD-L-1 ICI for 4+ weeks were enrolled from July 2017-May 2021. Patients received high-dose RT to 1-4 extracranial tumors and continued ICI until progression or unacceptable toxicity. The primary endpoint was PFS at 24 weeks, comparing to a historical control rate of 35%.Of 44 evaluable patients, median age was 71, 75% had adenocarcinoma, 64% had polymetastatic disease, and 85% of cancers with known PD-L1 percentage were PD-L1 positive. Median number of treated tumors was two and most common dose was 40 Gy in 10 fractions (41/81 tumors). Median follow-up was 23.3 months. The trial met the primary outcome: 24-week PFS was 60% (95% CI 44-75%), higher than the historical control rate (p<0.001). Median PFS was 6.9 months (95% CI 4.0-13.5 mo) and median OS was 27.4 months (95% CI 20.4-not reached). Several patients with pre-study disease progression on ICI treatment achieved durable responses to study treatment, up to 53 months. Local recurrence rate was low: cumulative incidence of 5% at one, two, and three years. Two dose-limiting toxicities were observed (5%), including one grade 5 pneumonitis.The strategy improved 24-week PFS compared to historical controls receiving ICI alone. The excellent local control supports the efficacy of high-dose RT in addressing macroscopic disease.
View details for DOI 10.1016/j.ijrobp.2024.09.038
View details for PubMedID 39357790
-
Consolidation ALK Tyrosine Kinase Inhibitors versus Durvalumab or Observation After Chemoradiation in Unresectable Stage III ALK+ Non-Small Cell Lung Cancer.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2024
Abstract
Patients with advanced ALK-positive non-small cell lung cancer (NSCLC) typically have poor response to immunotherapy; the benefit of consolidation durvalumab in patients with unresectable stage III ALK-positive NSCLC remains unclear. Herein, we compare the efficacy and safety of consolidation ALK tyrosine kinase inhibitor (TKI) versus durvalumab or observation after concurrent chemoradiation (cCRT).We conducted a retrospective study using a multi-center study of 17 institutions globally. Patients with unresectable stage III ALK-positive NSCLC treated between 2015-2022 were included. Patients received ALK TKI, durvalumab, or observation after cCRT. Real-world progression-free survival (rwPFS) and overall survival (OS) were estimated using Kaplan-Meier method. Treatment-related adverse events (trAE) were classified by Common Terminology Criteria for Adverse Events v5.0. Outcomes were assessed by multivariable Cox regression analysis.Sixty-seven patients were included, of whom 39 (58%) were female. Median age was 57 years (IQR: 49-67). Fifteen received consolidation ALK TKI, 30 received durvalumab, and 22 underwent observation. Baseline characteristics were similar across the 3 groups other than differences in race. After adjusting for stage, age, and nodal status, median rwPFS was significantly longer for ALK TKI (rwPFS not reached [NR], 95% CI 22.7-NR) versus durvalumab (11.3 months, 95% CI 8.9-18.5, hazard ratio [HR]=0.12, 95% CI: 0.026-0.5, p-adjusted=0.006) or observation (7.2 months, 95% CI 3.4-10.6, HR=0.04, 95% CI: 0.009-0.2, p-adjusted<0.0001). Durvalumab significantly improved median rwPFS compared to observation (HR=0.37, 95% CI: 0.19-0.71, p-adj = 0.002, p-adjusted=0.002). Median OS in the ALK TKI and durvalumab cohorts was significantly improved compared to patients on observation (ALK TKI-observation: p=0.04; durvalumab-observation: p=0.03). TrAE of any grade occurred in 8 (53%) and 11 (37%) patients treated with ALK-TKI and durvalumab, respectively. Grade ≥3 trAEs occurred in 27% (n=4) of patients treated with ALK TKI and 6.7% of patients treated with durvalumab.Patients with ALK-positive NSCLC experience significantly improved rwPFS when treated with consolidation ALK TKI therapy, surpassing outcomes seen with either durvalumab or observation. While both ALK TKI therapy and durvalumab offer an extension in OS compared to observation alone, it appears that ALK TKI therapy is the superior choice, underscoring its pivotal role in enhancing patient survival.
View details for DOI 10.1016/j.jtho.2024.09.1379
View details for PubMedID 39260522
-
Smoking and the Risk of Second Primary Lung Cancer Among Breast Cancer Survivors from the Population-Based UK Biobank Study.
Clinical lung cancer
2024
Abstract
Long-term breast cancer (BC) survivors are known to develop second malignancies, with second primary lung cancer (SPLC) one common type. Smoking was identified as a main risk factor for SPLC among BC survivors. These findings were limited to the U.S. and focused on smoking status, not incorporating cumulative smoking exposures (eg, pack-years). We examine SPLC incidence and evaluate the associations between SPLC risk and cumulative cigarette smoking exposures and other potential factors among BC survivors in a prospective European cohort.Of 502,505 participants enrolled in the UK Biobank in 2006 to 2010, we identified 8429 patients diagnosed with BC between 2006 and 2016 and followed for second malignancies through 2016. Smoking information was collected at enrollment, and treatment data were collected using electronic health records. Multivariable cause-specific Cox regression (CSC) evaluated the association between each factor and SPLC risk.Of 8429 BC patients, 40 (0.47%) developed SPLC over 45,376 person-years. The 10-year cumulative SPLC incidence was 0.48% (95% CI = 0.33%-0.62%). The CSC analysis confirmed the association between SPLC and ever-smoking status (adjusted hazard-ratio (aHR) = 3.46 (P < .001). The analysis showed a 24% increment in SPLC risk per 10 smoking pack-years among BC survivors (aHR = 1.24 per-10 pack-years, P = .01). The associations between SPLC and other variables remained statistically insignificant. We applied the USPSTF lung cancer screening eligibility criteria and found that 80% of the 40 BC survivors who developed SPLC would have been ineligible for lung cancer screening.In a large, European cohort, cumulative smoking exposure is significantly associated with SPLC risk among BC survivors.
View details for DOI 10.1016/j.cllc.2024.08.017
View details for PubMedID 39332922
-
Proceedings of the 1st biannual bridging the gaps in lung cancer conference.
The oncologist
2024
Abstract
Lung cancer is the leading cause of cancer death in the US and globally. The mortality from lung cancer has been declining, due to a reduction in incidence and advances in treatment. Although recent success in developing targeted and immunotherapies for lung cancer has benefitted patients, it has also expanded the complexity of potential treatment options for health care providers. To aid in reducing such complexity, experts in oncology convened a conference (Bridging the Gaps in Lung Cancer) to identify current knowledge gaps and controversies in the diagnosis, treatment, and outcomes of various lung cancer scenarios, as described here. Such scenarios relate to biomarkers and testing in lung cancer, small cell lung cancer, EGFR mutations and targeted therapy in non-small cell lung cancer (NSCLC), early-stage NSCLC, KRAS/BRAF/MET and other genomic alterations in NSCLC, and immunotherapy in advanced NSCLC.
View details for DOI 10.1093/oncolo/oyae228
View details for PubMedID 39237103
-
Racial and Ethnic Differences in Second Primary Lung Cancer Risk among Lung Cancer Survivors.
JNCI cancer spectrum
2024
Abstract
BACKGROUND: Recent therapeutic advances have improved survival among lung cancer (LC) patients, who are now at high risk of second primary lung cancer (SPLC). Hispanics comprise the largest minority in the U.S., who have shown a lower LC incidence and mortality than other races, yet their SPLC risk is poorly understood.We quantified the SPLC incidence patterns among Hispanics vs other races.METHODS: We used data from the Multiethnic Cohort, a population-based cohort of five races (African American, Japanese American, Hispanic, Native Hawaiian, and White), recruited between 1993-1996 and followed through 2017. We identified patients diagnosed with initial primary lung cancer (IPLC) and SPLC via linkage to SEER registries. We estimated the 10-year cumulative incidence of IPLC (in the entire cohort) and SPLC (among IPLC patients). A standardized incidence ratio (SIR) was calculated as the ratio of SPLC-to-IPLC incidence by race/ethnicity.RESULTS: Among 202,692 participants, 6,788 (3.3%) developed IPLC over 3,871,417 person-years. The 10-year cumulative IPLC incidence was lower among Hispanics (0.80%, [0.72-0.88]) vs Whites (1.67%, [1.56-1.78]) or Blacks (2.44%, [2.28-2.60]). However, the 10-year SPLC incidence following IPLC was higher among Hispanics (3.11%, [1.62-4.61]) vs Whites (2.80%, [1.94-3.66]) or Blacks (2.29%, [1.48-3.10]), resulting in a significantly higher SIR for Hispanics (SIR=8.27, [5.05-12.78]) vs Whites (SIR=5.60, [4.11-7.45]) or Blacks (SIR=3.48, [2.42-4.84])(p<.001).CONCLUSION: Hispanics have a higher SPLC incidence following IPLC than other races, which may be potentially due to better survival after IPLC and extended duration for SPLC development. Continuing surveillance is warranted to reduce racial disparities among LC survivors.
View details for DOI 10.1093/jncics/pkae072
View details for PubMedID 39186009
-
Ancestry-, Sex-, and Age-Based Differences of Gene Alterations in NSCLC: From the Real-World Data of Cancer Genomic Profiling Tests.
Journal of the National Comprehensive Cancer Network : JNCCN
2024: 1-10
Abstract
Some genomic alterations in non-small cell lung cancer (NSCLC) are known to differ according to race, sex, or age. These studies have been limited in sample size and thus they cannot detect the differences precisely and comprehensively.Tissue-based comprehensive genomic profiling was performed on 75,362 patients with NSCLC from the United States during routine clinical care. Additionally, we examined data of a Japanese NSCLC cohort with 1,019 patients. In the US cohort, 296 genes were examined for pathogenic alterations. Predominant genetic ancestry was inferred using a SNP-based approach, and patients were categorized into European (EUR), African (AFR), East Asian (EAS), Admixed American (AMR), and South Asian (SAS) ancestry groups. Patients were additionally stratified by histologic type, age (<40/≥40 years, <75/≥75 years), and sex. The prevalence of high tumor mutational burden (TMB-High) and microsatellite instability status was also calculated.Stratified by ancestry, EGFR alterations were significantly enriched in EAS versus other ancestry groups. The prevalence of ALK was significantly higher in the AMR, EAS, and SAS patients than in AFR and EUR patients. KRAS and STK11 were enriched in EUR and AFR patients versus other groups. TMB-High was significantly enriched in AFR patients versus all other groups. An analysis based on sex revealed differences in prevalence of alterations in 80 genes and TMB-High status. For example, EGFR, ALK, BRAF, and KRAS alterations were significantly enriched in females, whereas TP53, STK11, KEAP1, and TMB-High were significantly enriched in males. With respect to age, the prevalence of alterations in 41 genes, including ALK, RET, MET, EGFR, STK11, KEAP1, BRAF, and KRAS, as well as TMB-High, were significantly different between patients aged <40 years and those aged ≥40 years.Comprehensive analysis from a large real-world dataset revealed ancestry-associated differences in genomic alterations in NSCLC. Age- and sex-related differences in prevalence of genomic alterations and TMB-High status were also observed.
View details for DOI 10.6004/jnccn.2024.7021
View details for PubMedID 39116914
-
Molecular Characteristics and Pretreatment Neutrophil-to-Lymphocyte Ratio as Predictors of Durable Clinical Benefit from Immune Checkpoint Inhibition in Non-Small Cell Lung Cancer.
Clinical lung cancer
2024
Abstract
Prior research in non-small cell lung cancer (NSCLC) has shown that tumors with specific driver mutations may be less likely to respond to immune checkpoint inhibitors (ICI). In this analysis, we evaluated the characteristics of patients with durable clinical benefit (DCB) to ICI compared to those with no durable clinical benefit (NDB), with emphasis on the role of molecular alterations in EGFR, ALK, and ROS1 and pretreatment neutrophil-to-lymphocyte ratio (NLR).We retrospectively collected clinical characteristics and outcomes for patients who initiated ICI monotherapy for advanced NSCLC at Stanford University between April 2015 and May 2018. Patients were classified as having DCB if time on ICI therapy was greater than or equal to 180 days, or NDB if less than 180 days. Outcomes included best radiographic benefit while on ICI and survival from time of ICI initiation.Of 123 patients treated with ICI for NSCLC, 28 patients had DCB (23%), while 95 had NDB (77%). Median overall survival from initiation of ICI in the 33 patients with molecular alterations in EGFR (n = 31), ALK, or ROS1 and NLR of 5.9 or higher was 2.0 months, compared to 8.1 months in patients with these genomic alterations and NLR less than 5.9. Median overall survival in patients without alterations in EGFR, ALK, or ROS1 and NLR of 5.9 or higher was 4.3 months, compared to 12.1 months in patients with NLR less than 5.9 (P = .023).Elevation in pretreatment NLR was associated with significantly lower overall median survival from initiation of ICI, particularly when in combination with NSCLC with alterations in EGFR, ALK, or ROS1. This finding could influence clinical practice as NLR is readily available through routine blood testing.
View details for DOI 10.1016/j.cllc.2024.06.006
View details for PubMedID 38987048
-
Neoadjuvant and Adjuvant Treatment for Early-Stage Resectable Non-small Cell Lung Cancer (NSCLC): Consensus Recommendations from the International Association for the Study of Lung Cancer (IASLC).
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2024
Abstract
Advances in the multidisciplinary care of early-stage resectable non-small cell lung cancer (rNSCLC) are emerging at an unprecedented pace. Numerous phase 3 trials produced results that have transformed patient outcomes for the better, yet these findings also require important modifications to the patient treatment journey trajectory and re-organization of care pathways. Perhaps most notably, the need for multispecialty collaboration for this patient population has never been greater. These rapid advances have inevitably left us with important gaps in knowledge for which definitive answers will only become available in several years. To this end, the IASLC commissioned a diverse multidisciplinary international expert panel to evaluate the current landscape and provide diagnostic, staging, and therapeutic recommendations for patients with rNSCLC, with particular emphasis on patients with AJCC/UICC TNM 8th edition stage II and III disease. Using a team-based approach, we generated 19 recommendations, of which all but one achieved greater than 85% consensus amongst panel members. A public voting process was initiated, which successfully validated and provided qualitative nuance to our recommendations. Highlights include: 1) the critical importance of a multidisciplinary approach to the evaluation of patients with rNSCLC driven by shared clinical decision making of a multispecialty team of expert providers; 2) biomarker testing for rNSCLC; 3) a preference for neoadjuvant chemoimmunotherapy for stage III rNSCLC; 4) equipoise regarding the optimal management of patients with stage II between up-front surgery followed by adjuvant therapy and neoadjuvant/perioperative strategies; and 5) the robust preference for adjuvant targeted therapy for patients with rNSCLC and sensitizing EGFR and ALK tumor alterations. Our primary goals were to provide practical recommendations sensitive to the global differences in biology and resources for patients with rNSCLC, and to provide expert consensus guidance tailored to the individualized patient needs, goals, and preferences in their cancer care journey as these are areas where physicians must make daily clinical decisions in the absence of definitive data. These recommendations will continue to evolve as the treatment landscape for rNSCLC expands and more knowledge is acquired on the best therapeutic approach in specific patient and disease subgroups.
View details for DOI 10.1016/j.jtho.2024.06.010
View details for PubMedID 38901648
-
Health-related quality of life (HRQoL) outcomes from the randomized, double-blind phase 3 KEYNOTE-671 study of perioperative pembrolizumab for early-stage non-small-cell lung cancer (NSCLC)
LIPPINCOTT WILLIAMS & WILKINS. 2024
View details for Web of Science ID 001275557401805
-
Association of napsin A-specific T cell clonotypes with durable clinical benefit to immunotherapy in patients with metastatic NSCLC
LIPPINCOTT WILLIAMS & WILKINS. 2024
View details for Web of Science ID 001275557402025
-
Top advances of the year: Perioperative therapy for lung cancer.
Cancer
2024
Abstract
Emerging data supporting the rise of perioperative immune checkpoint inhibitors (ICIs) as a standard of care in the treatment of early stage, surgically resectable non-small cell lung cancer (NSCLC) dominated the NSCLC news in 2023. Adjuvant pembrolizumab became the second adjuvant ICI to receive US Food and Drug Administration approval in early 2023 after the 2021 approval of adjuvant atezolizumab and the 2022 approval of neoadjuvant nivolumab with chemotherapy. Subsequently in 2023, multiple phase 3 trials examining perioperative ICIs were positive and demonstrated clinically meaningful outcomes by prolonging event-free survival, improving pathologic complete response rates, and trending toward improved overall survival in most. Perioperative pembrolizumab became the first ICI to attain US Food and Drug Administration approval in this setting through the KEYNOTE-671 trial (ClinicalTrials.gov identifier NCT03425643), which also demonstrated a definitive overall survival benefit in the entire study population. However, questions remain regarding patient selection for either approach and how we can optimize biomarkers to determine who needs adjuvant therapy after surgery.
View details for DOI 10.1002/cncr.35357
View details for PubMedID 38717993
-
A Phase 1/2 Study to Evaluate the Safety and Activity of Nivolumab in Combination With Vorolanib, a Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitor, in Patients With Refractory Thoracic Tumors.
JTO clinical and research reports
2024; 5 (2): 100619
Abstract
Targeting the tumor microenvironment may enhance response to immunotherapy (immune checkpoint inhibitors) and improve outcomes for patients. This study tested the safety and efficacy of vorolanib, a novel tyrosine kinase inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and c-KIT, in combination with programmed cell death protein 1 blockade using nivolumab for refractory thoracic malignancies.This single-arm multicenter study enrolled patients with extensive-stage SCLC, thymic carcinoma, and NSCLC, either naive or had progressed on previous chemotherapy or immune checkpoint inhibitors (either primary or acquired resistance). The primary objective of phase 1 was to determine the maximum tolerated dose, and the primary end point for each dose-expansion cohort was the objective response rate.A total of 88 patients were enrolled in phase 1 (n = 11) and dose expansion (n = 77) cohorts. Transaminitis was dose-limiting and expansion proceeded with oral vorolanib 200 mg daily combined with intravenous nivolumab 240 mg every 2 weeks. The objective response rate per cohort were as follows: NSCLC naive 33% (five of 15, 95% confidence interval [CI]: 13%-60%), NSCLC primary refractory 5.9% (one of 17, 95% CI: 0%-17.6%), NSCLC acquired resistance 11.1% (two of 18, 95% CI: 0%-27.8%); SCLC 0% (zero of 18), and thymic carcinoma 11% (one of nine, 95% CI: 0%-33%). Disease control rate ranged from 11.1% in SCLC (two of 18, 0%-27.8%) to 66.7 % in thymic carcinoma (six of nine, 95% CI: 33.3%-100%). The most common adverse events were fatigue (32%), aspartate transaminase (27%) and alanine transaminase elevation (25%), and diarrhea (19%). Transaminitis was more common in patients with thymic carcinoma than other tumors.Vorolanib plus nivolumab had a manageable safety profile and may have clinical benefits in various thoracic malignancies. The disease control rate in thymic malignancies warrants further assessment.
View details for DOI 10.1016/j.jtocrr.2023.100619
View details for PubMedID 38328473
View details for PubMedCentralID PMC10847019
-
Consolidation Osimertinib versus Durvalumab versus Observation following Concurrent Chemoradiation in Unresectable EGFR-Mutant Non-Small-Cell Lung Cancer: A Multicenter Retrospective Cohort Study.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2024
Abstract
Durvalumab improves survival when used as consolidation therapy after chemoradiation (CRT) in patients with stage III NSCLC. However, the optimal consolidation therapy for patients with EGFR-mutant (EGFRmut) stage III NSCLC remains unknown.In this multi-institutional international retrospective analysis across 24 institutions, we evaluated outcomes in patients with stage III EGFRmut NSCLC treated with concurrent CRT followed by consolidation therapy with osimertinib, durvalumab, or observation between 2015 and 2022. Kaplan-Meier method was used to estimate real-world progression-free survival (rwPFS, primary endpoint) and overall survival (OS, secondary endpoint). Treatment-related adverse events (trAE) during consolidation treatment were defined using Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Multivariable Cox regression analysis was used.Of 136 patients with stage III EGFRmut NSCLC treated with definitive concurrent CRT, 56 received consolidation durvalumab, 33 received consolidation osimertinib, and 47 received observation alone. Baseline characteristics were similar across the 3 cohorts. With a median follow-up of 46 months for the entire cohort, the median duration of treatment was not reached (NR) for osimertinib (Inter-quartile range [IQR]: NR-NR) and was 5.5 (IQR:2.4-10.8) months with durvalumab. After adjusting for nodal status, stage III A/B/C, and age, patients treated with consolidation osimertinib had significantly longer 24-month rwPFS compared to those in the durvalumab or observation cohorts (osimertinib: 86%, durvalumab: 30%, observation: 27%, p<0.001 for both comparisons). There was no difference in rwPFS between durvalumab and the observation cohort. No significant difference in OS across the 3 cohorts was detected, possibly due to the limited follow-up. Any grade trAE occurred in 52% (2 [6.1%] grade ≥3) and 48% (10 [18%] grade ≥3) of patients treated with osimertinib and durvalumab, respectively. Of 45 patients who progressed on consolidation durvalumab, 37 (82%) subsequently received EGFR tyrosine kinase inhibitors (TKIs). Of these, 14 (38%) patients developed trAEs including 5 pneumonitis (14%; 2 [5.4%] grade ≥3) and 5 diarrhea (14%; 1 [2.7%] grade ≥3).This study suggests that among patients with stage III unresectable NSCLC with a sensitizing EGFR mutation, consolidation osimertinib was associated with significantly longer rwPFS than durvalumab or observation. No unanticipated safety signals were observed with consolidation osimertinib.
View details for DOI 10.1016/j.jtho.2024.01.012
View details for PubMedID 38278303
-
Phenotyping EMT and MET cellular states in lung cancer patient liquid biopsies at a personalized level using mass cytometry.
Scientific reports
2023; 13 (1): 21781
Abstract
Malignant pleural effusions (MPEs) can be utilized as liquid biopsy for phenotyping malignant cells and for precision immunotherapy, yet MPEs are inadequately studied at the single-cell proteomic level. Here we leverage mass cytometry to interrogate immune and epithelial cellular profiles of primary tumors and pleural effusions (PEs) from early and late-stage non-small cell lung cancer (NSCLC) patients, with the goal of assessing epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) states in patient specimens. By using the EMT-MET reference map PHENOSTAMP, we observe a variety of EMT states in cytokeratin positive (CK+) cells, and report for the first time MET-enriched CK+ cells in MPEs. We show that these states may be relevant to disease stage and therapy response. Furthermore, we found that the fraction of CD33+ myeloid cells in PEs was positively correlated to the fraction of CK+ cells. Longitudinal analysis of MPEs drawn 2 months apart from a patient undergoing therapy, revealed that CK+ cells acquired heterogeneous EMT features during treatment. We present this work as a feasibility study that justifies deeper characterization of EMT and MET states in malignant cells found in PEs as a promising clinical platform to better evaluate disease progression and treatment response at a personalized level.
View details for DOI 10.1038/s41598-023-46458-5
View details for PubMedID 38065965
View details for PubMedCentralID 2689101
-
Chemotherapy and immunotherapy in early-stage NSCLC: neoadjuvant vs adjuvant therapy.
Clinical advances in hematology & oncology : H&O
2023; 21 (12): 648-651
View details for PubMedID 38039058
-
Osimertinib-Associated Cardiomyopathy In Patients With Non-Small Cell Lung Cancer: A Case Series
JACC: CardioOncology
2023: 839-841
View details for DOI 10.1016/j.jaccao.2023.07.006
View details for PubMedCentralID PMC10774774
-
BRIEF REPORT: Real-world efficacy and safety of amivantamab for EGFR-mutant non-small cell lung cancer (NSCLC).
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2023
Abstract
Amivantamab-vmjw (amivantamab) is a bispecific EGFR/MET antibody approved for patients with advanced non-small cell lung cancer (NSCLC) with EGFR Exon 20 insertion mutations, after prior therapy. However, the benefits and safety of amivantamab in other EGFR-mutation lung cancer, with or without osimertinib, and with concurrent radiation therapy, are less known.We queried the MD Anderson Lung Cancer GEMINI, Fred Hutchinson Cancer Research Center, University of California Davis Comprehensive Cancer Center and Stanford Cancer Center's database for patients with EGFR-mutant NSCLC treated with amivantamab, not on a clinical trial. The data analyzed included initial response, duration of treatment, and concomitant radiation safety in overall population and prespecified subgroups.Sixty-one patients received amivantamab. Median age was 65 (31 - 81); 72.1% were female and 77% were patients with never smoking history. Median number of prior lines of therapies were four. Based on tumor's EGFR mutation, 39 patients were in the classical mutation cohort; 15 patients in the Exon20 cohort; and 7 patients in the atypical cohort. Thirty-seven patients (58.7%) received amivantamab concomitantly with osimertinib and 25 patients (39.1%) received concomitant radiation. Fifty-four patients were evaluable for response in the overall population; 19 patients (45.2%) had clinical response and disease control rate (DCR) was 64.3%. In the classical mutation cohort of the 33 evaluable patients, twelve (36.4%) had clinical response and DCR was 48.5%. In the atypical mutation cohort, six of the seven patients (85.7%) had clinical response and DCR was 100%. Of the 13 patient evaluable patients in the Exon 20 cohort, five patients (35.7%) had clinical response and DCR was 64.3%. Adverse events reported with amivantamab use were similar as previously described in product labeling. No additional toxicities were noted when amivantamab was given with radiation and/or osimertinib.Our real-world multi-center analysis demonstrated that amivantamab is a potentially effective treatment option for patients with EGFR mutations outside of Exon 20 insertion mutations. The combination of osimertinib with amivantamab is safe and feasible. Radiation therapy also appears safe when administered sequentially or concurrently with amivantamab.
View details for DOI 10.1016/j.jtho.2023.11.020
View details for PubMedID 38012986
-
Patient Selection and Outcomes for Hypofractionated Accelerated Radiation and Concurrent Chemotherapy for Non-Small-Cell Lung Cancer.
Clinical lung cancer
2023
Abstract
Adoption of hypofractionated accelerated radiation therapy (HART) with concurrent chemotherapy has been limited by toxicity concerns. We aimed to describe outcomes of patients treated with HART and concurrent chemotherapy and to evaluate dosimetry to organs at risk to guide patient selection.We evaluated a retrospective cohort of NSCLC patients treated with concurrent chemotherapy with HART (>2.2 Gy per fraction) or standard fractionated radiation therapy (SFRT; 2-2.2 Gy fractions). Dosimetric parameters to key organs at risk were compared, and toxicity, patterns of recurrence and survival were calculated for the cohorts.Fifty-three patients treated with HART were compared with 100 patients treated with SFRT. Median dose per fraction for the HART cohort was 2.75 Gy (range 2.4-3 Gy). HART patients had significantly lower doses to the lung, heart, and esophagus due to patient selection. The HART group and had rates of grade 2+ pneumonitis (9.4 vs. 19%, P = .16) and grade 2+ esophagitis (20.8 vs. 45%, P < .01) that compared favorably to SFRT. Cumulative incidence of in-field recurrence trended lower in the HART cohort (7.6% vs. 23.1%, P = .058). Among the HART group, 88.7% (47/53) met the newly proposed lung constraints based on the degree of hypofractionation CONCLUSION: In select patients with favorable dosimetry to organs at risk, definitive HART with concurrent chemotherapy achieved excellent local control with low toxicity. These results are being used to inform a prospective study on the safety and efficacy of HART with concurrent chemotherapy for select NSCLC patients.
View details for DOI 10.1016/j.cllc.2023.11.008
View details for PubMedID 38065707
-
Disparities in outcomes between Black and White patients in North America with thoracic malignancies and COVID-19 infection (TERAVOLT).
Lung cancer (Amsterdam, Netherlands)
2023; 186: 107423
Abstract
Patients with thoracic malignancies who develop COVID-19 infection have a higher hospitalization rate compared to the general population and to those with other cancer types, but how this outcome differs by race and ethnicity is relatively understudied.The TERAVOLT database is an international, multi-center repository of cross-sectional and longitudinal data studying the impact of COVID-19 on individuals with thoracic malignancies. Patients from North America with thoracic malignancies and confirmed COVID-19 infection were included for this analysis of racial and ethnic disparities. Patients with missing race data or races and ethnicities with fewer than 50 patients were excluded from analysis. Multivariable analyses for endpoints of hospitalization and death were performed on these 471 patients.Of the 471 patients, 73% were White and 27% were Black. The majority (90%) were non-Hispanic ethnicity, 5% were Hispanic, and 4% were missing ethnicity data. Black patients were more likely to have an Eastern Cooperative Oncology Group (ECOG) Performance Status ≥ 2 (p-value = 0.04). On multivariable analysis, Black patients were more likely than White patients to require hospitalization (Odds Ratio (OR): 1.69, 95% CI: 1.01-2.83, p-value = 0.044). These differences remained across different waves of the pandemic. However, no statistically significant difference in mortality was found between Black and White patients (OR 1.29, 95% CI: 0.69-2.40, p-value = 0.408).Black patients with thoracic malignancies who acquire COVID-19 infection are at a significantly higher risk of hospitalization compared to White patients, but there is no significant difference in mortality. The underlying drivers of racial disparity among patients with thoracic malignancies and COVID-19 infection require ongoing investigation.
View details for DOI 10.1016/j.lungcan.2023.107423
View details for PubMedID 37995456
-
Personalized Accelerated ChEmoRadiation (PACER) for Lung Cancer: Protocol for a Bayesian Optimal Phase I/II Trial.
Clinical lung cancer
2023
Abstract
Prior attempts to escalate radiation dose for non-small cell lung cancer (NSCLC) have not improved survival. Given the high risk for cardiopulmonary toxicity with treatment and heterogenous presentation of locally advanced NSCLC, it is unlikely that a single dose regimen is optimal for all patients. This phase I/II trial aims to evaluate a novel treatment approach where the level of accelerated hypofractionation is determined by the predicted toxicity from dose to organs at risk (OARs).Patients ≥ 18 years old with lung cancer planned for fractionated radiotherapy to the lung with concurrent chemotherapy will be eligible. Radiation therapy (RT) will be delivered to a total dose of 60 to 66 Gy in 30, 25, or 20 fractions depending on the ability to meet constraints to key organs at risk including the lungs, heart, and esophagus. The primary endpoint is high grade pulmonary, esophageal, or cardiac toxicity. A Bayesian optimized design is used to determine stopping boundaries and evaluate the primary endpoint.PACER will evaluate the safety and feasibility of personalized accelerated chemoradiotherapy for lung cancer.
View details for DOI 10.1016/j.cllc.2023.11.004
View details for PubMedID 38040540
-
Second Primary Lung Cancer Among Lung Cancer Survivors Who Never Smoked.
JAMA network open
2023; 6 (11): e2343278
Abstract
Lung cancer among never-smokers accounts for 25% of all lung cancers in the US; recent therapeutic advances have improved survival among patients with initial primary lung cancer (IPLC), who are now at high risk of developing second primary lung cancer (SPLC). As smoking rates continue to decline in the US, it is critical to examine more closely the epidemiology of lung cancer among patients who never smoked, including their risk for SPLC.To estimate and compare the cumulative SPLC incidence among lung cancer survivors who have never smoked vs those who have ever smoked.This population-based prospective cohort study used data from the Multiethnic Cohort Study (MEC), which enrolled participants between April 18, 1993, and December 31, 1996, with follow-up through July 1, 2017. Eligible individuals for this study were aged 45 to 75 years and had complete smoking data at baseline. These participants were followed up for IPLC and further SPLC development through the Surveillance, Epidemiology, and End Results registry. The data were analyzed from July 1, 2022, to January 31, 2023.Never-smoking vs ever-smoking exposure at MEC enrollment.The study had 2 primary outcomes: (1) 10-year cumulative incidence of IPLC in the entire study cohort and 10-year cumulative incidence of SPLC among patients with IPLC and (2) standardized incidence ratio (SIR) (calculated as the SPLC incidence divided by the IPLC incidence) by smoking history.Among 211 414 MEC participants, 7161 (3.96%) developed IPLC over 4 038 007 person-years, and 163 (2.28%) developed SPLC over 16 470 person-years. Of the participants with IPLC, the mean (SD) age at cohort enrollment was 63.6 (7.7) years, 4031 (56.3%) were male, and 3131 (43.7%) were female. The 10-year cumulative IPLC incidence was 2.40% (95% CI, 2.31%-2.49%) among ever-smokers, which was 7 times higher than never-smokers (0.34%; 95% CI, 0.30%-0.37%). However, the 10-year cumulative SPLC incidence following IPLC was as high among never-smokers (2.84%; 95% CI, 1.50%-4.18%) as ever-smokers (2.72%; 95% CI, 2.24%-3.20%), which led to a substantially higher SIR for never-smokers (14.50; 95% CI, 8.73-22.65) vs ever-smokers (3.50; 95% CI, 2.95-4.12).The findings indicate that SPLC risk among lung cancer survivors who never smoked is as high as among those with IPLC who ever-smoked, highlighting the need to identify risk factors for SPLC among patients who never smoked and to develop a targeted surveillance strategy.
View details for DOI 10.1001/jamanetworkopen.2023.43278
View details for PubMedID 37966839
-
Molecular Distribution of Patients with Non-Small Cell Lung Cancer Eligible for Lung Cancer Screening
ELSEVIER SCIENCE INC. 2023: S102-S103
View details for Web of Science ID 001098831600116
-
IMpower010: Exploratory Analysis of Tumour Mutational Burden and Disease-Free Survival with Adjuvant Atezolizumab in NSCLC
ELSEVIER SCIENCE INC. 2023: S139
View details for Web of Science ID 001098831600186
-
Risk Model-Based Lung Cancer Screening and Racial and Ethnic Disparities in the US.
JAMA oncology
2023
Abstract
The revised 2021 US Preventive Services Task Force (USPSTF) guidelines for lung cancer screening have been shown to reduce disparities in screening eligibility and performance between African American and White individuals vs the 2013 guidelines. However, potential disparities across other racial and ethnic groups in the US remain unknown. Risk model-based screening may reduce racial and ethnic disparities and improve screening performance, but neither validation of key risk prediction models nor their screening performance has been examined by race and ethnicity.To validate and recalibrate the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial 2012 (PLCOm2012) model-a well-established risk prediction model based on a predominantly White population-across races and ethnicities in the US and evaluate racial and ethnic disparities and screening performance through risk-based screening using PLCOm2012 vs the USPSTF 2021 criteria.In a population-based cohort design, the Multiethnic Cohort Study enrolled participants in 1993-1996, followed up through December 31, 2018. Data analysis was conducted from April 1, 2022, to May 19. 2023. A total of 105 261 adults with a smoking history were included.The 6-year lung cancer risk was calculated through recalibrated PLCOm2012 (ie, PLCOm2012-Update) and screening eligibility based on a 6-year risk threshold greater than or equal to 1.3%, yielding similar eligibility as the USPSTF 2021 guidelines.Predictive accuracy, screening eligibility-incidence (E-I) ratio (ie, ratio of the number of eligible to incident cases), and screening performance (sensitivity, specificity, and number needed to screen to detect 1 lung cancer).Of 105 261 participants (60 011 [57.0%] men; mean [SD] age, 59.8 [8.7] years), consisting of 19 258 (18.3%) African American, 27 227 (25.9%) Japanese American, 21 383 (20.3%) Latino, 8368 (7.9%) Native Hawaiian/Other Pacific Islander, and 29 025 (27.6%) White individuals, 1464 (1.4%) developed lung cancer within 6 years from enrollment. The PLCOm2012-Update showed good predictive accuracy across races and ethnicities (area under the curve, 0.72-0.82). The USPSTF 2021 criteria yielded a large disparity among African American individuals, whose E-I ratio was 53% lower vs White individuals (E-I ratio: 9.5 vs 20.3; P < .001). Under the risk-based screening (PLCOm2012-Update 6-year risk ≥1.3%), the disparity between African American and White individuals was substantially reduced (E-I ratio: 15.9 vs 18.4; P < .001), with minimal disparities observed in persons of other minoritized groups, including Japanese American, Latino, and Native Hawaiian/Other Pacific Islander. Risk-based screening yielded superior overall and race and ethnicity-specific performance to the USPSTF 2021 criteria, with higher overall sensitivity (67.2% vs 57.7%) and lower number needed to screen (26 vs 30) at similar specificity (76.6%).The findings of this cohort study suggest that risk-based lung cancer screening can reduce racial and ethnic disparities and improve screening performance across races and ethnicities vs the USPSTF 2021 criteria.
View details for DOI 10.1001/jamaoncol.2023.4447
View details for PubMedID 37883107
-
Asian American Women's Experiences of Discrimination and Health Behaviors during the COVID-19 Pandemic.
Journal of immigrant and minority health
2023
Abstract
The COVID-19 pandemic exacerbated racism experienced by Asian Americans, especially women and older individuals. Little is known about how discriminatory experiences during the pandemic have influenced health behaviors among Asian Americans. Between 10/2021 and 6/2022, we surveyed 193 Asian American women in the San Francisco area. Participants were asked to report types of discrimination they experienced since March 2020. We explored bivariable associations of discrimination and changes in health behaviors and healthcare utilization. Most women were Chinese American (75%) and over 45-years-old (87%). The top three discriminatory experiences reported were being treated with less respect (60%), being treated unfairly at restaurants/stores (49%), and people acting as if they are better (47%). Chinese American women (vs. non-Chinese Asian American women) reported higher frequencies of being threatened/harassed (40% vs. 22%). Women who reported any discriminatory experience (vs. none) were more likely to report less physical exercise (42.7% vs. 26.3%) and canceling/rescheduling medical appointments (65.0% vs. 45.1%). Our findings begin to elucidate Asian American women's experiences of discrimination since the pandemic and provide evidence of the harmful impacts of anti-Asian racism on health behaviors.
View details for DOI 10.1007/s10903-023-01558-2
View details for PubMedID 37882970
-
Risk model-based management for second primary lung cancer among lung cancer survivors through a validated risk prediction model.
Cancer
2023
Abstract
Recent therapeutic advances and screening technologies have improved survival among patients with lung cancer, who are now at high risk of developing second primary lung cancer (SPLC). Recently, an SPLC risk-prediction model (called SPLC-RAT) was developed and validated using data from population-based epidemiological cohorts and clinical trials, but real-world validation has been lacking. The predictive performance of SPLC-RAT was evaluated in a hospital-based cohort of lung cancer survivors.The authors analyzed data from 8448 ever-smoking patients diagnosed with initial primary lung cancer (IPLC) in 1997-2006 at Mayo Clinic, with each patient followed for SPLC through 2018. The predictive performance of SPLC-RAT and further explored the potential of improving SPLC detection through risk model-based surveillance using SPLC-RAT versus existing clinical surveillance guidelines.Of 8448 IPLC patients, 483 (5.7%) developed SPLC over 26,470 person-years. The application of SPLC-RAT showed high discrimination area under the receiver operating characteristics curve: 0.81). When the cohort was stratified by a 10-year risk threshold of ≥5.6% (i.e., 80th percentile from the SPLC-RAT development cohort), the observed SPLC incidence was significantly elevated in the high-risk versus low-risk subgroup (13.1% vs. 1.1%, p < 1 × 10-6 ). The risk-based surveillance through SPLC-RAT (≥5.6% threshold) outperformed the National Comprehensive Cancer Network guidelines with higher sensitivity (86.4% vs. 79.4%) and specificity (38.9% vs. 30.4%) and required 20% fewer computed tomography follow-ups needed to detect one SPLC (162 vs. 202).In a large, hospital-based cohort, the authors validated the predictive performance of SPLC-RAT in identifying high-risk survivors of SPLC and showed its potential to improve SPLC detection through risk-based surveillance.Lung cancer survivors have a high risk of developing second primary lung cancer (SPLC). However, no evidence-based guidelines for SPLC surveillance are available for lung cancer survivors. Recently, an SPLC risk-prediction model was developed and validated using data from population-based epidemiological cohorts and clinical trials, but real-world validation has been lacking. Using a large, real-world cohort of lung cancer survivors, we showed the high predictive accuracy and risk-stratification ability of the SPLC risk-prediction model. Furthermore, we demonstrated the potential to enhance efficiency in detecting SPLC using risk model-based surveillance strategies compared to the existing consensus-based clinical guidelines, including the National Comprehensive Cancer Network.
View details for DOI 10.1002/cncr.35069
View details for PubMedID 37877788
-
Comparison of SP263 and 22C3 immunohistochemistry PD-L1 assays for clinical efficacy of adjuvant atezolizumab in non-small cell lung cancer: results from the randomized phase III IMpower010 trial.
Journal for immunotherapy of cancer
2023; 11 (10)
Abstract
Tumor samples from the phase III IMpower010 study were used to compare two programmed death-ligand 1 (PD-L1) immunohistochemistry assays (VENTANA SP263 and Dako 22C3) for identification of PD-L1 patient subgroups (negative, positive, low, and high expression) and their predictive value for adjuvant atezolizumab compared with best supportive care (BSC) in resectable early-stage non-small cell lung cancer (NSCLC).PD-L1 expression was assessed by the SP263 assay, which measured the percentage of tumor cells with any membranous PD-L1 staining, and the 22C3 assay, which scored the percentage of viable tumor cells showing partial or complete membranous PD-L1 staining.When examining the concordance at the PD-L1-positive threshold (SP263: tumor cell (TC)≥1%; 22C3: tumor proportion score (TPS)≥1%), the results were concordant between assays for 83% of the samples. Similarly, at the PD-L1-high cut-off (SP263: TC≥50%; 22C3: TPS≥50%), the results were concordant between assays for 92% of samples. The disease-free survival benefit of atezolizumab over BSC was comparable between assays for PD-L1-positive (TC≥1% by SP263: HR, 0.58 (95% CI: 0.40 to 0.85) vs TPS≥1% by 22C3: HR, 0.65 (95% CI: 0.45 to 0.95)) and PD-L1-high (TC≥50% by SP263: HR, 0.27 (95% CI: 0.14 to 0.53) vs TPS≥50% by 22C3: HR, 0.31 (95% CI: 0.16 to 0.60)) subgroups.The SP263 and 22C3 assays showed high concordance and a comparable clinical predictive value of atezolizumab at validated PD-L1 thresholds, suggesting that both assays can identify patients with early-stage NSCLC most likely to experience benefit from adjuvant atezolizumab.NCT02486718.
View details for DOI 10.1136/jitc-2023-007047
View details for PubMedID 37903590
-
CNS Control after First-Line Osimertinib in Patients with Metastatic EGFR-Mutant NSCLC.
International journal of radiation oncology, biology, physics
2023; 117 (2S): e110
Abstract
Although osimertinib (osi) has excellent intracranial activity in EGFR-mutant metastatic non-small cell lung cancer (NSCLC), there is no consensus regarding whether to continue osi for central nervous system (CNS) control with second-line chemotherapy (chemo) at the time of systemic progression. We aimed to compare CNS outcomes after first-line osi in patients receiving second-line chemo with or without continuation of osi.We retrospectively reviewed patients with EGFR-mutant NSCLC with brain metastases (BrM) at the time of initiating first-line osi who experienced progression and started second-line chemo. Cumulative incidence of local and distant CNS progression, and extracranial (EC) progression was calculated from time of second-line chemo initiation with death as a competing risk. Overall survival (OS) was analyzed using Kaplan-Meier.We included 52 patients with a median follow up of 9.6 months (range 0.4-36.4). Median OS and CNS progression-free survival (PFS) from the time of starting second-line chemo was 12.5 months (95% CI 8.1-16.9), and 5.3 months (95% CI 3.35-7.26), respectively. The 1-year cumulative incidence of local, distant CNS progression, any CNS progression, and EC progression was 14.4% (95% CI 4.5-24.2), 42.8% (95% CI 22.8-56.8), 42.8% (95% CI 22.8-56.8) and 66.8% (95% CI 53.5-80.2), respectively. After progression on first-line osi, 25 (48.1%) and 27 patients (51.9%) continued and discontinued osi, respectively. Patients who continued osi had significantly higher BrM burden than those who did not, with 17 (68%), 3 (12%), and 5 (20%) versus 26 (96%), 0, and 1 (3.7%) patient having <10 or >11 parenchymal brain lesions, or leptomeningeal disease (LMD) at the time of second line therapy, respectively (p<0.01). In those who continued osi vs those who did not, median OS (10.8 vs 12.5 months; p = 0.37), median intracranial PFS (5.3 vs 4.8 months; p = 0.99), 1-year cumulative incidence of local (8.4% versus 20 % p = 0.26), and 1-year distant CNS progression (24.8% vs 60%; p = 0.08) was not significantly different. CNS complications such as symptomatic, hospitalizations, and steroid initiation for CNS disease, and progression of LMD were not significantly different between the two groups. Eventually, 10 patients underwent salvage RT post first-line osi and median time to salvage RT was 7.8 months (range 2-9.4). Of patients who underwent salvage RT, 2 patients (20%) had continued osi with second-line chemo. Twelve patients (44.4%) who did not continue osi eventually re-started osi for progressive disease.Patients who continued osi had significantly higher BrM tumor burden. Despite these patients being at higher risk for CNS progression, time to CNS progression and incidence of CNS complications were not significantly different in the two cohorts. Patients who discontinued osi were more likely to undergo salvage RT. Continuation of osi may allow patients to defer salvage RT.
View details for DOI 10.1016/j.ijrobp.2023.06.888
View details for PubMedID 37784648
-
Overall survival in the KEYNOTE-671 study of perioperative pembrolizumab for early-stage non-small-cell lung cancer NSCLC)
ELSEVIER. 2023: S1297-S1298
View details for DOI 10.1016/j.annonc.2023.10.052
View details for Web of Science ID 001087480203538
-
RAS-precision medicine trans-atlantic partnership: Comparative analysis of KRAS codon 12 and 13 mutations in non-small cell lung cancer
ELSEVIER. 2023: S1159-S1160
View details for DOI 10.1016/j.annonc.2023.09.1281
View details for Web of Science ID 001087480203251
-
IMpower010: Exploratory analysis of disease-free survival (DFS) by TGFβ cancer-associated fibroblast (CAF) gene signature expression in patients (pts) with resected NSCLC treated with atezolizumab (atezo) or best supportive care (BSC)
ELSEVIER. 2023: S732-S733
View details for DOI 10.1016/j.annonc.2023.09.742
View details for Web of Science ID 001087480201591
-
Individualized Stereotactic Ablative Radiotherapy for Lung Tumors: The iSABR Phase 2 Nonrandomized Controlled Trial.
JAMA oncology
2023
Abstract
Stereotactic ablative radiotherapy (SABR) is used for treating lung tumors but can cause toxic effects, including life-threatening damage to central structures. Retrospective data suggested that small tumors up to 10 cm3 in volume can be well controlled with a biologically effective dose less than 100 Gy.To assess whether individualizing lung SABR dose and fractionation by tumor size, location, and histological characteristics may be associated with local tumor control.This nonrandomized controlled trial (the iSABR trial, so named for individualized SABR) was a phase 2 multicenter trial enrolling participants from November 15, 2011, to December 5, 2018, at academic medical centers in the US and Japan. Data were analyzed from December 9, 2020, to May 10, 2023. Patients were enrolled in 3 groups according to cancer type: initial diagnosis of non-small cell lung cancer (NSCLC) with an American Joint Committee on Cancer 7th edition T1-3N0M0 tumor (group 1), a T1-3N0M0 new primary NSCLC with a history of prior NSCLC or multiple NSCLCs (group 2), or lung metastases from NSCLC or another solid tumor (group 3).Up to 4 tumors were treated with once-daily SABR. The dose ranged from 25 Gy in 1 fraction for peripheral tumors with a volume of 0 to 10 cm3 to 60 Gy in 8 fractions for central tumors with a volume greater than 30 cm3.Per-group freedom from local recurrence (same-lobe recurrence) at 1 year, with censoring at time of distant recurrence, death, or loss to follow-up.In total, 217 unique patients (median [IQR] age, 72 [64-80] years; 129 [59%] male; 150 [69%] current or former smokers) were enrolled (some multiple times). There were 240 treatment courses: 79 in group 1, 82 in group 2, and 79 in group 3. A total of 285 tumors (211 [74%] peripheral and 74 [26%] central) were treated. The most common dose was 25 Gy in 1 fraction (158 tumors). The median (range) follow-up period was 33 (2-109) months, and the median overall survival was 59 (95% CI, 49-82) months. Freedom from local recurrence at 1 year was 97% (90% CI, 91%-99%) for group 1, 94% (90% CI, 87%-97%) for group 2, and 96% (90% CI, 89%-98%) for group 3. Freedom from local recurrence at 5 years ranged from 83% to 93% in the 3 groups. The proportion of patients with grade 3 to 5 toxic effects was low, at 5% (including a single patient [1%] with grade 5 toxic effects).The results of this nonrandomized controlled trial suggest that individualized SABR (iSABR) used to treat lung tumors may allow minimization of treatment dose and is associated with excellent local control. Individualized dosing should be considered for use in future trials.ClinicalTrials.gov Identifier: NCT01463423.
View details for DOI 10.1001/jamaoncol.2023.3495
View details for PubMedID 37707820
-
Genomic characterization of thymic epithelial tumors in a real-world dataset.
ESMO open
2023; 8 (5): 101627
Abstract
Thymic epithelial tumors (TETs) are rare neoplasms arising in the mediastinum, including thymic carcinomas and thymomas. Due to their rarity, little is known about the genomic profiles of TETs. Herein, we investigated the genomic characteristics of TETs evaluated in a large comprehensive genomic profiling database in a real-world setting.We included data from two different cohorts: Foundation Medicine Inc. (FMI) in the United States and the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan. Samples profiled were examined for all classes of alterations in 253 genes targeted across all assays. Tumor mutational burden (TMB) and microsatellite instability (MSI) were also evaluated.A total of 794 patients were collected in our study, including 722 cases from FMI and 72 cases from C-CAT. In the FMI data, CDKN2A (39.9%), TP53 (30.2%) and CDKN2B (24.6%) were frequently altered in thymic carcinoma, versus TP53 (7.8%), DNMT3A (6.8%), and CDKN2A (5.8%) in thymoma. TMB-high (≥10 mutations/Mb) and MSI were present in 7.0% and 2.3% of thymic carcinomas, and 1.6% and 0.3% of thymomas, respectively. Within C-CAT data, CDKN2A (38.5%), TP53 (36.5%) and CDKN2B (30.8%) were also frequently altered in thymic carcinoma, while alterations of TSC1, SETD2 and LTK (20.0% each) were found in thymoma.To the best of our knowledge, this is the largest cohort in which genomic alterations, TMB and MSI status of TETs were investigated. Potential targets for treatment previously unbeknownst in TETs are identified in this study, entailing newfound opportunities to advance therapeutic development.
View details for DOI 10.1016/j.esmoop.2023.101627
View details for PubMedID 37703595
-
Software Application Profile: dynamicLM-a tool for performing dynamic risk prediction using a landmark supermodel for survival data under competing risks.
International journal of epidemiology
2023
Abstract
MOTIVATION: Providing a dynamic assessment of prognosis is essential for improved personalized medicine. The landmark model for survival data provides a potentially powerful solution to the dynamic prediction of disease progression. However, a general framework and a flexible implementation of the model that incorporates various outcomes, such as competing events, have been lacking. We present an R package, dynamicLM, a user-friendly tool for the landmark model for the dynamic prediction of survival data under competing risks, which includes various functions for data preparation, model development, prediction and evaluation of predictive performance.IMPLEMENTATION: dynamicLM as an R package.GENERAL FEATURES: The package includes options for incorporating time-varying covariates, capturing time-dependent effects of predictors and fitting a cause-specific landmark model for time-to-event data with or without competing risks. Tools for evaluating the prediction performance include time-dependent area under the ROC curve, Brier Score and calibration.AVAILABILITY: Available on GitHub [https://github.com/thehanlab/dynamicLM].
View details for DOI 10.1093/ije/dyad122
View details for PubMedID 37670428
-
Overall Survival Among Patients With De Novo Stage IV Metastatic and Distant Metastatic Recurrent Non-Small Cell Lung Cancer.
JAMA network open
2023; 6 (9): e2335813
Abstract
Despite recent breakthroughs in therapy, advanced lung cancer still poses a therapeutic challenge. The survival profile of patients with metastatic lung cancer remains poorly understood by metastatic disease type (ie, de novo stage IV vs distant recurrence).To evaluate the association of metastatic disease type on overall survival (OS) among patients with non-small cell lung cancer (NSCLC) and to identify potential mechanisms underlying any survival difference.Cohort study of a national US population based at a tertiary referral center in the San Francisco Bay Area using participant data from the National Lung Screening Trial (NLST) who were enrolled between 2002 and 2004 and followed up for up to 7 years as the primary cohort and patient data from Stanford Healthcare (SHC) for diagnoses between 2009 and 2019 and followed up for up to 13 years as the validation cohort. Participants from NLST with de novo metastatic or distant recurrent NSCLC diagnoses were included. Data were analyzed from January 2021 to March 2023.De novo stage IV vs distant recurrent metastatic disease.OS after diagnosis of metastatic disease.The NLST and SHC cohort consisted of 660 and 180 participants, respectively (411 men [62.3%] vs 109 men [60.6%], 602 White participants [91.2%] vs 111 White participants [61.7%], and mean [SD] age of 66.8 [5.5] vs 71.4 [7.9] years at metastasis, respectively). Patients with distant recurrence showed significantly better OS than patients with de novo metastasis (adjusted hazard ratio [aHR], 0.72; 95% CI, 0.60-0.87; P < .001) in NLST, which was replicated in SHC (aHR, 0.64; 95% CI, 0.43-0.96; P = .03). In SHC, patients with de novo metastasis more frequently progressed to the bone (63 patients with de novo metastasis [52.5%] vs 19 patients with distant recurrence [31.7%]) or pleura (40 patients with de novo metastasis [33.3%] vs 8 patients with distant recurrence [13.3%]) than patients with distant recurrence and were primarily detected through symptoms (102 patients [85.0%]) as compared with posttreatment surveillance (47 patients [78.3%]) in the latter. The main finding remained consistent after further adjusting for metastasis sites and detection methods.In this cohort study, patients with distant recurrent NSCLC had significantly better OS than those with de novo disease, and the latter group was associated with characteristics that may affect overall survival. This finding can help inform future clinical trial designs to ensure a balance for baseline patient characteristics.
View details for DOI 10.1001/jamanetworkopen.2023.35813
View details for PubMedID 37751203
-
The IASLC Early Lung Imaging Confederation (ELIC) Open-Source Deep Learning and Quantitative Measurement Initiative.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2023
Abstract
BACKGROUND: With global adoption of CT lung cancer screening, there is increasing interest to use artificial intelligence (AI) deep learning methods to improve the clinical management process. To enable AI research using an open source, cloud-based, globally distributed, screening CT imaging dataset and computational environment that are compliant with the most stringent international privacy regulations that also protects the intellectual properties of researchers, the International Association of the Study of Lung Cancer (IASLC) sponsored development of the Early Lung Imaging Confederation (ELIC) resource in 2018. The objective of this report is to describe the updated capabilities of ELIC and illustrate how this resource can be utilized for clinically relevant AI research.METHODS: In this second Phase of the initiative, metadata and screening CT scans from two time points were collected from 100 screening participants in seven countries. An automated deep learning AI lung segmentation algorithm, automated quantitative emphysema metrics, and a quantitative lung nodule volume measurement algorithm were run on these scans.RESULTS: A total of 1,394 CTs were collected from 697 participants. The LAV950 quantitative emphysema metric was found to be potentially useful in distinguishing lung cancer from benign cases using a combined slice thickness ≥ 2.5 mm. Lung nodule volume change measurements had better sensitivity and specificity for classifying malignant from benign lung nodules when applied to solid lung nodules from high quality CT scans.CONCLUSION: These initial experiments demonstrated that ELIC can support deep learning AI and quantitative imaging analyses on diverse and globally distributed cloud-based datasets.
View details for DOI 10.1016/j.jtho.2023.08.016
View details for PubMedID 37595684
-
Optimizing Lung Cancer Screening With Risk Prediction: Current Challenges and the Emerging Role of Biomarkers.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
2023: JCO2301060
Abstract
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.Lung cancer screening has been demonstrated to reduce lung cancer mortality, but its benefits must be weighed against the potential harms of unnecessary procedures, false-positive radiological findings, and overdiagnosis. Individuals at highest risk of lung cancer are more likely to maximize benefits while minimizing harm from screening. Although current lung cancer screening guidelines recommended by the US Preventive Services Task Force (USPSTF) only consider age and smoking history for screening eligibility, National Comprehensive Cancer Network and other society guidelines recommend screening on the basis of individualized risk assessment including family history, environmental exposures, and presence of chronic lung disease. Risk prediction models have been developed to integrate various risk factors into an individualized risk prediction score. Previous evidence showed that risk prediction model-based screening eligibility could improve sensitivity for detecting lung cancer cases without reducing specificity. Furthermore, recent advances in lung cancer biomarkers have enhanced the performance of risk prediction in identifying lung cancer cases relative to the USPSTF criteria. These risk prediction models can be used to guide shared decision-making discussions before proceeding with lung cancer screening. This study aims to provide a concise overview of these prediction models and the emerging role of biomarker testing in risk prediction to facilitate conversations with patients. The goal was to assist clinicians in assessing individual patient risk, leading to more informed decision making.
View details for DOI 10.1200/JCO.23.01060
View details for PubMedID 37540816
-
Early-Stage Lung Cancer: Using Circulating Tumor DNA to Get Personal.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
2023: JCO2300258
View details for DOI 10.1200/JCO.23.00258
View details for PubMedID 37352477
-
EGFR tyrosine kinase inhibitors (TKIs) versus durvalumab (durva) following concurrent chemoradiation (CRT) in unresectable EGFR-mutant non-small-cell lung cancer (NSCLC)
LIPPINCOTT WILLIAMS & WILKINS. 2023
View details for Web of Science ID 001053772003642
-
IMpower010: Exploratory analysis of disease-free survival by KRAS status in patients with stage II-IIIA NSCLC treated with adjuvant atezolizumab vs best supportive care
LIPPINCOTT WILLIAMS & WILKINS. 2023
View details for Web of Science ID 001053772003598
-
Predicting benefit from immune checkpoint inhibitors in patients with non-small-cell lung cancer by CT-based ensemble deep learning: a retrospective study.
The Lancet. Digital health
2023
Abstract
Only around 20-30% of patients with non-small-cell lung cancer (NCSLC) have durable benefit from immune-checkpoint inhibitors. Although tissue-based biomarkers (eg, PD-L1) are limited by suboptimal performance, tissue availability, and tumour heterogeneity, radiographic images might holistically capture the underlying cancer biology. We aimed to investigate the application of deep learning on chest CT scans to derive an imaging signature of response to immune checkpoint inhibitors and evaluate its added value in the clinical context.In this retrospective modelling study, 976 patients with metastatic, EGFR/ALK negative NSCLC treated with immune checkpoint inhibitors at MD Anderson and Stanford were enrolled from Jan 1, 2014, to Feb 29, 2020. We built and tested an ensemble deep learning model on pretreatment CTs (Deep-CT) to predict overall survival and progression-free survival after treatment with immune checkpoint inhibitors. We also evaluated the added predictive value of the Deep-CT model in the context of existing clinicopathological and radiological metrics.Our Deep-CT model demonstrated robust stratification of patient survival of the MD Anderson testing set, which was validated in the external Stanford set. The performance of the Deep-CT model remained significant on subgroup analyses stratified by PD-L1, histology, age, sex, and race. In univariate analysis, Deep-CT outperformed the conventional risk factors, including histology, smoking status, and PD-L1 expression, and remained an independent predictor after multivariate adjustment. Integrating the Deep-CT model with conventional risk factors demonstrated significantly improved prediction performance, with overall survival C-index increases from 0·70 (clinical model) to 0·75 (composite model) during testing. On the other hand, the deep learning risk scores correlated with some radiomics features, but radiomics alone could not reach the performance level of deep learning, indicating that the deep learning model effectively captured additional imaging patterns beyond known radiomics features.This proof-of-concept study shows that automated profiling of radiographic scans through deep learning can provide orthogonal information independent of existing clinicopathological biomarkers, bringing the goal of precision immunotherapy for patients with NSCLC closer.National Institutes of Health, Mark Foundation Damon Runyon Foundation Physician Scientist Award, MD Anderson Strategic Initiative Development Program, MD Anderson Lung Moon Shot Program, Andrea Mugnaini, and Edward L C Smith.
View details for DOI 10.1016/S2589-7500(23)00082-1
View details for PubMedID 37268451
-
Phase II Randomized Trial of Carboplatin, Pemetrexed, and Bevacizumab With and Without Atezolizumab in Stage IV Nonsquamous Non-Small-Cell Lung Cancer Patients Who Harbor a Sensitizing EGFR Mutation or Have Never Smoked.
Clinical lung cancer
2023
Abstract
INTRODUCTION: Patients with non-small-cell lung cancer (NSCLC) who have never smoked or have tumors with mutations in EGFR generally derive minimal benefit from single-agent PD-1/PD-L1 checkpoint inhibitors. Prior data indicate that adding PD-L1 inhibition to anti-VEGF and cytotoxic chemotherapy may be a promising approach to overcoming immunotherapy resistance in these patients, however prospective validation is needed. This trial in progress (NCT03786692) is evaluating patients with stage IV NSCLC who have never smoked or who have tumors with sensitizing EGFR alterations to determine if a 4-drug combination of atezolizumab, carboplatin, pemetrexed, and bevacizumab can improve outcomes compared to carboplatin, pemetrexed and bevacizumab without atezolizumab.METHODS: This is a randomized, phase II, multicenter study evaluating carboplatin, pemetrexed, bevacizumab with and without atezolizumab in 117 patients with stage IV nonsquamous NSCLC. Randomization is 2 to 1 favoring the atezolizumab containing arm. Eligible patients include: 1) those with tumors with sensitizing EGFR alterations in exons 19 or 21 or 2) patients who have never smoked and have wild-type tumors (ie, no EGFR, ALK or ROS1 alterations). Patients are defined as having never smoked if they have smoked less than 100 cigarettes in a lifetime. Patients with EGFR-mutated tumors must have disease progression or intolerance to prior tyrosine kinase inhibitor (TKI) therapy. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), response rate, duration of response, and time to response.CONCLUSION: This phase II trial is accruing patients at U.S. sites through the National Comprehensive Cancer Network (NCCN). The trial opened in August 2019 and accrual is expected to be completed in the Fall of 2024.
View details for DOI 10.1016/j.cllc.2023.05.003
View details for PubMedID 37451930
-
Pulmonary Hemorrhage in Patients Treated with Thoracic Stereotactic Ablative Radiotherapy and Anti-Angiogenic Agents.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2023
Abstract
Severe pulmonary hemorrhage can occur in patients treated with thoracic stereotactic ablative radiotherapy (SABR) and vascular endothelial growth factor inhibitors (VEGFi). There is limited understanding of which patients are at risk for toxicity with the combination of thoracic SABR and VEGFis or how the risk differs over either therapy alone.We evaluated a prospectively maintained cohort of 690 patients with 818 pulmonary tumors treated with highly conformal SABR. Rates of any grade and grade-three-plus (G3+) pulmonary hemorrhage were compared between patients treated with or without VEGFi therapy across tumor locations. Outcomes were compared between patients treated with SABR + VEGFi and a propensity-matched cohort of those treated with VEGFi therapy alone.Treatment with VEGFi + SABR was associated with higher rates of G3+ pulmonary hemorrhage compared to those treated with SABR alone for the overall cohort (3-year incidence: 7.9% vs 0.6%, p<0.01) and those with central tumors (19.1% vs 3.3%, p=0.04). When further subdivided, there were significantly higher toxicity rates with VEGFi for the ultracentral (9.0% vs 45.0%, p = 0.044), but not central non-abutting tumors (0.0% vs 1.3% p = 0.69). There was an increased incidence of G3+ hemorrhage in patients treated with VEGFi + SABR compared to VEGFi alone (9.6 vs 1.3%, p=0.04).The combination of VEGFi and SABR was associated with an increased risk of high-grade pulmonary hemorrhage over either therapy alone. Low rates of toxicity were observed when excluding patients with SABR to ultracentral tumors and applying highly conformal SABR techniques.
View details for DOI 10.1016/j.jtho.2023.04.007
View details for PubMedID 37085030
-
Co-mutations and KRAS G12C inhibitor efficacy in advanced NSCLC.
Cancer discovery
2023
Abstract
Molecular modifiers of KRAS G12C inhibitor (KRAS G12Ci) efficacy in advanced KRAS G12C-mutant NSCLC are poorly defined. In a large unbiased clinico-genomic analysis of 424 NSCLC patients, we identified and validated co-alterations in KEAP1, SMARCA4 and CDKN2A as major independent determinants of inferior clinical outcomes with KRAS G12Ci monotherapy. Collectively, co-mutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ~50% of those with early disease progression (PFS≤3 months) with KRAS G12Ci. Pathway-level integration of less prevalent co-alterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRAS G12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRAS G12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRAS G12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies.
View details for DOI 10.1158/2159-8290.CD-22-1420
View details for PubMedID 37068173
-
Brief Report: High Levels of CD47 Expression in Thymic Epithelial Tumors.
JTO clinical and research reports
2023; 4 (4): 100498
Abstract
CD47 is a tumor antigen that inhibits phagocytosis leading to immune evasion. Anti-CD47 therapy is a promising new immunotherapy across numerous tumor types, but it has not been tested in thymic epithelial tumors (TETs): thymomas and thymic carcinomas. TETs are rare tumors that are difficult to treat, especially with programmed cell death protein 1/programmed death-ligand 1 checkpoint inhibitors, owing to the excessive rates of immune-related adverse events. This study investigated the levels of CD47 expression in TETs to explore the possibility of anti-CD47 therapy.A total of 67 thymic tumors (63 thymomas and 4 thymic carcinomas) and 14 benign thymus controls and their clinical data were included. Samples were stained for CD47 expression (rabbit monoclonal antibody SP279, Abcam, Waltham, MA) and scored for both intensity and H-score (intensity multiplied by the percentage of tumor involved). Intensity was defined as follows: 0 = none, 1 = weak, 2 = moderate, and 3 = strong. H-scores ranged from 0 to 300. Samples with an intensity score below 2 or an H-score below 150 were considered CD47low, whereas the rest were CD47high.Compared with normal thymic tissues, TETs were more frequently CD47 positive and had significantly higher levels of CD47 expression. CD47 was positive in 79.1% of TETs compared with 57.1% of normal thymus. The level of CD47 expression was 16-fold higher in TETs (mean H-score 75.0 versus 4.6, p = 0.003). Multivariate analysis adjusted for age, sex, stage, resection status, and performance status revealed that CD47-high tumors were highly correlated with WHO histology type (p = 0.028). The most frequent CD47high tumors, in contrast to CD47low tumors, were types A (28.6% versus 7.5%) and AB (57.1% versus 13.2%), and the least frequent were B1 (7.1% versus 24.5%), B2 (0% versus 35.8%), B3 (7.1% versus 11.3%), and C (0% versus 7.5%).In contrast to normal thymus, TETs had significantly higher levels of CD47 expression. Tumor samples with high CD47 expression were mostly WHO types A and AB. This is the first study to explore CD47 expression in thymic cancers and lends support for ongoing investigation of anti-CD47 macrophage checkpoint inhibitor therapy in these tumors.
View details for DOI 10.1016/j.jtocrr.2023.100498
View details for PubMedID 37020927
View details for PubMedCentralID PMC10067933
-
Real-world risk of brain metastases in stage III non-small cell lung cancer in the era of PET and MRI staging.
Frontiers in oncology
2023; 13: 1139940
Abstract
The 2-year incidence of brain metastases (BrMs) in stage III non-small lung cell cancer (NSCLC) has been estimated to be around 30%. However, recent clinical trials have demonstrated considerably lower BrMs rates in this patient population. In this study, we aimed to review the real-world incidence, surveillance, and treatment patterns of BrMs in stage III NSCLC.Using a retrospective single-center study design, we identified patients with stage III NSCLC who received radiation with curative intent over a 10-year period. Outcome variables included BrMs incidence, overall survival (OS), and survival from date of BrMs. Additionally, we assessed patterns of BrMs surveillance in stage III NSCLC and treatment.We identified a total of 279 stage III NSCLC patients, of which 160 with adequate records were included in the final analyses [adenocarcinoma (n = 96), squamous cell carcinoma (n = 53), other histology subtype (n = 11)]. The median OS for the entire cohort was 41 months (95% CI, 28-53), while the median time from BrMs to death was 19 months (95% CI, 9-21). Twenty-three patients (14.4%) received planned surveillance brain MRIs at 6, 12, and 24 months after completion of treatment. The remaining 137 patients (85.6%) received brain MRIs at systemic recurrence (restaging) or when neurologically symptomatic. A total of 37 patients (23%) developed BrMs, with a 2-year cumulative BrMs incidence of 17% (95% CI, 11-23). A higher incidence of BrMs was identified in patients with adenocarcinoma relative to those with squamous cell carcinoma (p < 0.01). Similarly, a higher 2-year BrMs incidence was observed in patients who received planned surveillance brain MRI relative to those who did not, although statistical significance was not reached. Stereotactic radiosurgery (SRS) treated 29 of BrMs patients (78.4%) and was preferred over WBRT, which treated only 3 patients (8.1%).At our center, BrMs incidence in stage III NSCLC patients was lower than historically reported but notably higher than the incidence described in recent clinical trials. Routine BrMs surveillance potentially allows earlier detection of asymptomatic BrMs. However, asymptomatic BrMs were mostly detected on restaging MRI at the time of recurrence.
View details for DOI 10.3389/fonc.2023.1139940
View details for PubMedID 37035171
View details for PubMedCentralID PMC10080021
-
Osimertinib in NSCLC With Atypical EGFR-Activating Mutations: A Retrospective Multicenter Study.
JTO clinical and research reports
2023; 4 (3): 100459
Abstract
Introduction: EGFR mutations drive a subset of NSCLC. Patients harboring the common EGFR mutations, deletion ofexon 19 and L858R, respond well to osimertinib, a third-generation tyrosine kinase inhibitor. Nevertheless, the effect of osimertinib on NSCLC with atypical EGFR mutations is not well described. This multicenter retrospective study evaluates the efficacy of osimertinib among patients with NSCLC harboring atypical EGFR mutations.Methods: Patients with metastatic NSCLC treated with osimertinib, harboring at least one atypical EGFR mutation, excluding concurrent deletion of exon 19, L858R, or T790M mutations, from six U.S. academic cancer centers were included. Baseline clinical characteristics were collected. The primary end point was the time to treatment discontinuation (TTD) of osimertinib. Objective response rate by the Response Evaluation Criteria in Solid Tumors version 1.1 was also assessed.Results: A total of 50 patients with NSCLC with uncommon EGFR mutations were identified. The most frequent EGFR mutations were L861Q (40%, n= 18), G719X (28%, n= 14), and exon 20 insertion (14%, n= 7). The median TTD of osimertinib was 9.7 months (95% confidence interval [CI]: 6.5-12.9 mo) overall and 10.7 months (95% CI: 3.2-18.1 mo) in the first-line setting (n= 20). The objective response rate was 31.7% (95% CI: 18.1%-48.1%) overall and 41.2% (95% CI: 18.4%-67.1%) in the first-line setting. The median TTD varied among patients with L861Q (17.2 mo), G719X (7.8 mo), and exon 20 insertion (1.5 mo) mutations.Conclusions: Osimertinib has activity in patients with NSCLC harboring atypical EGFR mutations. Osimertinib activity differs by the type of atypical EGFR-activating mutation.
View details for DOI 10.1016/j.jtocrr.2022.100459
View details for PubMedID 36879929
-
Second Primary Lung Cancer among Lung Cancer Survivors Who Never Smoked
ELSEVIER SCIENCE INC. 2023: E1
View details for Web of Science ID 000989330100001
-
A hybrid modelling approach for abstracting CT imaging indications by integrating natural language processing from radiology reports with structured data from electronic health records.
AMER ASSOC CANCER RESEARCH. 2023
View details for Web of Science ID 001057852300077
-
Risk factors for second primary lung cancer among breast cancer survivors
AMER ASSOC CANCER RESEARCH. 2023
View details for Web of Science ID 001057852300067
-
Use of Machine Learning and Lay Care Coaches to Increase Advance Care Planning Conversations for Patients With Metastatic Cancer.
JCO oncology practice
2022: OP2200128
Abstract
Patients with metastatic cancer benefit from advance care planning (ACP) conversations. We aimed to improve ACP using a computer model to select high-risk patients, with shorter predicted survival, for conversations with providers and lay care coaches. Outcomes included ACP documentation frequency and end-of-life quality measures.In this study of a quality improvement initiative, providers in four medical oncology clinics received Serious Illness Care Program training. Two clinics (thoracic/genitourinary) participated in an intervention, and two (cutaneous/sarcoma) served as controls. ACP conversations were documented in a centralized form in the electronic medical record. In the intervention, providers and care coaches received weekly e-mails highlighting upcoming clinic patients with < 2 year computer-predicted survival and no prior prognosis documentation. Care coaches contacted these patients for an ACP conversation (excluding prognosis). Providers were asked to discuss and document prognosis.In the four clinics, 4,968 clinic visits by 1,251 patients met inclusion criteria (metastatic cancer with no prognosis previously documented). In their first visit, 28% of patients were high-risk (< 2 year predicted survival). Preintervention, 3% of both intervention and control clinic patients had ACP documentation during a visit. By intervention end (February 2021), 35% of intervention clinic patients had ACP documentation compared with 3% of control clinic patients. Providers' prognosis documentation rate also increased in intervention clinics after the intervention (2%-27% in intervention clinics, P < .0001; 0%-1% in control clinics). End-of-life care intensity was similar in intervention versus control clinics, but patients with ≥ 1 provider ACP edit met fewer high-intensity care measures (P = .04).Combining a computer prognosis model with care coaches increased ACP documentation.
View details for DOI 10.1200/OP.22.00128
View details for PubMedID 36395436
-
Induction EGFR tyrosine kinase inhibitors prior to definitive chemoradiotherapy in unresectable stage III EGFR-mutated non-small cell lung cancer.
Cancer treatment and research communications
2022; 33: 100659
Abstract
INTRODUCTION: Increasing evidence suggests that consolidation durvalumab confers limited benefits for patients with stage III EGFR-mutated NSCLC. Induction or maintenance EGFR tyrosine kinase inhibitors (TKIs) added to concurrent chemoradiotherapy (CRT) may optimize definitive treatment, but there are limited data supporting an induction TKI strategy.METHODS: We evaluated the efficacy and safety of induction EGFR TKIs administered before concurrent CRT in a retrospective series of patients with unresectable locally advanced EGFR-mutated NSCLC. Circulating tumor DNA (ctDNA) analysis was performed on a patient subset using CAPP-seq and correlated with outcomes.RESULTS: Of six patients, three received erlotinib and three osimertinib as induction therapy before CRT. Induction TKIs were administered for a median of 2.5 months. The objective response rate after induction TKI was 83%. One patient had a complete response to induction erlotinib and continued erlotinib for 4 years until local progression, which was treated with CRT. Two patients completed maintenance erlotinib after CRT, and another received consolidation durvalumab. After a median follow-up of 20.5 months, only one patient developed disease recurrence, with rising ctDNA coinciding with recurrence. ctDNA remained undetectable in patients without recurrence, or low-level in a patient receiving maintenance erlotinib. Adverse events were mild and expected, and none developed pneumonitis.CONCLUSION: Induction EGFR TKI before CRT may achieve high disease control rates with promising signs of durability in patients with locally advanced EGFR-mutated NSCLC. ctDNA analysis after CRT can correlate well with clinical outcomes. Prospective studies are needed to define the role of induction EGFR TKIs in this setting.
View details for DOI 10.1016/j.ctarc.2022.100659
View details for PubMedID 36427429
-
Atezolizumab (atezo) vs best supportive care (BSC) in stage II-IIIA NSCLC with high PD-L1 expression: sub-analysis from the pivotal phase III IMpower010 study
KARGER. 2022: 146-147
View details for Web of Science ID 000883051700343
-
Local Control of Brain Metastases with Osimertinib Alone in Patients with EGFR-Mutant Non-Small Cell Lung Cancer
ELSEVIER SCIENCE INC. 2022: E54-E55
View details for Web of Science ID 000892639300120
-
Local control of brain metastases with osimertinib alone in patients with EGFR-mutant non-small cell lung cancer.
Journal of neuro-oncology
2022
Abstract
Although osimertinib has excellent intracranial activity in metastatic non-small cell lung cancer (NSCLC) with exon 19 deletion or L858R EGFR alterations, measures of local control of brain metastases are less well-reported. We describe lesion-level outcomes of brain metastases treated with osimertinib alone.We retrospectively reviewed patients with EGFR-mutant NSCLC with untreated brain metastasis measuring ≥ 5 mm at the time of initiating osimertinib. Cumulative incidence of local recurrence in brain (LRiB) was calculated with death as a competing risk, and univariable and multivariable analyses were conducted to identify factors associated with LRiB.We included 284 brain metastases from 37 patients. Median follow-up was 20.1 months. On initial MRI after starting osimertinib, patient-level response was complete response (CR) in 11 (15%), partial response (PR) in 33 (45%), stable disease (SD) in 18 (25%) and progressive disease (PD) in 11 (15%). The 1-year cumulative incidence of LRiB was 14% (95% CI 9.9-17.9) and was significantly different in patients with a CR (0%), PR (4%), and SD (11%; p = 0.02). Uncontrolled primary tumor (adjusted hazard ratio [aHR] 3.78, 95% CI 1.87-7.66; p < 0.001), increasing number of prior systemic therapies (aHR 2.12, 95% CI 1.49-3.04; p < 0.001), and higher ECOG score (aHR 7.8, 95% CI 1.99-31.81; p = 0.003) were associated with LRiB.Although 1-year cumulative incidence of LRiB is < 4% with a CR or PR, 1-year cumulative incidence of LRiB is over 10% for patients with less than a PR to osimertinib on initial MRI. These patients should be followed closely for need for additional treatment such as stereotactic radiosurgery.
View details for DOI 10.1007/s11060-022-04145-x
View details for PubMedID 36227422
-
Racial diversity and reporting in United States Food and Drug Administration registration trials for thoracic malignancies from 2006-2020.
Cancer investigation
2022: 1-6
Abstract
There is significant racial disparity in thoracic malignancies in terms of epidemiology and outcomes. We analyzed race reporting and racial diversity in the registration trials of drugs approved by the FDA for thoracic malignancies from 2006-2020. We found a significant under-representation of non-white participants in FDA drug registration trials in thoracic malignancies. Furthermore, though almost all trials report some race information, FDA guidelines are not universally followed. There is a disproportionate disease burden of lung cancer in under-represented race communities, and clinical trials should prioritize racial diversity and inclusion efforts.
View details for DOI 10.1080/07357907.2022.2131808
View details for PubMedID 36197034
-
Predictive Model to Guide Brain Magnetic Resonance Imaging Surveillance in Patients With Metastatic Lung Cancer: Impact on Real-World Outcomes.
JCO precision oncology
2022; 6: e2200220
Abstract
Brain metastasis is common in lung cancer, and treatment of brain metastasis can lead to significant morbidity. Although early detection of brain metastasis may improve outcomes, there are no prediction models to identify high-risk patients for brain magnetic resonance imaging (MRI) surveillance. Our goal is to develop a machine learning-based clinicogenomic prediction model to estimate patient-level brain metastasis risk.A penalized regression competing risk model was developed using 330 patients diagnosed with lung cancer between January 2014 and June 2019 and followed through June 2021 at Stanford HealthCare. The main outcome was time from the diagnosis of distant metastatic disease to the development of brain metastasis, death, or censoring.Among the 330 patients, 84 (25%) developed brain metastasis over 627 person-years, with a 1-year cumulative brain metastasis incidence of 10.2% (95% CI, 6.8 to 13.6). Features selected for model inclusion were histology, cancer stage, age at diagnosis, primary site, and RB1 and ALK alterations. The prediction model yielded high discrimination (area under the curve 0.75). When the cohort was stratified by risk using a 1-year risk threshold of > 14.2% (85th percentile), the high-risk group had increased 1-year cumulative incidence of brain metastasis versus the low-risk group (30.8% v 6.1%, P < .01). Of 48 high-risk patients, 24 developed brain metastasis, and of these, 12 patients had brain metastasis detected more than 7 months after last brain MRI. Patients who missed this 7-month window had larger brain metastases (58% v 33% largest diameter > 10 mm; odds ratio, 2.80, CI, 0.51 to 13) versus those who had MRIs more frequently.The proposed model can identify high-risk patients, who may benefit from more intensive brain MRI surveillance to reduce morbidity of subsequent treatment through early detection.
View details for DOI 10.1200/PO.22.00220
View details for PubMedID 36201713
-
High Levels of CD47 Expression in Thymic Epithelial Tumors
ELSEVIER SCIENCE INC. 2022: S79
View details for Web of Science ID 000858678100122
-
IMpower010:Overall Survival Interim Analysis of a Phase III Study of Atezolizumab vs Best Supportive Care in Resected NSCLC
ELSEVIER SCIENCE INC. 2022: S2
View details for Web of Science ID 000858678100004
-
Phenotyping Malignant Pleural Effusions with Mass Cytometry: Evidence of EMT and MET States in Late-Stage NSCLC
ELSEVIER SCIENCE INC. 2022: S577-S578
View details for Web of Science ID 000858678101493
-
Resistance to EGFR Tyrosine Kinase Inhibitor Therapy in Non-Small-Cell Lung Cancer via Newly Acquired Targetable Oncogenic Driver Alterations With an Emphasis on BRAF: Case Series and Literature Review of Treatment.
JCO precision oncology
2022; 6: e2100551
View details for DOI 10.1200/PO.21.00551
View details for PubMedID 35952324
-
Isolated Nodal Recurrence After Definitive Stereotactic Ablative Radiotherapy for Non-Small Cell Lung Cancer.
Practical radiation oncology
2022
Abstract
Stereotactic ablative radiotherapy (SABR) results in high rates of primary tumor control for early-stage non-small cell lung cancer (NSCLC). For patients with isolated hilar or mediastinal nodal recurrences (INR) after SABR, the optimal salvage treatment strategy is unclear. The purpose of this study is to determine the rate of INR after SABR for early-stage NSCLC and to describe patterns of care and treatment outcomes after salvage therapy.This retrospective cohort study included 342 patients with Stage T1-3N0M0 NSCLC treated with definitive SABR from 2003-2018. We evaluated the incidence of INR and baseline factors between patients who did and did not experience INR. Among patients who experienced INR, we described treatment patterns and outcomes including overall (OS) and progression free survival (PFS) from the time of nodal failure using the Kaplan-Meier method.With a median follow-up of 3.3 years, the 3-year INR rate was 10.6% (6.6% -13.4%). Among the 34 patients experiencing INR, the 3-year rates of OS and PFS were 39.3% (24.4 - 63.3%) and 26.7% (14.1 - 50.3%), respectively. The 34 patients with INR were treated with RT alone (26.7 %), concurrent chemoradiotherapy (CRT) (43.3 %), chemotherapy alone (13.3%), or observation (16.7%). CRT had the best survival outcomes with a 3-year OS and PFS of 81.5% (61.1 - 100.0%) and 63.9% (40.7 - 100.0%), respectively. Of the patients treated with salvage RT or CRT, 14.3% experienced grade 3 toxicity with no patients having grade 4+ toxicity.INR occurred in approximately 10% of patients treated with SABR for early-stage NSCLC. The highest rates of OS an PFS among patients with INR were observed in those treated with salvage chemoradiotherapy.
View details for DOI 10.1016/j.prro.2022.06.013
View details for PubMedID 35858658
-
A brief report on the mutational landscape in non-small cell lung cancer of South Asian patients: Comparison at a US and an Indian Institution.
Lung India : official organ of Indian Chest Society
2022; 39 (4): 315-318
Abstract
Background: Various molecular underpinnings of lung cancer have been noted in Asian populations, especially with targetable oncogenic drivers such as EGFR mutations and ALK rearrangements, although they have been lesser described in South Asian/Indian patients.Methods: Tumour molecular testing results from non-small cell lung cancer (NSCLC) patients with a name of South Asian origin and diagnosed from 2005 to 2019 at the Stanford Cancer Center in the United States were retrospectively reviewed and compared to the results of molecular testing from PGIMER in Chandigarh, India, from the patients diagnosed from 2011 to 2019.Results: We identified 72 patients of South Asian (largely Indian) origin, of whom 64 patients (51% female) had mutational testing at Stanford. Of the tested patients, 33% of cases harboured either an EGFR exon 19 deletion or exon 21 L858R mutation, and 12.5% had ALK rearrangements. At PGIMER, a larger sample of 1,264 patients was identified (33% female), with 22.5% of patients having two main EGFR activating mutations, and 9.5% harbouring an ALK rearrangement.Conclusions: South Asian, largely Indian, patients with NSCLC appear to have a higher chance of harbouring EGFR mutations and ALK translocation as compared to Caucasians. The percentage of South Asian patients with these molecular abnormalities was largely similar in two different geographical locations. These findings corroborate prior single-institution findings and emphasise the importance of molecular testing.
View details for DOI 10.4103/lungindia.lungindia_428_21
View details for PubMedID 35848661
-
IMpower010: results from Asian patients in a phase 3 study of adjuvant atezolizumab in resected stage IB-IIIA NSCLC
ELSEVIER. 2022: S464
View details for DOI 10.1016/j.annonc.2022.05.063
View details for Web of Science ID 000834940400148
-
Identification of Pathogenic Immune Cell Subsets Associated With Checkpoint Inhibitor-Induced Myocarditis.
Circulation
2022: 101161CIRCULATIONAHA121056730
Abstract
Immune checkpoint inhibitors (ICIs) are monoclonal antibodies used to activate the immune system against tumor cells. Despite therapeutic benefits, ICIs have the potential to cause immune-related adverse events such as myocarditis, a rare but serious side effect with up to 50% mortality in affected patients. Histologically, patients with ICI myocarditis have lymphocytic infiltrates in the heart, implicating T cell-mediated mechanisms. However, the precise pathological immune subsets and molecular changes in ICI myocarditis are unknown.To identify immune subset(s) associated with ICI myocarditis, we performed time-of-flight mass cytometry on peripheral blood mononuclear cells from 52 individuals: 29 patients with autoimmune adverse events (immune-related adverse events) on ICI, including 8 patients with ICI myocarditis, and 23 healthy control subjects. We also used multiomics single-cell technology to immunophenotype 30 patients/control subjects using single-cell RNA sequencing, single-cell T-cell receptor sequencing, and cellular indexing of transcriptomes and epitopes by sequencing with feature barcoding for surface marker expression confirmation. To correlate between the blood and the heart, we performed single-cell RNA sequencing/T-cell receptor sequencing/cellular indexing of transcriptomes and epitopes by sequencing on MRL/Pdcd1-/- (Murphy Roths large/programmed death-1-deficient) mice with spontaneous myocarditis.Using these complementary approaches, we found an expansion of cytotoxic CD8+ T effector cells re-expressing CD45RA (Temra CD8+ cells) in patients with ICI myocarditis compared with control subjects. T-cell receptor sequencing demonstrated that these CD8+ Temra cells were clonally expanded in patients with myocarditis compared with control subjects. Transcriptomic analysis of these Temra CD8+ clones confirmed a highly activated and cytotoxic phenotype. Longitudinal study demonstrated progression of these Temra CD8+ cells into an exhausted phenotype 2 months after treatment with glucocorticoids. Differential expression analysis demonstrated elevated expression levels of proinflammatory chemokines (CCL5/CCL4/CCL4L2) in the clonally expanded Temra CD8+ cells, and ligand receptor analysis demonstrated their interactions with innate immune cells, including monocytes/macrophages, dendritic cells, and neutrophils, as well as the absence of key anti-inflammatory signals. To complement the human study, we performed single-cell RNA sequencing/T-cell receptor sequencing/cellular indexing of transcriptomes and epitopes by sequencing in Pdcd1-/- mice with spontaneous myocarditis and found analogous expansions of cytotoxic clonal effector CD8+ cells in both blood and hearts of such mice compared with controls.Clonal cytotoxic Temra CD8+ cells are significantly increased in the blood of patients with ICI myocarditis, corresponding to an analogous increase in effector cytotoxic CD8+ cells in the blood/hearts of Pdcd1-/- mice with myocarditis. These expanded effector CD8+ cells have unique transcriptional changes, including upregulation of chemokines CCL5/CCL4/CCL4L2, which may serve as attractive diagnostic/therapeutic targets for reducing life-threatening cardiac immune-related adverse events in ICI-treated patients with cancer.
View details for DOI 10.1161/CIRCULATIONAHA.121.056730
View details for PubMedID 35762356
-
Long term effect of radiotherapy on risk of second primary lung cancer and overall mortality among lung cancer patients
AMER ASSOC CANCER RESEARCH. 2022
View details for Web of Science ID 000892509507119
-
Characterization of ERBB2 (HER2) Alterations in Metastatic Non-small Cell Lung Cancer and Comparison of Outcomes of Different Trastuzumab-based Regimens.
Clinical lung cancer
2022
Abstract
About 3%-5% of mNSCLC have ERBB2 (HER2) alterations, but currently, there are no FDA-approved targeted therapies for this indication. We compared treatment response between trastuzumab-based and non-targeted regimens in ERBB2-mutant mNSCLC.This retrospective, single-institution study included patients with mNSCLC with ERBB2 alterations identified by next-generation sequencing. Best overall response was determined using Response Evaluation Criteria in Solid Tumors 1.1.We identified 3 groups of patients: ERBB2-mutant/EGFR-wildtype mNSCLC (n = 33), ERBB2-amplified/EGFR-wildtype mNSCLC without concurrent ERBB2 mutations (n = 6), and ERBB2-altered/EGFR-mutant mNSCLC (n = 8). Observed mutations included A775_G776insYVMA (n = 23), Gly778_Pro780dup (n = 4), Ser310Phe (n = 3), and others (n = 5). Among the 33 with ERBB2-mutant/EGFR-wildtype mNSCLC, those with and without A775_G776insYVMA had significantly different median overall survival (OS) of 17.7 and 52.9 months, respectively (Cox regression multivariable HR: 5.03, 95% CI: 1.37-18.51, P = .02). In those with mNSCLC with A775_G776insYVMA, trastuzumab-based therapies were associated with greater OS (20.3 vs. 9.8 months; multivariable HR: 0.19, 95% CI: 0.04-0.87, P = .032). Objective response and disease control rates (median tumor size change) in the 33 patients with ERBB2-mutant/EGFR-wildtype mNSCLC were 40.0% and 80.0% (-35.8%), respectively, for patients treated with trastuzumab deruxtecan; 0% and 30.0% (-5.2%) for trastuzumab emtansine; and 7.1% and 50.0% (-13.0%) for trastuzumab/chemotherapy combinations.In ERBB2-mutant/EGFR-wildtype mNSCLC, while most trastuzumab-based regimens had modest activity in this real-world analysis, trastuzumab deruxtecan had highest response rates and best tumor size reduction. Receipt of any trastuzumab-based regimen was associated with greater OS with A775_G776insYVMA. There remains an unmet need for approved targeted therapies for ERBB2-mutant/EGFR-wildtype NSCLC.
View details for DOI 10.1016/j.cllc.2022.05.015
View details for PubMedID 35753988
-
High-Dose Osimertinib for CNS Progression in EGFR+ NSCLC: A Multi-Institutional Experience.
JTO clinical and research reports
2022; 3 (6): 100328
Abstract
This multicenter review evaluated the efficacy and safety of osimertinib dose escalation for central nervous system (CNS) progression developing on osimertinib 80 mg in EGFR-mutant NSCLC.Retrospective review identified 105 patients from eight institutions with advanced EGFR-mutant NSCLC treated with osimertinib 160 mg daily between October 2013 and January 2020. Radiographic responses were clinically assessed, and Kaplan-Meier analyses were used. We defined CNS disease control as the interval from osimertinib 160 mg initiation to CNS progression or discontinuation of osimertinib 160 mg.Among 105 patients treated with osimertinib 160 mg, 69 were escalated for CNS progression, including 24 treated with dose escalation alone (cohort A), 34 who received dose-escalated osimertinib plus concurrent chemotherapy and/or radiation (cohort B), and 11 who received osimertinib 160 mg without any prior 80 mg exposure. The median duration of CNS control was 3.8 months (95% confidence interval [CI], 1.7-5.8) in cohort A, 5.1 months (95% CI, 3.1-6.5) in cohort B, and 4.2 months (95% CI 1.6-not reached) in cohort C. Across all cohorts, the median duration of CNS control was 6.0 months (95% CI, 5.1-9.0) in isolated leptomeningeal progression (n = 27) and 3.3 months (95% CI, 1.0-3.1) among those with parenchymal-only metastases (n = 23). Patients on osimertinib 160 mg experienced no severe or unexpected side effects.Among patients with EGFR-mutant NSCLC experiencing CNS progression on osimertinib 80 mg daily, dose escalation to 160 mg provided modest benefit with CNS control lasting approximately 3 to 6 months and seemed more effective in patients with isolated leptomeningeal CNS progression.
View details for DOI 10.1016/j.jtocrr.2022.100328
View details for PubMedID 35637759
View details for PubMedCentralID PMC9142556
-
Osimertinib plus necitumumab in EGFR-mutant NSCLC: Final results from an ETCTN California Cancer Consortium phase I study.
LIPPINCOTT WILLIAMS & WILKINS. 2022
View details for Web of Science ID 000863680302204
-
Genomic characterization of thymic epithelial tumor from real-world data.
LIPPINCOTT WILLIAMS & WILKINS. 2022
View details for Web of Science ID 000863680302188
-
Ancestry-based differences in gene alterations in non-small cell lung cancer: Realworld data using genetic ancestry analysis.
LIPPINCOTT WILLIAMS & WILKINS. 2022
View details for Web of Science ID 000863680302310
-
CD47 expression patterns in thymic epithelial tumors.
LIPPINCOTT WILLIAMS & WILKINS. 2022
View details for Web of Science ID 000863680302187
-
Characterization of Metastatic Non-Small Cell Lung Cancer and Oligometastatic Incidence in an Era of Changing Treatment Paradigms.
International journal of radiation oncology, biology, physics
2022
Abstract
Due to the limitations of current staging systems and evolving definitions, there are limited data on oligometastatic non-small cell lung cancer (NSCLC) epidemiology. The purpose of this study is to evaluate metastatic disease burden and the incidence of oligometastatic disease using recent clinical trial edibility criteria.A cohort of patients with metastatic NSCLC, diagnosed from 2016 to 2019, were randomly sampled from a curated tumor registry. Definitions for oligometastatic disease were obtained from relevant clinical trials. The Stanford Cancer Institute Research Database (SCIRDB) was used to identify baseline patient factors, systemic and local therapy, extent and location of metastatic lesions, and survival outcomes.Among 120 patients presenting with metastatic NSCLC, the majority had de novo metastatic disease (75%) with a median of 4 metastatic lesions involving 3 organ systems. 37.5% would have been eligible for at least one oligometastatic trial with 28.3% meeting criteria for MDACC, 20.0% for NRG-LU002, 6.7% for SINDAS and 16.7% for SABR-COMET. By adding malignant pleural effusions (MPE) and early progression as exclusionary criteria, only 54.1% of patients with ≤3 synchronous metastases were eligible for consideration of local therapy. Early progression on systemic therapy was associated with worse survival (10.0 vs. 42.4 months, p < 0.001), whereas presence of MPE was not. Of those tumors identified as oligometastatic, 44.4% received local therapy and 28.9% underwent ablative therapy to all sites. There was a trend towards greater overall survival (44.4 vs 24.9 months, p=0.055) and progression free survival (8.0 vs. 5.4 months, p=0.06) in patients meeting eligibility for at least one oligometastatic trial.Around 48% of patients with metastatic NSCLC had ≤3 metastases at presentation and 28% met clinical trial criteria for oligometastatic disease. Future research is needed to better define the oligometastatic state and identify patients most likely to benefit from local therapy.
View details for DOI 10.1016/j.ijrobp.2022.04.050
View details for PubMedID 35654305
-
COVID-19 Outcomes, Patient Vaccination Status, and Cancer-Related Delays during the Omicron Wave: A Brief Report from the TERAVOLT Analysis.
JTO clinical and research reports
2022: 100335
Abstract
The Thoracic Centers International COVID-19 Collaboration (TERAVOLT) registry found ∼ 30% mortality in patients with thoracic malignancies during the initial COVID surges. Data from South Africa suggested a decrease in severity and mortality with the Omicron wave. Our objective was to assess mortality of patients with thoracic malignancies with the Omicron-predominant wave, and efficacy of vaccination.A prospective, multicenter observational study was conducted. Twenty-eight institutions contributed data from January 14, 2022 through February 4, 2022. Inclusion criteria was any thoracic cancer and a COVID-19 diagnosis on or after November 1, 2021. Endpoints included mortality, hospitalization, symptomatic COVID infection, asymptomatic COVID infection, and delay in cancer therapy. Analysis was done through contingency tables and a multivariable logistic model.We enrolled 346 patients. Median age was 65, 52.3% were female, 74.2% were current or former smokers, 86% had NSCLC, 72% were Stage IV at time of COVID diagnosis, and 66% were receiving therapy. Variant was unknown for 70%; for those known, Omicron represented 82%. Overall mortality was 3.2%. Using multivariate analysis, COVID vaccination with booster compared with no vaccination showed a protective effect on hospitalization or death (OR 0.30, CI 0.15-0.57, p=0.0003), while vaccination without booster did not (OR of 0.64, CI 0.33-1.24, p=0.1864). Cancer care was delayed in 56.4% of patients.TERAVOLT found reduced patient mortality with the most recent COVID surge. COVID vaccination with booster improved outcomes of hospitalization or death. Delays in cancer therapy remain an issue, which has the potential to worsen cancer-related mortality.
View details for DOI 10.1016/j.jtocrr.2022.100335
View details for PubMedID 35619644
View details for PubMedCentralID PMC9119707
-
Racial and Ethnic Disparities in Lung Cancer Screening by the 2021 USPSTF Guidelines Versus Risk-Based Criteria: The Multiethnic Cohort Study.
JNCI cancer spectrum
2022; 6 (3)
Abstract
BACKGROUND: In 2021, the US Preventive Services Task Force (USPSTF) revised its lung cancer screening guidelines to expand screening eligibility. We evaluated screening sensitivities and racial and ethnic disparities under the 2021 USPSTF criteria vs alternative risk-based criteria in a racially and ethnically diverse population.METHODS: In the Multiethnic Cohort, we evaluated the proportion of ever-smoking lung cancer cases eligible for screening (ie, screening sensitivity) under the 2021 USPSTF criteria and under risk-based criteria through the PLCOm2012 model (6-year risk≥1.51%). We also calculated the screening disparity (ie, absolute sensitivity difference) for each of 4 racial or ethnic groups (African American, Japanese American, Latino, Native Hawaiian) vs White cases.RESULTS: Among 5900 lung cancer cases, 43.3% were screen eligible under the 2021 USPSTF criteria. Screening sensitivities varied by race and ethnicity, with Native Hawaiian (56.7%) and White (49.6%) cases attaining the highest sensitivities and Latino (37.3%), African American (38.4%), and Japanese American (40.0%) cases attaining the lowest. Latino cases had the greatest screening disparity vs White cases at 12.4%, followed by African American (11.2%) and Japanese American (9.6%) cases. Under risk-based screening, the overall screening sensitivity increased to 75.7%, and all racial and ethnic groups had increased sensitivities (54.5%-91.9%). Whereas the screening disparity decreased to 5.1% for African American cases, it increased to 28.6% for Latino cases and 12.8% for Japanese American cases.CONCLUSIONS: In the Multiethnic Cohort, racial and ethnic disparities decreased but persisted under the 2021 USPSTF lung cancer screening guidelines. Risk-based screening through PLCOm2012 may increase screening sensitivities and help to reduce disparities in some, but not all, racial and ethnic groups. Further optimization of risk-based screening strategies across diverse populations is needed.
View details for DOI 10.1093/jncics/pkac033
View details for PubMedID 35642317
-
Autoimmune Disease in Patients With Advanced Thymic Epithelial Tumors.
JTO clinical and research reports
2022; 3 (5): 100323
Abstract
Paraneoplastic autoimmune diseases (ADs) are a hallmark of thymic epithelial tumors (TETs) and affect treatment management in patients with advanced-stage tumors, yet the risk factors for development of AD in advanced TET remain poorly understood.All patients with advanced TET treated at Stanford University between 2006 and 2020 were included. Charts were retrospectively reviewed for the presence of AD, demographic information, and treatment history. Next-generation sequencing was performed on available TET tissue. Multivariate regression was used to evaluate variables associated with AD.A total of 48 patients were included in the analysis with a median follow-up of 5.4 years. One-third (n = 16, 33%) were diagnosed with having ADs, with 28 distinct ADs identified. The only significant difference observed in the AD cohort compared with the non-AD cohort was a higher proportion of thymoma histotype (81% versus 47%, p = 0.013). The most common AD events were myasthenia gravis (n = 7, 44%) followed by pure red cell aplasia (n = 5, 31%). In the multivariate models, there were no independent factors associated with AD, either at TET diagnosis or subsequent to TET diagnosis. Genomic data were available on 18 patients, and there were no overlapping mutations identified in the nine patients with AD.ADs are common in patients with advanced TETs. Prior total thymectomy does not affect the development of subsequent AD. Patients who developed AD other than myasthenia gravis were more likely to do so several years after TET diagnosis. Additional work, including multiomic analyses, is needed to develop predictive markers for AD in advanced TET.
View details for DOI 10.1016/j.jtocrr.2022.100323
View details for PubMedID 35601925
View details for PubMedCentralID PMC9121321
-
Atezolizumab (atezo) vs best supportive care (BSC) in stage II-IIIA NSCLC with high PD-L1 expression: Sub-analysis from the pivotal phase III IMpower010 study
ELSEVIER. 2022: S71
View details for DOI 10.1016/j.annonc.2022.02.090
View details for Web of Science ID 000778453100082
-
Bevacizumab's Association With a Decreased Risk of Brain Metastases in ECOG-ACRIN E1505, a Phase 3 Randomized Trial of Adjuvant Chemotherapy With or Without Bevacizumab in Surgically Resected NSCLC.
JTO clinical and research reports
2022; 3 (3): 100274
Abstract
Introduction: ECOG-ACRIN E1505 was a phase 3 randomized trial of adjuvant chemotherapy with or without bevacizumab for patients with stages IB (>4 cm) to IIIA NSCLC. We sought to estimate the incidence and risk factors for brain recurrence as compared with extracranial recurrences (ECRs).Methods: ECOG-ACRIN E1505 noted that bevacizumab failed to improve overall survival (OS) (OS hazard ratio [HR]= 0.99 [0·82-1·19], p= 0.90) or recurrence-free survival when added to chemotherapy in the adjuvant setting. The cumulative incidence of brain/ECR was estimated after adjusting for recurrence at other sites and death as competing events. A multivariable regression model was fitted using competing risk analysis to evaluate the effect of covariates on brain recurrence incidence.Results: Median follow-up was 50.4 months. Among the 1501 patients enrolled, 472 developed ECR. There were 122 patients who had recurrence in the brain with or without simultaneous ECR as the first recurrence site (all-brain recurrences [ABRs]), and 84 of those with ABRs had recurrence in the brain only (isolated-brain recurrence [IBR]). The incidence of ABR, IBR, and ECR at 6 years was 9.9%, 5.9%, and 38.8%, respectively. Chemotherapy plus bevacizumab was associated with a decreased incidence of ABR (HR= 0.64, p= 0.02) and IBR (HR= 0.62, p= 0.032), but there was no significant trend for an OS decrement in the bevacizumab arm versus the control arm for both ABR and IBR. Median survivals associated with IBR, ABR, and ECR were 9.5, 9.5, and 14.1 months, respectively. Nonsquamous histology (HR= 1.87, p= 0.003) was also associated with ABR. ECR was associated with nonsquamous NSCLC histology (HR= 1.79, p < 0.01) and stage/N2 involvement (HR= 1.13/1.37, both p < 0.01).Conclusions: The addition of bevacizumab to chemotherapy was associated with reduction in brain recurrences, but not ECR. Brain metastases whether isolated or not are associated with a lower median survival than ECR and unlike ECR are not associated with traditional staging variables.
View details for DOI 10.1016/j.jtocrr.2021.100274
View details for PubMedID 35281954
-
Adjuvant therapy for early-stage non-small cell lung cancer: The breaking of a new dawn.
The Journal of thoracic and cardiovascular surgery
2022
View details for DOI 10.1016/j.jtcvs.2022.01.046
View details for PubMedID 35256160
-
International Association for the Study of Lung Cancer (IASLC) Study of the Impact of COVID-19 on International Lung Cancer Clinical Trials.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2022
Abstract
INTRODUCTION: To determine the effects of the global COVID-19 pandemic on lung cancer trials, we surveyed investigators and collected aggregate enrollment data for lung cancer trials across the world before and during the pandemic.METHODS: A Data Collection Survey collected aggregate monthly enrollment numbers from 294 global lung cancer trials for 2019-2020. A 64-question Action Survey assessed the impact of COVID-19 on clinical trials and identified mitigation strategies implemented.RESULTS: Clinical trial enrollment declined from 2019 to 2020 by 14% globally. Most reductions in enrollment occurred in April-June where we found significant decreases in individual site enrollment (p=0.0309). Enrollment was not significantly different in October-December of 2019 versus 2020 (p=0.25). The most frequent challenges identified by the Action Survey (N=173) were fewer eligible patients (63%), decrease in protocol compliance (56%), and suspension of trials (54%). Patient-specific challenges included access to trial site (49%), ability to travel (54%), and willingness to visit site (59%). The most frequent mitigation strategies included modified monitoring requirements (47%), telehealth visits (45%), modified required visits (25%), mail-order medications (25%), and laboratory (27%) and radiology (21%) tests at non-study facilities. Sites felt the most effective mitigation strategies were telehealth visits (85%), remote patient reported symptom collection (85%), off-site procedures (85%), and remote consenting (89%).CONCLUSION: The COVID-19 pandemic created many challenges for lung cancer clinical trials conduct and enrollment. Mitigation strategies were employed and, although the pandemic worsened, trial enrollment improved. A more flexible approach may improve enrollment and access to clinical trials, even beyond the pandemic.
View details for DOI 10.1016/j.jtho.2022.01.017
View details for PubMedID 35183774
-
In Response to: "Comparing Addition of Radiotherapy in EGFR- and ALK-Positive NSCLC With Brain Metastases: Are We Evaluating the Optimal Endpoint?"
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
1800; 17 (2): e12-e14
View details for DOI 10.1016/j.jtho.2021.11.017
View details for PubMedID 35074229
-
ASCEND-7: Efficacy and Safety of Ceritinib Treatment in Patients With ALK-Positive Non-Small Cell Lung Cancer Metastatic to the Brain and/or Leptomeninges.
Clinical cancer research : an official journal of the American Association for Cancer Research
1800
Abstract
PURPOSE: Central nervous system (CNS) metastases are a prominent cause of morbidity and mortality in patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC). The phase 2 ASCEND-7 (NCT02336451) study was specifically designed to assess the efficacy and safety of ALK inhibitor (ALKi) ceritinib in patients with ALK+ NSCLC metastatic to the brain and/or leptomeninges.EXPERIMENTAL DESIGN: Patients with active brain metastases were allocated to study arms 1-4 based on prior exposure to an ALKi and/or prior brain radiation (arm 1: prior radiotherapy/ALKi-pretreated; arm 2: no radiotherapy/ALKi-pretreated; arm 3: prior radiotherapy/ALKi-naive; arm 4: no radiotherapy/ALKi-naive). Arm 5 included patients with leptomeningeal carcinomatosis. Patients received ceritinib 750 mg once daily (fasted condition). Primary endpoint was investigator-assessed whole-body overall response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR) and intracranial/extracranial responses.RESULTS: Per investigator assessment, in arms 1 (n=42), 2 (n=40), 3 (n=12), and 4 (n=44), respectively: whole-body ORRs (95% CI) were 35.7% (21.6-52.0), 30.0% (16.6-46.5), 50.0% (21.1-78.9), and 59.1% (43.2-73.7); whole-body DCR (95% CI): 66.7% (50.5-80.4), 82.5% (67.2-92.7), 66.7% (34.9-90.1), and 70.5% (54.8-83.2); intracranial ORRs (95% CI): 39.3% (21.5-59.4), 27.6% (12.7-47.2), 28.6% (3.7-71.0), and 51.5% (33.5-69.2). In arm 5 (n=18), whole-body ORR was 16.7% (95% CI, 3.6-41.4) and DCR was 66.7% (95% CI, 41.0-86.7). Paired cerebrospinal fluid and plasma sampling revealed that ceritinib penetrated the human blood-brain barrier.CONCLUSIONS: Ceritinib showed antitumor activity in patients with ALK+ NSCLC with active brain metastases and/or leptomeningeal disease, and could be considered in the management of intracranial disease.
View details for DOI 10.1158/1078-0432.CCR-21-1838
View details for PubMedID 35091443
-
A definitive prognostication system for patients with thoracic malignancies diagnosed with COVID-19: an update from the TERAVOLT registry.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2022
Abstract
BACKGROUND: Patients with thoracic malignancies are at increased risk for mortality from Coronavirus disease 2019 (COVID-19) and large number of intertwined prognostic variables have been identified so far.METHODS: Capitalizing data from the TERAVOLT registry, a global study created with the aim of describing the impact of COVID-19 in patients with thoracic malignancies, we used a clustering approach, a fast-backward step-down selection procedure and a tree-based model to screen and optimize a broad panel of demographics, clinical COVID-19 and cancer characteristics.RESULTS: As of April 15, 2021, 1491 consecutive evaluable patients from 18 countries were included in the analysis. With a mean observation period of 42 days, 361 events were reported with an all-cause case fatality rate of 24.2%. The clustering procedure screened approximately 73 covariates in 13 clusters. A further multivariable logistic regression for the association between clusters and death was performed, resulting in five clusters significantly associated with the outcome. The fast-backward step-down selection then identified seven major determinants of death ECOG-PS (OR 2.47 1.87-3.26), neutrophil count (OR 2.46 1.76-3.44), serum procalcitonin (OR 2.37 1.64-3.43), development of pneumonia (OR 1.95 1.48-2.58), c-reactive protein (CRP) (OR 1.90 1.43-2.51), tumor stage at COVID-19 diagnosis (OR 1.97 1.46-2.66) and age (OR 1.71 1.29-2.26). The ROC analysis for death of the selected model confirmed its diagnostic ability (AUC 0.78; 95%CI: 0.75 - 0.81). The nomogram was able to classify the COVID-19 mortality in an interval ranging from 8% to 90% and the tree-based model recognized ECOG-PS, neutrophil count and CRP as the major determinants of prognosis.CONCLUSION: From 73 variables analyzed, seven major determinants of death have been identified. Poor ECOG-PS demonstrated the strongest association with poor outcome from COVID-19. With our analysis we provide clinicians with a definitive prognostication system to help determine the risk of mortality for patients with thoracic malignancies and COVID-19.
View details for DOI 10.1016/j.jtho.2021.12.015
View details for PubMedID 35121086
-
Progression Versus Radiation Treatment Changes After Stereotactic Ablative Radiation Therapy of a Liver Metastasis
PRACTICAL RADIATION ONCOLOGY
2022; 12 (1): 1-2
View details for DOI 10.1016/j.prro.2021.06.013
View details for Web of Science ID 000740674400002
-
ITMIG 2021 Tumor Board: a case of a 37-year-old man with TNM stage IVA thymoma.
Mediastinum (Hong Kong, China)
2022; 6: 26
View details for DOI 10.21037/med-22-3
View details for PubMedID 36164363
-
Impact of the COVID-19 Pandemic on Global Lung Cancer Clinical Trials: Why it matters to people with lung cancer.
JTO clinical and research reports
1800: 100269
View details for DOI 10.1016/j.jtocrr.2021.100269
View details for PubMedID 34961851
-
Afatinib After Progression on Osimertinib in EGFR-Mutated Non-Small Cell Lung Cancer.
Cancer treatment and research communications
1800; 30: 100497
Abstract
INTRODUCTION: After the development of acquired resistance to osimertinib, the standard-of-care treatment for advanced EGFR-mutated NSCLC is chemotherapy. Whether afatinib, a pan-ErbB family tyrosine kinase inhibitor, is active after progression on osimertinib is unknown.METHODS: We conducted a single-institution retrospective analysis of patients with advanced EGFR-mutated NSCLC who received afatinib-containing therapy after progression on osimertinib. Kaplan-Meier analyses evaluated progression-free survival (PFS) and overall survival (OS) from initiation of afatinib.RESULTS: After progression on first (N=3) or second-line plus (N=12) osimertinib, 15 patients received afatinib monotherapy (N=3), afatinib and cetuximab (N=10), or afatinib and bevacizumab (N=2). The objective response rate was 6.7% and disease control rate was 53.3%. Median PFS was 2.5 months and median OS was 7.7 months. Median PFS of ≥ 6 months versus < 6 months on osimertinib was associated with a significantly greater median PFS on afatinib (4.0 versus 1.4 months; P=0.003), although there was no significant difference in median OS (9.3 versus 6.6 months; P=0.123). Best response of stable disease/partial response versus progressive disease on osimertinib was associated with a significantly greater median PFS on afatinib (3.4 versus 1.6 months; P=0.036) and a significantly greater median OS (8.7 versus 4.6 months; P=0.017).CONCLUSION: Afatinib-containing therapy had limited activity in patients with EGFR-mutated NSCLC after progression on osimertinib in this cohort of mostly second-line plus osimertinib. Response and longer PFS to prior osimertinib may be predictive of response to afatinib. Strategies based on osimertinib resistance mechanisms may further define the role of subsequent afatinib.
View details for DOI 10.1016/j.ctarc.2021.100497
View details for PubMedID 34920242
-
IMpower010: Biomarkers of disease-free survival (DFS) in a phase III study of atezolizumab (atezo) vs best supportive care (BSC) after adjuvant chemotherapy in stage IB-IIIA NSCLC
ELSEVIER. 2021: S1374
View details for DOI 10.1016/j.annonc.2021.10.018
View details for Web of Science ID 000731051400003
-
Consolidation Durvalumab Should Not Be Administered to Patients With Stage III EGFR-Mutant NSCLC.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2021; 16 (12): 1994-1998
View details for DOI 10.1016/j.jtho.2021.07.033
View details for PubMedID 34809803
-
A phase 1b study of erlotinib and momelotinib for the treatment of EGFR-mutated, tyrosine kinase inhibitor-naive metastatic non-small cell lung cancer.
Cancer chemotherapy and pharmacology
2021
Abstract
INTRODUCTION: Preclinical evidence suggests the feedforward cytokine loop of interleukin-6/Janus kinases (JAK)/STAT3 plays a role in epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resistance in EGFR-mutated non-small cell lung cancer (NSCLC).METHODS: In this phase 1b study, the JAK1/2 and TANK-binding kinase 1 (TBK1) inhibitor momelotinib was evaluated in combination with erlotinib in patients with EGFR TKI-naive, EGFR-mutated NSCLC. After erlotinib lead-in (50, 75, 100, or 150mg oral daily [QD]), momelotinib was combined and dose escalated in a 3+3 study design. The primary endpoint of maximum tolerated dose (MTD) of momelotinib was determined based on the incidence of dose-limiting toxicities (DLTs) during the first 28-day cycle. Secondary endpoints included efficacy and pharmacokinetics (PK).RESULTS: Eleven patients were enrolled across 3 dose levels of momelotinib (100mg QD, 200mg QD, and 100mg twice daily [BID]). The MTD was momelotinib 200mg QD in combination with erlotinib. Two DLTs of grade 4 neutropenia without fever and grade 3 diarrhea occurred at momelotinib 100mg BID. Most common treatment-emergent adverse events included diarrhea, dry skin, fatigue, and decreased appetite; the vast majority being grades 1-2. The overall response rate was 54.5% (90% CI 27.1-80.0; all partial) and median progression-free survival was 9.2months (90% CI 6.2-12.4). Momelotinib did not affect the PK of erlotinib.CONCLUSIONS: The JAK1/2 and TBK1 inhibitor momelotinib in combination with erlotinib did not appear to enhance benefit over the historical data of erlotinib monotherapy in patients with EGFR-mutated NSCLC. CLINICALTRIALS.GOV IDENTIFIER: NCT02206763.
View details for DOI 10.1007/s00280-021-04369-0
View details for PubMedID 34773474
-
Chemotherapy Plus Immunotherapy Versus Chemotherapy Plus Bevacizumab Versus Chemotherapy Alone in EGFR-Mutant NSCLC After Progression on Osimertinib.
Clinical lung cancer
2021
Abstract
INTRODUCTION: Patients with EGFR-mutant lung cancer who have had disease progression on osimertinib commonly receive platinum doublet chemotherapy, but whether adding immunotherapy or bevacizumab provides additional benefit is unknown.MATERIALS AND METHODS: This was a retrospective analysis at 2 university-affiliated institutions. Patients with EGFR-mutant lung cancer who had progression on osimertinib and received next-line therapy with platinum doublet chemotherapy (chemo), platinum doublet chemotherapy plus immunotherapy (chemo-IO), or platinum doublet chemotherapy plus bevacizumab (chemo-bev), were identified; patients who continued osimertinib with these regimens were included. Efficacy outcomes including duration on treatment (DOT) and overall survival (OS) from the start of chemotherapy were assessed. Associations of treatment regimen with outcomes were evaluated using adjusted Cox regression models, using pairwise comparisons between groups.RESULTS: 104 patients were included: 57 received chemo, 12 received chemo-IO, and 35 received chemo-bev. In adjusted models, patients who received chemo-IO had worse OS than did those who received chemo (hazard ratio (HR) 2.66, 95% CI 1.25-5.65; P= .011) or those who received chemo-bev (HR 2.37, 95% CI 1.09-5.65; P= .030). A statistically significant difference in OS could not be detected in patients who received chemo-bev versus those who received chemo (HR 1.50, 95% CI 0.84-2.69; P= .17).CONCLUSION: In this retrospective study, giving immunotherapy with platinum doublet chemotherapy after progression on osimertinib was associated with a worse OS compared with platinum doublet chemotherapy alone. Platinum doublet chemotherapy without immunotherapy (with consideration of continuation of osimertinib, in selected cases) is a reasonable choice in this setting, while we await results of clinical trials examining optimal next-line chemotherapy-based regimens in EGFR-mutant lung cancer.
View details for DOI 10.1016/j.cllc.2021.11.001
View details for PubMedID 34887193
-
Management of brain metastases in lung cancer: evolving roles for radiation and systemic treatment in the era of targeted and immune therapies.
Neuro-oncology advances
2021; 3 (Suppl 5): v52-v62
Abstract
Brain metastases are a common occurrence in both non-small cell and small cell lung cancer with the potential to affect quality of life and prognosis. Due to concerns about the accessibility of the central nervous system by systemic chemotherapy agents, the management of brain metastases has historically relied on local therapies including surgery and radiation. However, novel targeted and immune therapies that improve overall outcomes in lung cancer have demonstrated effective intracranial activity. As a result, the management of brain metastases in lung cancer has evolved, with both local and systemic therapies now playing an important role. Factors such as tumor histology (non-small versus small cell), oncogenic driver mutations, and symptom burden from intracranial disease impact treatment decisions. Here, we review the current management of brain metastases in lung cancer, highlighting the roles of stereotactic radiosurgery and novel systemic therapies as well as the ongoing questions that remain under investigation.
View details for DOI 10.1093/noajnl/vdab106
View details for PubMedID 34859233
-
SKYSCRAPER-03: A Phase III, Open-Label, Randomized Study of Atezolizumab Plus Tiragolumab Compared With Durvalumab in Patients With Locally Advanced, Unresectable, Stage III NSCLC Who Have Not Progressed After Platinum-Based Concurrent Chemoradiation
ELSEVIER SCIENCE INC. 2021: E420-E421
View details for Web of Science ID 000715803800863
-
A Phase II Trial of Individualized Stereotactic Ablative Radiotherapy for Lung Tumors (iSABR)
ELSEVIER SCIENCE INC. 2021: S89-S90
View details for Web of Science ID 000715803801515
-
Patterns of Care in Patients With Isolated Nodal Recurrence After Definitive Stereotactic Ablative Radiotherapy for Non-Small Cell Lung Cancer
ELSEVIER SCIENCE INC. 2021: E435
View details for Web of Science ID 000715803800895
-
Pulmonary Hemorrhage in Patients Treated With Thoracic Stereotactic Ablative Radiotherapy and Anti-Angiogenic Agents
ELSEVIER SCIENCE INC. 2021: E423
View details for Web of Science ID 000715803800868
-
A Phase II Trial of Individualized Stereotactic Ablative Radiotherapy for Lung Tumors (iSABR).
International journal of radiation oncology, biology, physics
2021; 111 (3S): S89-S90
Abstract
PURPOSE/OBJECTIVE(S): Stereotactic ablative radiotherapy (SABR) is an effective treatment for lung tumors, but can result in toxicity such as chest wall pain and life-threatening damage to central lung structures. We hypothesized that while larger tumors require higher dose, small tumors up to 10cc in volume can be controlled with biologically effective dose < 100Gy. In this phase II single-arm trial, we tested the hypothesis that individualizing lung SABR dose and fractionation to tumor size, location, and histology would result in excellent local control with acceptable toxicity. The trial was conducted at two centers in the United States and Japan (NCT# redacted for blinded review).MATERIALS/METHODS: Patients in three groups were enrolled: initial diagnosis of non-small cell lung cancer (NSCLC), AJCC 7th edition stage T1-3 N0 M0 (group 1); new primary NSCLC with history of NSCLC, or multiple synchronously diagnosed NSCLCs (group 2); and lung metastases from NSCLC or another primary site (group 3). Up to four tumors could be treated with once-daily SABR. There were six dose/fractionation schedules used, depending on gross tumor volume (≤10cc, 10-30cc, > 30cc) and location (peripheral vs. central). Larger tumors received higher dose and central tumors generally received lower dose per fraction. Dose ranged from 25Gy in one fraction for 0-10cc peripheral tumors to 60Gy in 8 fractions for > 30cc central tumors. Colorectal cancer metastases were treated to higher dose, at least 50Gy in 4 fractions. The primary endpoint was per-group cumulative incidence of local recurrence at 1 year (recurrence of treated tumor within same lobe), with distant recurrence and death as competing risks. Treated tumor recurrence (recurrence with epicenter within 1cm of PTV) and toxicity were also analyzed.RESULTS: A total of 217 patients were enrolled from 2011-2018 (some patients were enrolled multiple times). Median age was 72, 59% were male, and 69% were current/former smokers. There were 240 treatment courses and 285 tumors treated (range 1-3 tumors per course). 211 tumors were peripheral and 74 were central. Tumor size distribution was: ≤10cc, 74%; 10-30cc, 19%; > 30cc, 7%. The most common dose was 25Gy in one fraction (158 tumors). Median follow-up was 30 months (range 2-95). Median overall survival was 57 months. Local recurrence data are currently being updated and will be presented at the meeting. The rate of grade 2 or higher pneumonitis was 16/217 (7%) and grade 3 or higher pneumonitis was 3/217 (1%). The rate of grade 2 or higher chest wall pain was 13/217 (6%). One patient had a grade 5 adverse event, developing pulmonary hemorrhage that was possibly related to radiotherapy, 17 months after treatment of a large central NSCLC.CONCLUSION: Individualized SABR to lung cancers resulted in excellent local control and favorable toxicity profile.
View details for DOI 10.1016/j.ijrobp.2021.07.212
View details for PubMedID 34700657
-
Patterns of Care in Patients With Isolated Nodal Recurrence After Definitive Stereotactic Ablative Radiotherapy for Non-Small Cell Lung Cancer.
International journal of radiation oncology, biology, physics
2021; 111 (3S): e435
Abstract
PURPOSE/OBJECTIVE(S): Patients treated with stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer (NSCLC) have high rates of local control but may be at increased risk of nodal recurrence compared to those who undergo surgical resection with more invasive nodal evaluation. The optimal treatment for patients with isolated nodal recurrence (INR) is unclear. The purpose of this study is to determine the rate of INR after SABR for early-stage NSCLC and describe patterns of care and treatment outcomes for patients that experience INR.MATERIALS/METHODS: This retrospective cohort study included 342 patients with stage T1-3N0 NSCLC treated with definitive SABR. We evaluated the estimated rate of INR using the cumulative incidence function with death as a competing risk and compared baseline factors among patients who did or did not experience INR. Among patients that experienced INR, we describe patterns of treatment and outcomes including overall (OS) and progression free survival (PFS) from the time of nodal failure using the Kaplan-Meier method. OS and PFS outcomes were compared between treatment groups using the log-rank test.RESULTS: Of the 342 patients treated with SABR from 2003-2018, 34 developed INR and 19 developed any nodal recurrence. Patients were treated with definitive SABR for T1 (62.6%, n = 214), T2 (25.4%, n = 87) and T3 (12.0%, n = 41) NSCLC with a median BED10 of 87.5. The 3- and 5-year cumulative incidence of INR was 9.3 (95% CI 6.1 - 12.4) and 10.1 (6.8 -13.4) %, respectively. Pathologic nodal staging prior to SBRT was 9.1 and 13.3 % (P = 0.68) for patients who did or did not experience INR, respectively. The median number of involved nodes at the time of recurrence was one with a maximum of four. Among the 30 patients with a known treatment course after INR, patients were treated with RT alone (26.7 %, n = 8), chemotherapy and RT (CRT) (43.3 %, n = 13), chemotherapy alone (13.3%, n = 4) or observation (16.7%, n = 5). RT regimens included standard fractionation (38.0%, n = 8), hypofractionation (52.4%, n = 11) or SABR (9.5%, n = 2). The estimated two-year OS and PFS for patients experiencing INR were 48.0 (32.6 - 70.7) % and 27.6 (14.7 - 52.8) %, respectively. Treatment with CRT was associated with improved OS (2 year est: 91.7 vs 16.7 %, P < 0.01) and PFS (2 year est: 63.9 vs 0 %, P < 0.01) over RT alone. Similarly, CRT was associated with improved OS (91.7 vs 25.0 %, P < 0.01) and PFS (63.9 vs 0%, P < 0.01) over chemotherapy alone. Median follow-up time after INR was 21.7 months.CONCLUSION: INR occurred in approximately 10% of patients treated for early-stage NSCLC with SABR. Treatment paradigms for post-SABR INR varied significantly at our institution and included combined chemotherapy and radiation, chemotherapy alone, SABR and hypofractionated RT. The highest rates of survival in patients with post-SABR INR were observed in those treated with combined chemotherapy and radiation.
View details for DOI 10.1016/j.ijrobp.2021.07.1235
View details for PubMedID 34701446
-
SKYSCRAPER-03: A Phase III, Open-Label, Randomized Study of Atezolizumab Plus Tiragolumab Compared With Durvalumab in Patients With Locally Advanced, Unresectable, Stage III NSCLC Who Have Not Progressed After Platinum-Based Concurrent Chemoradiation.
International journal of radiation oncology, biology, physics
2021; 111 (3S): e420-e421
Abstract
PURPOSE/OBJECTIVE(S): Until recently, the standard of care for patients (pts) with locally advanced, unresectable, stage III non-small cell lung cancer (NSCLC) has been platinum-based concurrent chemoradiation (cCRT); however, the 5-year OS rates are poor (13-36%; Goldstraw et al. J Thorac Oncol 2015). Durvalumab (anti-PD-L1) monotherapy was recently approved for pts without progressive disease (PD) after cCRT. However, long-term OS data are not yet available and further evaluation of novel cancer immunotherapy combinations should be explored. Targeted inhibition of a novel checkpoint TIGIT/PVR, by the anti-TIGIT antibody tiragolumab, may amplify the anti-cancer activity of anti-PD-L1/PD-1 antibodies. In the phase II CITYSCAPE study (NCT03563716), tiragolumab plus atezolizumab (anti-PD-L1) was well tolerated and improved ORR compared with atezolizumab alone (31.3 vs 16.2%) in 1L pts with PD-L1+ (TPS ≥1%) metastatic NSCLC; with greater benefit in the PD-L1-high (TPS ≥50%) subset. We hypothesize that tiragolumab plus atezolizumab may provide greater clinical benefit vs single-agent anti-PD-L1 as maintenance therapy in pts with unresectable, stage III NSCLC who have not progressed after platinum-based cCRT. SKYSCRAPER-03 (NCT04513925) will determine if tiragolumab plus atezolizumab provides superior clinical benefit to durvalumab in this setting. Current data suggests that cCRT upregulates PD-L1 expression, potentially enabling PD-L1 low or negative tumors to derive benefit, so outcomes will be evaluated in all-comer (ITT) and PD-L1+ sub-populations.MATERIALS/METHODS: Eligible pts (≥18 years) must have unresectable, stage III NSCLC without PD after ≥2 cycles of platinum-based cCRT per NCCN/ESMO guidelines, and without an EGFR mutation or ALK rearrangement; known PD-L1 status; ECOG PS 0-1. Approximately 800 pts will be randomized 1:1 to receive tiragolumab 840mg IV plus atezolizumab 1680mg IV Q4W or durvalumab 10mg/kg IV Q2W / 1500mg IV Q4W. Treatment will continue for up to 13 cycles of 28 days, or until unacceptable toxicity or symptomatic deterioration due to PD; in pts with radiographic PD (per RECIST v1.1) treatment may continue if evidence of ongoing clinical benefit. Stratification factors include PD-L1 status, histology (squamous vs non-squamous), staging (IIIA vs IIIB or IIIC) and ECOG PS (0 vs 1). Primary endpoint is independent review facility-assessed PFS in the ITT and PD-L1+ (TC ≥1%) populations. Secondary endpoints include investigator-assessed PFS, OS, ORR and DoR. Safety and biomarker analyses will be performed. Recruitment is ongoing.RESULTS: forthcoming CONCLUSION: forthcoming.
View details for DOI 10.1016/j.ijrobp.2021.07.1203
View details for PubMedID 34701413
-
Computational Biological Modeling Identifies PD-(L)1 Immunotherapy Sensitivity Among Molecular Subgroups of KRAS-Mutated Non-Small-Cell Lung Cancer.
JCO precision oncology
2021; 5: 153-162
Abstract
KRAS-mutated (KRASMUT) non-small-cell lung cancer (NSCLC) is emerging as a heterogeneous disease defined by comutations, which may confer differential benefit to PD-(L)1 immunotherapy. In this study, we leveraged computational biological modeling (CBM) of tumor genomic data to identify PD-(L)1 immunotherapy sensitivity among KRASMUT NSCLC molecular subgroups.In this multicohort retrospective analysis, the genotype clustering frequency ranked method was used for molecular clustering of tumor genomic data from 776 patients with KRASMUT NSCLC. These genomic data were input into the CBM, in which customized protein networks were characterized for each tumor. The CBM evaluated sensitivity to PD-(L)1 immunotherapy using three metrics: programmed death-ligand 1 expression, dendritic cell infiltration index (nine chemokine markers), and immunosuppressive biomarker expression index (14 markers).Genotype clustering identified eight molecular subgroups and the CBM characterized their shared cancer pathway characteristics: KRASMUT/TP53MUT, KRASMUT/CDKN2A/B/CMUT, KRASMUT/STK11MUT, KRASMUT/KEAP1MUT, KRASMUT/STK11MUT/KEAP1MUT, KRASMUT/PIK3CAMUT, KRAS MUT/ATMMUT, and KRASMUT without comutation. CBM identified PD-(L)1 immunotherapy sensitivity in the KRASMUT/TP53MUT, KRASMUT/PIK3CAMUT, and KRASMUT alone subgroups and resistance in the KEAP1MUT containing subgroups. There was insufficient genomic information to elucidate PD-(L)1 immunotherapy sensitivity by the CBM in the KRASMUT/CDKN2A/B/CMUT, KRASMUT/STK11MUT, and KRASMUT/ATMMUT subgroups. In an exploratory clinical cohort of 34 patients with advanced KRASMUT NSCLC treated with PD-(L)1 immunotherapy, the CBM-assessed overall survival correlated well with actual overall survival (r = 0.80, P < .001).CBM identified distinct PD-(L)1 immunotherapy sensitivity among molecular subgroups of KRASMUT NSCLC, in line with previous literature. These data provide proof-of-concept that computational modeling of tumor genomics could be used to expand on hypotheses from clinical observations of patients receiving PD-(L)1 immunotherapy and suggest mechanisms that underlie PD-(L)1 immunotherapy sensitivity.
View details for DOI 10.1200/PO.20.00172
View details for PubMedID 34994595
-
Impact of Tumor Suppressor Gene Co-Mutations on Differential Response to EGFR TKI Therapy in EGFR L858R and Exon 19 Deletion Lung Cancer.
Clinical lung cancer
2021
Abstract
BACKGROUND: In most studies, patients with EGFR L858R mutant non-small cell lung cancer (NSCLC) have a shorter duration of response to EGFR tyrosine kinase inhibitor (TKI) therapy than do patients with EGFR exon 19 deletion NSCLC. The role that co-mutations play in this observation is unknown.METHODS: We performed a single-institution retrospective analysis of patients with EGFR-mutant NSCLC (exon 19 deletion or L858R mutation) who received frontline EGFR TKI for metastatic disease between 2014 and 2019, and who had STAMP next-generation sequencing (NGS), a 130-gene platform. Time to treatment failure (TTF) and overall survival were calculated using Cox models adjusted for age, race, and brain metastases. Co-mutations in key tumor suppressor genes (TP53, RB1, KEAP1, CDKN2A, or CTNNB1) were identified and their effects on outcomes were evaluated. Analyses were stratified according to receipt of osimertinib versus nonosimertinib as frontline EGFR TKI.RESULTS: Of 137 patients, 72 (57%) had EGFR exon 19 deletions and 65 (43%) had EGFR L858R mutations. Median TTF and OS on frontline TKI was shorter for the L858R cohort versus the exon 19 deletion cohort in univariate analysis. In adjusted models, this difference persisted for TTF but was no longer significant for OS. The difference in TTF in L858R mutant tumors was driven by the presence of co-mutations in key tumor suppressor genes.CONCLUSION: Patients with metastatic NSCLC with mutations in EGFR L858R had shorter TTF on frontline TKI compared to patients with EGFR exon 19 deletions. Co-mutations in tumor suppressor genes may play an important role in the differential response to TKI therapy.
View details for DOI 10.1016/j.cllc.2021.09.004
View details for PubMedID 34838441
-
Racial diversity and reporting in FDA registration trials for thoracic malignancies from 2006 to 2020
LIPPINCOTT WILLIAMS & WILKINS. 2021
View details for DOI 10.1200/JCO.2020.39.28_suppl.135
View details for Web of Science ID 000707130200134
-
The Association of Bevacizumab with a Decreased Risk of Brain Metastases in ECOG-ACRIN E1505 in Completely Resected Stage IB-IIIA NSCLC
ELSEVIER SCIENCE INC. 2021: S944
View details for Web of Science ID 000709606500204
-
Survival After Distant Recurrent Versus De Novo Stage IV Metastatic Lung Cancer Under Low-Dose Computed Tomography Screening
ELSEVIER SCIENCE INC. 2021: S1177-S1178
View details for Web of Science ID 000709606500646
-
International Association for the Study of Lung Cancer (IASLC) Study of the Impacts of COVID-19 on International Lung Cancer Clinical Trials
ELSEVIER SCIENCE INC. 2021: S847-S848
View details for Web of Science ID 000709606500032
-
IMpower010: Characterization of Stage IB-IIIA NSCLC Patients by Type and Extent of Therapy Prior to Adjuvant Atezolizumab
ELSEVIER SCIENCE INC. 2021: S845-S846
View details for Web of Science ID 000709606500030
-
A Predictive Model to Guide Brain MRI Surveillance in Patients With Metastatic Lung Cancer: Impact on Real World Outcomes
ELSEVIER SCIENCE INC. 2021: S1177
View details for Web of Science ID 000709606500645
-
Smoking Cessation After Lung Cancer Diagnosis and the Risk of Second Primary Lung Cancer: The Multiethnic Cohort Study.
JNCI cancer spectrum
2021; 5 (5): pkab076
Abstract
Background: Smoking cessation reduces lung cancer mortality. However, little is known about whether diagnosis of lung cancer impacts changes in smoking behaviors. Furthermore, the effects of smoking cessation on the risk of second primary lung cancer (SPLC) have not been established yet. This study aims to examine smoking behavior changes after initial primary lung cancer (IPLC) diagnosis and estimate the effect of smoking cessation on SPLC risk following IPLC diagnosis.Methods: The study cohort consisted of 986 participants in the Multiethnic Cohort Study who were free of lung cancer and active smokers at baseline (1993-1996), provided 10-year follow-up smoking data (2003-2008), and were diagnosed with IPLC in 1993-2017. The primary outcome was a change in smoking status from "current" at baseline to "former" at 10-year follow-up (ie, smoking cessation), analyzed using logistic regression. The second outcome was SPLC incidence after smoking cessation, estimated using cause-specific Cox regression. All statistical tests were 2-sided.Results: Among 986 current smokers at baseline, 51.1% reported smoking cessation at 10-year follow-up. The smoking cessation rate was statistically significantly higher (80.6%) for those diagnosed with IPLC between baseline and 10-year follow-up vs those without IPLC diagnosis (45.4%) during the 10-year period (adjusted odds ratio = 5.12, 95% confidence interval [CI] = 3.38 to 7.98; P<.001). Incidence of SPLC was statistically significantly lower among the 504 participants who reported smoking cessation at follow-up compared with those without smoking cessation (adjusted hazard ratio = 0.31, 95% CI = 0.14 to 0.67; P=.003).Conclusion: Lung cancer diagnosis has a statistically significant impact on smoking cessation. Quitting smoking after IPLC diagnosis may reduce the risk of developing a subsequent malignancy in the lungs.
View details for DOI 10.1093/jncics/pkab076
View details for PubMedID 34611582
-
Pulmonary Hemorrhage in Patients Treated with Thoracic Stereotactic Ablative Radiotherapy and Anti-Angiogenic Agents
LIPPINCOTT WILLIAMS & WILKINS. 2021: S105
View details for Web of Science ID 000701779700169
-
Implementation of a cloud-based electronic patient-reported outcome (ePRO) platform in patients with advanced cancer.
Journal of patient-reported outcomes
2021; 5 (1): 91
Abstract
BACKGROUND: Patient reported outcomes (PROs) have been associated with improved symptom management and quality of life in patients with cancer. However, the implementation of PROs in an academic clinical practice has not been thoroughly described. Here we report on the execution, feasibility and healthcare utilization outcomes of an electronic PRO (ePRO) application for cancer patients at an academic medical center.METHODS: We conducted a randomized trial comparing an experimental ePRO arm to standard of care in patients with advanced cancer in the thoracic, gastrointestinal, and genitourinary oncology groups at Stanford Cancer Center from March 2018 to November 2019. We describe the pre-implementation, implementation, and post-implementation phases of the ePRO arm, technological barriers, electronic health record (EHR) integration, clinician burden, and patient data privacy and security. Feasibility was pre-specified to be at least 70% completion of all questionnaires. Acceptability was based on patient and clinician feedback. Ambulatory healthcare utilization was assessed by reviewing numbers of phone messages, electronic portal messages, and referrals for supportive care.RESULTS: Of 617 ePRO questionnaires sent to 72 patients, 445 (72%) were completed. Most clinicians (87.5%) and patients (93%) felt neutral or positive about the ePRO tool's ease of use. Exposure to ePRO did not cause a measurable change in ambulatory healthcare utilization, with a median of less than two phone messages and supportive care referrals, and 5-6 portal messages.CONCLUSIONS: Web-based ePRO tools for patients with advanced cancer are feasible and acceptable without increasing clinical burden. Key lessons include the importance of pilot testing, engagement of stakeholders at all levels, and the need for customization by disease group. Future directions for this work include completion of EHR integration, expansion to other centers, and development of integrated workflows for routine clinical practice.
View details for DOI 10.1186/s41687-021-00358-2
View details for PubMedID 34524558
-
Ensartinib vs Crizotinib for Patients With Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Randomized Clinical Trial.
JAMA oncology
2021
Abstract
Importance: Ensartinib, an oral tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system efficacy for patients with ALK-positive non-small cell lung cancer (NSCLC).Objective: To compare ensartinib with crizotinib among patients with advanced ALK-positive NSCLC who had not received prior treatment with an ALK inhibitor.Design, Setting, and Participants: This open-label, multicenter, randomized, phase 3 trial conducted in 120 centers in 21 countries enrolled 290 patients between July 25, 2016, and November 12, 2018. Eligible patients were 18 years of age or older and had advanced, recurrent, or metastatic ALK-positive NSCLC.Interventions: Patients were randomized (1:1) to ensartinib, 225 mg once daily, or crizotinib, 250 mg twice daily.Main Outcomes and Measures: The primary end point was blinded independent review committee-assessed progression-free survival (PFS). Secondary end points included systemic and intracranial response, time to central nervous system progression, and overall survival. Efficacy was evaluated in the intent-to-treat (ITT) population as well as a prespecified modified ITT (mITT) population consisting of patients with central laboratory-confirmed ALK-positive NSCLC.Results: A total of 290 patients (149 men [51.4%]; median age, 54 years [range, 25-90 years]) were randomized. In the ITT population, the median PFS was significantly longer with ensartinib than with crizotinib (25.8 [range, 0.03-44.0 months] vs 12.7 months [range, 0.03-38.6 months]; hazard ratio, 0.51 [95% CI, 0.35-0.72]; log-rank P<.001), with a median follow-up of 23.8 months (range, 0-44 months) for the ensartinib group and 20.2 months (range, 0-38 months) for the crizotinib group. In the mITT population, the median PFS in the ensartinib group was not reached, and the median PFS in the crizotinib group was 12.7 months (95% CI, 8.9-16.6 months; hazard ratio, 0.45; 95% CI, 0.30-0.66; log-rank P<.001). The intracranial response rate confirmed by a blinded independent review committee was 63.6% (7 of 11) with ensartinib vs 21.1% (4 of 19) with crizotinib for patients with target brain metastases at baseline. Progression-free survival for patients without brain metastases was not reached with ensartinib vs 16.6 months with crizotinib as a result of a lower central nervous system progression rate (at 12 months: 4.2% with ensartinib vs 23.9% with crizotinib; cause-specific hazard ratio, 0.32; 95% CI, 0.16-0.63; P=.001). Frequencies of treatment-related serious adverse events (ensartinib: 11 [7.7%] vs crizotinib: 9 [6.1%]), dose reductions (ensartinib: 34 of 143 [23.8%] vs crizotinib: 29 of 146 [19.9%]), or drug discontinuations (ensartinib: 13 of 143 [9.1%] vs crizotinib: 10 of 146 [6.8%]) were similar, without any new safety signals.Conclusions and Relevance: In this randomized clinical trial, ensartinib showed superior efficacy to crizotinib in both systemic and intracranial disease. Ensartinib represents a new first-line option for patients with ALK-positive NSCLC.Trial Registration: ClinicalTrials.gov Identifier: NCT02767804.
View details for DOI 10.1001/jamaoncol.2021.3523
View details for PubMedID 34473194
-
Radiological tumor classification across imaging modality and histology.
Nature machine intelligence
2021; 3: 787-798
Abstract
Radiomics refers to the high-throughput extraction of quantitative features from radiological scans and is widely used to search for imaging biomarkers for prediction of clinical outcomes. Current radiomic signatures suffer from limited reproducibility and generalizability, because most features are dependent on imaging modality and tumor histology, making them sensitive to variations in scan protocol. Here, we propose novel radiological features that are specially designed to ensure compatibility across diverse tissues and imaging contrast. These features provide systematic characterization of tumor morphology and spatial heterogeneity. In an international multi-institution study of 1,682 patients, we discover and validate four unifying imaging subtypes across three malignancies and two major imaging modalities. These tumor subtypes demonstrate distinct molecular characteristics and prognoses after conventional therapies. In advanced lung cancer treated with immunotherapy, one subtype is associated with improved survival and increased tumor-infiltrating lymphocytes compared with the others. Deep learning enables automatic tumor segmentation and reproducible subtype identification, which can facilitate practical implementation. The unifying radiological tumor classification may inform prognosis and treatment response for precision medicine.
View details for DOI 10.1038/s42256-021-00377-0
View details for PubMedID 34841195
View details for PubMedCentralID PMC8612063
-
Brain Metastases in EGFR- and ALK-positive Non-Small Cell Lung Cancer: Outcomes of CNS Penetrant Tyrosine Kinase Inhibitors (TKIs) Alone versus in Combination with Radiation.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2021
Abstract
INTRODUCTION: Management of central nervous system (CNS) metastases in patients with driver-mutated non-small cell lung cancer (NSCLC) has traditionally incorporated both tyrosine kinase inhibitors (TKIs) and intracranial radiation. Whether next-generation, CNS-penetrant TKIs can be used alone without upfront radiation, however, remains unknown. This multi-institutional retrospective analysis aimed to compare outcomes in patients with EGFR- or ALK-positive NSCLC who received CNS-penetrant TKI therapy alone versus in combination with radiation for new or progressing intracranial metastases.METHODS: Data was retrospectively collected from 3 academic institutions. Two treatment groups (CNS-penetrant TKI alone vs TKI+CNS RT) were compared for both EGFR- and ALK-positive cohorts. Outcome variables included time to progression, time to intracranial progression, and time to treatment failure, measured from the date of initiation of CNS-penetrant TKI therapy.RESULTS: A total of 147 patients were included (EGFR n=94, ALK n=52, both n=1). In patients receiving radiation, larger metastases, neurological symptoms, and receipt of steroids were more common. There were no significant differences between TKI vs CNS RT+TKI groups for any of the study outcomes, including time to progression (8.5 vs 6.9 months, p=0.13 [EFGR] and 11.4 vs 13.4 months, p=0.98 [ALK]), time to intracranial progression (14.8 vs 20.5 months, p=0.51 [EGFR] and 18.1 vs 21.8 months, p=0.65 [ALK]), or time to treatment failure (13.8 vs 8.6 months, p=0.26 [EGFR] and 13.5 vs 23.2 months, p=0.95 [ALK]).CONCLUSION: These results provide preliminary evidence that intracranial activity of CNS-penetrant TKIs may enable local radiation to be deferred in appropriately selected patients without negatively impacting progression.
View details for DOI 10.1016/j.jtho.2021.08.009
View details for PubMedID 34455066
-
Pharmacovigilance analysis of cardiac toxicities associated with targeted therapies for metastatic non-small cell lung carcinoma.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2021
Abstract
INTRODUCTION: Targeted therapies have transformed treatment of driver-mutated metastatic non-small cell lung carcinoma (NSCLC). We compared cardiovascular adverse events between and within targeted therapy classes.METHODS: We used WHO pharmacovigilance database VigiBase to compare odds of heart failure, conduction disease, QT prolongation, supraventricular tachycardia (SVT), and ventricular arrhythmias between inhibitors of EGFR (erlotinib, gefitinib, afatinib, osimertinib), BRAF (dabrafenib), MEK (trametinib), and ALK ± ROS1 (alectinib, brigatinib, ceritinib, crizotinib, lorlatinib).RESULTS: Of 98,765 adverse reactions reported with NSCLC targeted therapies, 1,783 (1.8%) were arrhythmias and 1,146 (1.2%) were heart failure. ALK/ROS1 inhibitors were associated with increased odds of conduction disease (reporting odds ratio [ROR] 12.95, 99% CI: 10.14-16.55) and QT prolongation (ROR 5.16, 99% CI: 3.92-6.81) relative to BRAF and EGFR inhibitors. Among ALK/ROS1 inhibitors, crizotinib had highest odds of conduction disease (ROR 1.75, 99% CI: 1.30-2.36) and QT prolongation (ROR 1.91, 99% CI: 1.22-3.00). Dabrafenib (ROR 2.24, 99% CI: 1.86-2.70) and trametinib (ROR 2.44, 99% CI: 2.03-2.92) had higher odds of heart failure than other targeted therapies. Osimertinib was strongly associated with QT prolongation (ROR 6.13, 99% CI: 4.43-8.48), heart failure (ROR 3.64, 99% CI: 2.94-4.50), and SVT (ROR 1.90, 99% CI: 1.26-2.86) relative to other targeted therapies.CONCLUSIONS: ALK/ROS1 inhibitors are associated with higher odds of conduction disease and QT prolongation than other targeted therapies. Osimertinib is strongly associated with QT prolongation, SVT, and heart failure relative to other EGFR inhibitors and targeted therapies. Monitoring for heart failure and arrhythmias should be considered with NSCLC targeted therapies, especially osimertinib.
View details for DOI 10.1016/j.jtho.2021.07.030
View details for PubMedID 34418561
-
Radiological tumour classification across imaging modality and histology
NATURE MACHINE INTELLIGENCE
2021
View details for DOI 10.1038/s42256-021-00377-0
View details for Web of Science ID 000685037800005
-
Incidence of Lung Cancer Among Never-Smoking Asian American, Native Hawaiian, and Pacific Islander Females.
Journal of the National Cancer Institute
2021
Abstract
BACKGROUND: Although lung cancer incidence rates according to smoking status, sex, and detailed race/ethnicity have not been available, it is estimated that over half of Asian American, Native Hawaiian, and Pacific Islander (AANHPI) females with lung cancer have never smoked.METHODS: We calculated age-adjusted incidence rates for lung cancer according to smoking status and detailed race/ethnicity among females, focusing on AANHPI ethnic groups, and assessed relative incidence across racial/ethnic groups. We used a large-scale dataset that integrates data from electronic health records from two large healthcare systems-Sutter Health in Northern California and Kaiser Permanente Hawai'i-linked to state cancer registries for incident lung cancer diagnoses between 2000-2013. The study population included 1,222,694 females (n=244,147 AANHPI), 3,297 of which were diagnosed with lung cancer (n=535 AANHPI).RESULTS: Incidence of lung cancer among never-smoking AANHPI as an aggregate group was 17.1 per 100,000 (95% confidence interval [CI] = 14.9, 19.4), but varied widely across ethnic groups. Never-smoking Chinese American females had the highest rate (22.8 per 100,000, 95% CI=17.3, 29.1). Except for Japanese American females, incidence among every never-smoking AANHPI female ethnic group was higher than that of never-smoking non-Hispanic White females, from 66% greater among Native Hawaiian females (incidence rate ratio = 1.66; 95% CI=1.03, 2.56) to over 100% greater among Chinese American females (incidence rate ratio = 2.26; 95% CI=1.67-3.02).CONCLUSIONS: Our study revealed high rates of lung cancer among most never-smoking AANHPI female ethnic groups. Our approach illustrates the use of innovative data integration to dispel the myth that AANHPI females are at overall reduced risk of lung cancer and demonstrates the need to disaggregate this highly diverse population.
View details for DOI 10.1093/jnci/djab143
View details for PubMedID 34345919
-
A Moving Target: Integration of Smoking Cessation Into Screening for Second Primary Lung Cancer.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2021; 16 (8): e59-e60
View details for DOI 10.1016/j.jtho.2021.05.008
View details for PubMedID 34304856
-
EGFR exon 20 Insertion NSCLC and Response to Platinum-Based Chemotherapy.
Clinical lung cancer
2021
Abstract
INTRODUCTION: In classical EGFR mutant non-small-cell lung cancer (NSCLC), EGFR tyrosine kinase inhibitor (TKI) therapy yields better outcomes than platinum-based chemotherapy. However, EGFR exon 20 insertion (ex20ins) NSCLC is relatively resistant to currently available EGFR TKIs. Though platinum-based chemotherapy is the frontline standard of care for EGFR ex20ins NSCLC, its efficacy is not fully described.STUDY DESIGN: A retrospective, single-center, case series METHODS: Patients were identified through an electronic research database at a single institution and included if they had advanced EGFR ex20ins NSCLC, received platinum-based chemotherapy for metastatic disease, and had scans evaluable for response. Each patient's demographics, tumor characteristics, and clinical course were recorded. Treatment response was evaluated using RECIST v1.1 criteria, and the PFS was calculated by the Kaplan-Meier method.RESULTS: Among 27 patients identified with EGFR ex20ins NSCLC at our institution, 18 (67%) received platinum-based chemotherapy for metastatic disease and had scans evaluable for response. These patients received platinum-based chemotherapy in the first-line (N=17, 94%) and second-line settings (N=1, 6%). The objective response rate (ORR) to platinum-based chemotherapy was 39% (7 of 18 patients; 95% confidence interval [CI] 16-61). The median PFS with platinum-based chemotherapy was 7.1 months (95% CI, 6.3 -13.7), and the median overall survival was 3.2 years (95% CI, 1.92 - NR).CONCLUSIONS: The efficacy of platinum-based chemotherapy in EGFR ex20ins NSCLC is similar to that expected for TKI sensitive EGFR mutant NSCLC. Novel agents designed to specifically target ex20ins mutant EGFR should additionally improve outcomes.
View details for DOI 10.1016/j.cllc.2021.07.001
View details for PubMedID 34391686
-
Development and Validation of a Risk Prediction Tool for Second Primary Lung Cancer.
Journal of the National Cancer Institute
2021
Abstract
BACKGROUND: With advancing therapeutics, lung cancer (LC) survivors are rapidly increasing in number. While mounting evidence suggests LC survivors have high risk of second primary lung cancer (SPLC), there is no validated prediction tool available for clinical use to identify high-risk LC survivors for SPLC.METHODS: Using data from 6,325 ever-smokers in the Multiethnic Cohort (MEC) diagnosed with initial primary lung cancer (IPLC) in 1993-2017, we developed a prediction model for 10-year SPLC risk after IPLC diagnosis using cause-specific Cox regression. We evaluated the model's clinical utility using decision curve analysis and externally validated it using two population-based data, PLCO and NLST, that included 2,963 and 2,844 IPLC (101 and 93 SPLC cases), respectively.RESULTS: Over 14,063 person-years, 145 (2.3%) developed SPLC in MEC. Our prediction model demonstrated a high predictive accuracy (Brier score = 2.9, 95% confidence interval [CI] = 2.4-3.3) and discrimination (AUC = 81.9%, 95% CI=78.2%-85.5%) based on bootstrap validation in MEC. Stratification by the estimated risk quartiles showed that the observed SPLC incidence was statistically significantly higher in the 4th versus 1st quartile (9.5% versus 0.2%; P<.001). Decision curve analysis indicated that in a wide range of 10-year risk thresholds from 1% to 20%, the model yielded a larger net-benefit versus hypothetical all-screening or no-screening scenarios. External validation using PLCO and NLST showed an AUC of 78.8% (95% CI=74.6%-82.9%) and 72.7% (95% CI=67.7%-77.7%), respectively.CONCLUSIONS: We developed and validated a SPLC prediction model based on large population-based cohorts. The proposed prediction tool can help identify high-risk LC patients for SPLC and can be incorporated into clinical decision-making for SPLC surveillance and screening.
View details for DOI 10.1093/jnci/djab138
View details for PubMedID 34255071
-
Liquid Biopsy for Advanced Non-Small Cell Lung Cancer: A Consensus Statement from The International Association for the Study of Lung Cancer (IASLC).
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2021
View details for DOI 10.1016/j.jtho.2021.06.017
View details for PubMedID 34246791
-
Genomic clustering analysis identifies molecular subtypes of thymic epithelial tumors independent of World Health Organization histologic type.
Oncotarget
2021; 12 (12): 1178-1186
Abstract
Further characterization of thymic epithelial tumors (TETs) is needed. Genomic information from 102 evaluable TETs from The Cancer Genome Atlas (TCGA) dataset and from the IU-TAB-1 cell line (type AB thymoma) underwent clustering analysis to identify molecular subtypes of TETs. Six novel molecular subtypes (TH1-TH6) of TETs from the TCGA were identified, and there was no association with WHO histologic subtype. The IU-TAB-1 cell line clustered into the TH4 molecular subtype and in vitro testing of candidate therapeutics was performed. The IU-TAB-1 cell line was noted to be resistant to everolimus (mTORC1 inhibitor) and sensitive to nelfinavir (AKT1 inhibitor) across the endpoints measured. Sensitivity to nelfinavir was due to the IU-TAB-1 cell line's gain-of function (GOF) mutation in PIK3CA and amplification of genes observed from array comparative genomic hybridization (aCGH), including AURKA, ERBB2, KIT, PDGFRA and PDGFB, that are known upregulate AKT, while resistance to everolimus was primarily driven by upregulation of downstream signaling of KIT, PDGFRA and PDGFB in the presence of mTORC1 inhibition. We present a novel molecular classification of TETs independent of WHO histologic subtype, which may be used for preclinical validation studies of potential candidate therapeutics of interest for this rare disease.
View details for DOI 10.18632/oncotarget.27978
View details for PubMedID 34136086
-
Phase I/II study of nivolumab plus vorolanib in patients with thoracic malignancies: Interim efficacy of the SCLC and primary refractory NSCLC cohorts, and safety data across all cohorts.
LIPPINCOTT WILLIAMS & WILKINS. 2021
View details for DOI 10.1200/JCO.2021.39.15_suppl.2578
View details for Web of Science ID 000708120601099
-
Randomized phase III Trial of MEDI4736 (durvalumab) as concurrent and consolidative therapy or consolidative therapy alone for unresectable stage 3 NSCLC: A trial of the ECOG-ACRIN Cancer Research Group (EA5181).
LIPPINCOTT WILLIAMS & WILKINS. 2021
View details for DOI 10.1200/JCO.2021.39.15_suppl.TPS8584
View details for Web of Science ID 000708120307032
-
IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC).
LIPPINCOTT WILLIAMS & WILKINS. 2021
View details for DOI 10.1200/JCO.2021.39.15_suppl.8500
View details for Web of Science ID 000708120604214
-
Integrating electronic health record, cancer registry, and geospatial data to study lung cancer in Asian American, Native Hawaiian and Pacific Islander ethnic groups.
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
2021
Abstract
BACKGROUND: A relatively high proportion of Asian American, Native Hawaiian, and Pacific Islander (AANHPI) females with lung cancer have never smoked. We used an integrative data approach to assemble a large-scale cohort to study lung cancer risk among AANHPI by smoking status with attention to representation of specific AANHPI ethnic groups.METHODS: We leveraged electronic health records (EHRs) from two healthcare systems-Sutter Health in northern California and Kaiser Permanente Hawai'i- that have high representation of AANHPI populations. We linked EHR data on lung cancer risk factors (i.e., smoking, lung diseases, infections, reproductive factors, and body size) to data on incident lung cancer diagnoses from statewide population-based cancer registries of California and Hawai'i for the period 2000-2013. Geocoded address data were linked to data on neighborhood contextual factors and regional air pollutants.RESULTS: The dataset comprises over 2.2 million adult females and males of any race/ethnicity. Over 250,000 are AANHPI females (19.6% of the female study population). Smoking status is available for over 95% of individuals. The dataset includes 7,274 lung cancer cases, including 613 cases among AANHPI females. Prevalence of never-smoking status varied greatly among AANHPI females with incident lung cancer, from 85.7% among Asian Indian to 14.4% among Native Hawaiian females.CONCLUSION: We have developed a large, multilevel dataset particularly well-suited to conduct prospective studies of lung cancer risk among AANHPI females who never smoked.IMPACT: The integrative data approach is an effective way to conduct cancer research assessing multilevel factors on cancer outcomes among small populations.
View details for DOI 10.1158/1055-9965.EPI-21-0019
View details for PubMedID 34001502
-
Immune Checkpoint Inhibitor Pneumonitis: Heterogeneity in Clinical Management
AMER THORACIC SOC. 2021
View details for Web of Science ID 000685468901382
-
The Survival Impact of Second Primary Lung Cancer in Patients with Lung Cancer
AMER THORACIC SOC. 2021
View details for Web of Science ID 000685468904797
-
Pragmatic Application of Computed Tomography Lung Texture Analysis in Immune Checkpoint Inhibitor Pneumonitis: An Exploratory Study
AMER THORACIC SOC. 2021
View details for Web of Science ID 000685468901148
-
Chemotherapy with or without immunotherapy or bevacizumab for EGFR-mutated lung cancer after progression on osimertinib
ELSEVIER SCIENCE INC. 2021: S773–S774
View details for Web of Science ID 000634855900139
-
Circulating tumor DNA kinetics to identify genomic predictors of rapid response to chemoradiation in non-small cell lung cancer.
AMER ASSOC CANCER RESEARCH. 2021
View details for Web of Science ID 000641160600097
-
Investigating gene expression profiles associated with clinical radiation resistance in KEAP1/NFE2L2 wildtype lung cancer.
AMER ASSOC CANCER RESEARCH. 2021
View details for Web of Science ID 000641160600087
-
Genetic determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In Vivo.
Cancer discovery
2021
Abstract
In lung adenocarcinoma, oncogenic EGFR mutations co-occur with many tumor suppressor gene alterations, however the extent to which these contribute to tumor growth and response to therapy in vivo remains largely unknown. By quantifying the effects of inactivating ten putative tumor suppressor genes in a mouse model of EGFR-driven Trp53-deficient lung adenocarcinoma, we found that Apc, Rb1, or Rbm10 inactivation strongly promoted tumor growth. Unexpectedly, inactivation of Lkb1 or Setd2 - the strongest drivers of growth in a Kras-driven model - reduced EGFR-driven tumor growth. These results are consistent with mutational frequencies in human EGFR- and KRAS-driven lung adenocarcinomas. Furthermore, Keap1 inactivation reduced the sensitivity of EGFR-driven tumors to the EGFR inhibitor osimertinib and mutations in the KEAP1 pathway were associated with decreased time on tyrosine kinase inhibitor treatment in patients. Our study highlights how the impact of genetic alterations differ across oncogenic contexts and that the fitness landscape shifts upon treatment.
View details for DOI 10.1158/2159-8290.CD-20-1385
View details for PubMedID 33707235
-
Metabolomic profiling for second primary lung cancer: A pilot case-control study.
Lung cancer (Amsterdam, Netherlands)
2021; 155: 61–67
Abstract
OBJECTIVES: Lung cancer survivors have a high risk of developing a second primary lung cancer (SPLC). While national screening guidelines have been established for initial primary lung cancer (IPLC), no consensus guidelines exist for SPLC. Furthermore, the factors that contribute to SPLC risk have not been established. This study examines the potential for using serum metabolomics to identify metabolite biomarkers that differ between SPLC cases and IPLC controls.MATERIAL AND METHODS: In this pilot case-control study, we applied an untargeted metabolomics approach based on ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) to serum samples of 82 SPLC cases and 82 frequency matched IPLC controls enrolled in the Boston Lung Cancer Study. Random forest and unconditional logistic regression models identified metabolites associated with SPLC. Candidate metabolites were integrated into a SPLC risk prediction model and the model performance was evaluated through a risk stratification approach.RESULTS: The untargeted analysis detected 1008 named and 316 unnamed metabolites among all study participants. Metabolites that were significantly associated with SPLC (False Discovery Rate q-value < 0.2) included 5-methylthioadenosine (odds ratio [OR] = 2.04, 95 % confidence interval [CI] 1.39-3.01; P = 2.8 * 10-4) and phenylacetylglutamine (OR = 2.65, 95 % CI 1.56-4.51; P = 3.2 * 10-4), each exhibiting approximately 1.5-fold increased levels among SPLC cases versus IPLC controls. In stratifying the study participants across quartiles of estimated SPLC risk, the risk prediction model identified a significantly higher proportion of SPLC cases in the fourth compared to the first quartile (68.3 % versus 39.0 %; P = 0.044).CONCLUSION: SPLC cases may have distinct metabolomic profiles compared to those in IPLC patients without SPLC. A risk stratification approach integrating metabolomics may be useful for distinguishing patients based on SPLC risk. Prospective validation studies are needed to further evaluate the potential for leveraging metabolomics in SPLC surveillance and screening.
View details for DOI 10.1016/j.lungcan.2021.03.007
View details for PubMedID 33743383
-
Healthcare Utilization with an Electronic Patient Reported Outcome (ePRO) tool for Symptom Management in Thoracic Cancers
ELSEVIER SCIENCE INC. 2021: S170–S171
View details for Web of Science ID 000631349600192
-
Myocarditis Surveillance with High-Sensitivity Troponin I During Cancer Treatment with Immune Checkpoint Inhibitors.
JACC. CardioOncology
2021; 3 (1): 137–39
View details for DOI 10.1016/j.jaccao.2021.01.004
View details for PubMedID 33796869
-
Coping Strategy Influences Quality of Life in Patients With Advanced Lung Cancer by
CLINICAL LUNG CANCER
2021; 22 (2): E153–E156
View details for DOI 10.1016/j.cllc.2020.09.020ClinicalLungCancerMarch2021-e153
View details for Web of Science ID 000632897400012
-
Time to First Progression in Patients with NSCLC with Brain Metastases Receiving 3rd Generation TKI alone vs TKI plus Brain Radiation
ELSEVIER SCIENCE INC. 2021: S591–S592
View details for Web of Science ID 000631349601489
-
Quality of Life and Subgroup Analysis in a Phase 3 Randomized Study of Ensartinib vs Crizotinib in ALK-Positive NSCLC Patients: eXalt3.
ELSEVIER SCIENCE INC. 2021: S232–S233
View details for Web of Science ID 000631349600306
-
RAS Precision Medicine Trans-Atlantic Partnership: Multi-Centre Pooled Analysis of RAS Pathway Mutations in Advanced NSCLC
ELSEVIER SCIENCE INC. 2021: S696
View details for Web of Science ID 000631349602095
-
The Mutational Landscape in South Asian Patients with Non-Small Cell Lung Cancer at an US Academic Medical Center
ELSEVIER SCIENCE INC. 2021: S428
View details for Web of Science ID 000631349601162
-
COVID-19 Outcomes in Patients With Thoracic Malignancies According to Gender and Ethnicity (TERAVOLT)
ELSEVIER SCIENCE INC. 2021: S297
View details for Web of Science ID 000631349600429
-
Impact of Medicaid Enrollment on Mortality in Elderly Dual-Eligible Lung Cancer Patients
ELSEVIER SCIENCE INC. 2021: S306
View details for Web of Science ID 000631349600447
-
Impact of Low-Dose CT Screening for Primary Lung Cancer on Subsequent Risk of Brain Metastasis: Secondary Analysis of NLST
ELSEVIER SCIENCE INC. 2021: S149–S150
View details for Web of Science ID 000631349600153
-
Afatinib and Necitumumab in EGFR mutant NSCLC with Acquired Resistance to 1st or 3rd Generation EGFR Tyrosine Kinase Inhibitors
ELSEVIER SCIENCE INC. 2021: S626
View details for Web of Science ID 000631349601560
-
Afatinib After Progression on Osimertinib in Patients with EGFR-Mutated Lung Adenocarcinoma
ELSEVIER SCIENCE INC. 2021: S619
View details for Web of Science ID 000631349601545
-
A review of immunotherapy for stage 3 and metastatic NSCLC & the rationale for the ECOG-ACRIN EA5181 study.
The oncologist
2021
Abstract
ECOG-ACRIN EA5181 is a phase III prospective, randomized trial that randomizes patients undergoing chemo/radiation for locally advanced non-small cell lung cancer (LA- NSCLC) to concomitant durvalumab or no additional therapy with both arms receiving one year of consolidative durvalumab. Radiation dose-escalation failed to improve overall survival in RTOG 0617. However, conventionally-fractionated radiation to 60Gy with concomitant chemotherapy is associated with a high risk of local failure (38-46%). It is hoped that concomitant immunotherapy during chemo/radiation can help decrease the risk of local failure, thereby improving overall survival and progression-free survival with acceptable toxicity. In this article, we will review conventional chemo/radiation therapy for LA-NSCLC as well as the quickly evolving world of immunotherapy in the treatment of NSCLC and discuss the rationale and study design of EA5181. IMPLICATIONS FOR PRACTICE: Our article provides an up-to-date assessment of how immunotherapy is re-shaping the landscape of metastatic NSCLC and how the impact of this therapy is now rapidly moving into the treatment of patients with locally advanced NSCLC who are presenting for curative treatment. We will review the history of concurrent chemo/radiation, the recent publications of immunotherapy combined with chemotherapy or chemo/radiation, and our strategy for improving the OS of patients with locally advanced NSCLC by using concomitant immunotherapy with standard concurrent chemo/radiation.
View details for DOI 10.1002/onco.13725
View details for PubMedID 33594771
-
Efficacy and Safety of Rociletinib Versus Chemotherapy in Patients With EGFR-Mutated NSCLC: The Results of TIGER-3, a Phase 3 Randomized Study.
JTO clinical and research reports
2021; 2 (2): 100114
Abstract
Introduction: The TIGER-3 (NCT02322281) study was initiated to compare the efficacy and safety of rociletinib, a third-generation EGFR tyrosine kinase inhibitor (TKI) that targets EGFR T790M and common EGFR-activating mutations, versus chemotherapy in patients with NSCLC who progressed on first- or second-generation EGFR TKIs.Methods: Patients with advanced or metastatic EGFR-mutated NSCLC with disease progression on standard therapy (previous EGFR TKI and platinum-based chemotherapy) were randomized to oral rociletinib (500 or 625 mg twice daily) or single-agent chemotherapy (pemetrexed, gemcitabine, docetaxel, or paclitaxel).Results: Enrollment was halted when rociletinib development was discontinued in 2016. Of 149 enrolled patients, 75 were randomized to rociletinib (n= 53: 500 mg twicedaily; n= 22: 625 mg twice daily) and 74 to chemotherapy. The median investigator-assessed progression-free survival (PFS) was 4.1 months (95% confidence interval [CI]: 2.6-5.4) in the rociletinib 500-mg group and 5.5 months (95% CI: 1.8-8.1) in the 625-mg group versus 2.5 months (95% CI: 1.4-2.9) in the chemotherapy group. An improved PFS was observed in patients with T790M-positive NSCLC treated with rociletinib (n= 25; 500 mg and 625 mg twice daily) versus chemotherapy (n= 20; 6.8 versus 2.7 mo; hazard ratio= 0.55, 95% CI: 0.28-1.07, p=0.074). Grade 3 or higher hyperglycemia (24.0%), corrected QT prolongation (6.7%), diarrhea (2.7%), and vomiting (1.3%) were more frequent with rociletinib than chemotherapy (0%, 0%, 1.4%, and 0%, respectively).Conclusions: Rociletinib had a more favorable median PFS versus chemotherapy but had higher rates of hyperglycemia and corrected QT prolongation in patients with advanced EGFR-mutated NSCLC who progressed on previous EGFR TKI. Incomplete enrollment prevented evaluation of the primary efficacy end point.
View details for DOI 10.1016/j.jtocrr.2020.100114
View details for PubMedID 34589984
-
Computational Biological Modeling Identifies PD-(L)1 Immunotherapy Sensitivity Among Molecular Subgroups of KRAS-Mutated Non-Small-Cell Lung Cancer
JCO PRECISION ONCOLOGY
2021; 5: 153–62
View details for DOI 10.1200/PO.20.00172
View details for Web of Science ID 000636553300004
-
Global analysis of shared T cell specificities in human non-small cell lung cancer enables HLA inference and antigen discovery.
Immunity
2021; 54 (3): 586–602.e8
Abstract
To identify disease-relevant T cell receptors (TCRs) with shared antigen specificity, we analyzed 778,938 TCRβ chain sequences from 178 non-small cell lung cancer patients using the GLIPH2 (grouping of lymphocyte interactions with paratope hotspots 2) algorithm. We identified over 66,000 shared specificity groups, of which 435 were clonally expanded and enriched in tumors compared to adjacent lung. The antigenic epitopes of one such tumor-enriched specificity group were identified using a yeast peptide-HLA A∗02:01 display library. These included a peptide from the epithelial protein TMEM161A, which is overexpressed in tumors and cross-reactive epitopes from Epstein-Barr virus and E. coli. Our findings suggest that this cross-reactivity may underlie the presence of virus-specific T cells in tumor infiltrates and that pathogen cross-reactivity may be a feature of multiple cancers. The approach and analytical pipelines generated in this work, as well as the specificity groups defined here, present a resource for understanding the T cell response in cancer.
View details for DOI 10.1016/j.immuni.2021.02.014
View details for PubMedID 33691136
-
Impact of Low-Dose CT Screening for Primary Lung Cancer on Subsequent Risk of Brain Metastasis.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2021
Abstract
Brain metastasis (BM) is one of the most common metastases from primary lung cancer (PLC). Recently, the National Lung Screening Trial (NLST) demonstrated the efficacy of low-dose computed tomography (LDCT) screening on LC mortality reduction. However, it remains unknown if early detection of PLC through LDCT may be potentially beneficial in reducing the risk of subsequent metastases. Our study aimed to investigate the impact of LDCT screening for PLC on the risk of developing BM after PLC diagnosis.We used NLST data to identify 1,502 participants who were diagnosed with PLC in 2002-2009 and have follow-up data for BM. Cause-specific competing risk regression was applied to evaluate an association between BM risk and the mode of PLC detection-i.e., LDCT screen-detected versus non-LDCT screen-detected. Subgroup analyses were conducted in early-stage PLC patients and those who underwent surgery for PLC.Of 1502 participants, 41.4% had PLC detected through LDCT-screening versus 58.6% detected through other methods, e.g., chest X-Ray or incidental detection. Patients whose PLC was detected with LDCT-screening had a significantly lower 3-year incidence of BM (6.5%) versus those without (11.9%), with a cause-specific hazard ratio (HR) of 0.53 (p=0.001), adjusting for PLC stage, histology, diagnosis age and smoking status. This significant reduction in BM risk among PLCs detected through LDCT-screening persisted in subgroups of early-stage PLC participants (HR 0.47, p=0.002) and those who underwent surgery (HR 0.37, p=0.001).Early detection of PLC using LDCT-screening is associated with lower risk of BM after PLC diagnosis based on a large population-based study.
View details for DOI 10.1016/j.jtho.2021.05.010
View details for PubMedID 34091050
-
Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial.
Lancet (London, England)
2021
Abstract
Novel adjuvant strategies are needed to optimise outcomes after complete surgical resection in patients with early-stage non-small-cell lung cancer (NSCLC). We aimed to evaluate adjuvant atezolizumab versus best supportive care after adjuvant platinum-based chemotherapy in these patients.IMpower010 was a randomised, multicentre, open-label, phase 3 study done at 227 sites in 22 countries and regions. Eligible patients were 18 years or older with completely resected stage IB (tumours ≥4 cm) to IIIA NSCLC per the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system (7th edition). Patients were randomly assigned (1:1) by a permuted-block method (block size of four) to receive adjuvant atezolizumab (1200 mg every 21 days; for 16 cycles or 1 year) or best supportive care (observation and regular scans for disease recurrence) after adjuvant platinum-based chemotherapy (one to four cycles). The primary endpoint, investigator-assessed disease-free survival, was tested hierarchically first in the stage II-IIIA population subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells (SP263), then all patients in the stage II-IIIA population, and finally the intention-to-treat (ITT) population (stage IB-IIIA). Safety was evaluated in all patients who were randomly assigned and received atezolizumab or best supportive care. IMpower010 is registered with ClinicalTrials.gov, NCT02486718 (active, not recruiting).Between Oct 7, 2015, and Sept 19, 2018, 1280 patients were enrolled after complete resection. 1269 received adjuvant chemotherapy, of whom 1005 patients were eligible for randomisation to atezolizumab (n=507) or best supportive care (n=498); 495 in each group received treatment. After a median follow-up of 32·2 months (IQR 27·4-38·3) in the stage II-IIIA population, atezolizumab treatment improved disease-free survival compared with best supportive care in patients in the stage II-IIIA population whose tumours expressed PD-L1 on 1% or more of tumour cells (HR 0·66; 95% CI 0·50-0·88; p=0·0039) and in all patients in the stage II-IIIA population (0·79; 0·64-0·96; p=0·020). In the ITT population, HR for disease-free survival was 0·81 (0·67-0·99; p=0·040). Atezolizumab-related grade 3 and 4 adverse events occurred in 53 (11%) of 495 patients and grade 5 events in four patients (1%).IMpower010 showed a disease-free survival benefit with atezolizumab versus best supportive care after adjuvant chemotherapy in patients with resected stage II-IIIA NSCLC, with pronounced benefit in the subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells, and no new safety signals. Atezolizumab after adjuvant chemotherapy offers a promising treatment option for patients with resected early-stage NSCLC.F Hoffmann-La Roche and Genentech.
View details for DOI 10.1016/S0140-6736(21)02098-5
View details for PubMedID 34555333
-
RAS precision medicine trans-Atlantic partnership: Multi-centre analysis of RAS and NF1 co-mutations in advanced NSCLC
ELSEVIER. 2021: S1221
View details for DOI 10.1016/j.annonc.2021.08.1730
View details for Web of Science ID 000700527703330
-
SKYSCRAPER-03: Phase III, open-label randomised study of atezolizumab plus tiragolumab vs durvalumab in patients with locally advanced, unresectable, stage III non-small cell lung cancer (NSCLC) who have not progressed after platinum-based concurrent chemoradiation (cCRT)
ELSEVIER. 2021: S947-S948
View details for DOI 10.1016/j.annonc.2021.08.1794
View details for Web of Science ID 000700527702207
-
IMpower010: Sites of relapse and subsequent therapy from a phase III study of atezolizumab vs best supportive care after adjuvant chemotherapy in stage IB-IIIA NSCLC
ELSEVIER. 2021: S1319
View details for DOI 10.1016/j.annonc.2021.08.2120
View details for Web of Science ID 000700527703519
-
The Survival Impact of Second Primary Lung Cancer in Patients with Lung Cancer.
Journal of the National Cancer Institute
2021
Abstract
Lung cancer survivors have a high risk of developing second primary lung cancer (SPLC), but little is known about the survival impact of SPLC diagnosis.We analyzed data from 138,969 patients in the Surveillance, Epidemiology, and End Results (SEER), who were surgically treated for initial primary lung cancer (IPLC) in 1988-2013. Each patient was followed from the date of IPLC diagnosis to SPLC diagnosis (for those with SPLC) and last vital status through 2016. We performed multivariable Cox regression to evaluate the association between overall survival and SPLC diagnosis as a time-varying predictor. To investigate potential effect modification, we tested interaction between SPLC and IPLC stage. Using data from the Multiethnic Cohort Study (MEC) (N = 1,540 IPLC patients with surgery), we evaluated the survival impact of SPLC by smoking status. All statistical tests were 2-sided.A total of 12,115 (8.7%) patients developed SPLC in SEER over 700,421 person-years of follow up. Compared to patients with single primary lung cancer, those with SPLC had statistically significantly reduced overall survival (hazard ratio [HR]=2.12, 95% confidence interval [CI] = 2.06-2.17; P < .001). The effect of SPLC on reduced survival was more pronounced among patients with early-stage IPLC vs. advanced-stage IPLC (HR = 2.14 [95% CI = 2.08-2.20] vs. 1.43 [95% CI = 1.21-1.70], respectively; Pinteraction <0.001). Analysis using MEC data showed that the effect of SPLC on reduced survival was statistically significantly larger among persons who actively smoked at initial diagnosis vs. those who formerly or never smoked (HR = 2.31 [95% CI = 1.48-3.61] vs. 1.41 [95% CI = 0.98-2.03], respectively; Pinteraction=0.04).SPLC diagnosis is statistically significantly associated with decreased survival in SEER and MEC. Intensive surveillance targeting patients with early-stage IPLC and active smoking at IPLC diagnosis may lead to a larger survival benefit.
View details for DOI 10.1093/jnci/djab224
View details for PubMedID 34893871
-
Brief Report: Role of Consolidation Durvalumab in patients with EGFR and HER2 Mutant Unresectable Stage III NSCLC.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2021
Abstract
Despite the recent advance of consolidation durvalumab in the treatment of unresectable stage III non-small cell lung cancer (NSCLC), not every patient benefits from durvalumab and predictive markers of response have been difficult to identify.We performed a retrospective analysis of patients with unresectable stage III NSCLC treated with consolidation durvalumab following definitive chemoradiation from January 2018 to March 2020.Thirty-six patients with unresectable stage III NSCLC were treated with consolidation durvalumab. Fourteen of these patients had tumor mutations in the ERBB family including 11 EGFR and 3 ERBB2. The ERBB2/EGFR tumor mutation cohort was more likely to be non-smokers; otherwise the two groups were similar in age, sex, PD-L1 expression and type of prior chemotherapy regimen. Patients in the ERBB2/EGFR cohort had a significantly shorter disease free survival compared to the EGFR/ERBB2 wildtype cohort (7.5 months vs NR, p= 0.04).Consolidation durvalumab appears to be less efficacious in patients with ERBB2/EGFR mutant tumors. Future work should seek to evaluate this in the prospective setting and provide insight into the optimal treatment of ERBB2/EGFR-mutant stage III NSCLC.
View details for DOI 10.1016/j.jtho.2020.12.020
View details for PubMedID 33539970
-
Smoking Behavior in Patients with Early Stage NSCLC: A Report from ECOG-ACRIN 1505 Trial.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2021
Abstract
Smoking cessation has been reported to benefit patients even after a diagnosis of lung cancer. We studied the smoking behavior of patients who participated in a phase 3 trial of adjuvant therapy following resection of stages IB-IIIA non-small cell lung cancer (NSCLC).ECOG-ACRIN 1505 was conducted to determine whether the addition of bevacizumab to adjuvant chemotherapy would improve overall survival (OS) for patients with early stage NSCLC. Studying the association between smoking status and OS was a secondary endpoint. Patients completed a questionnaire about their smoking habits at baseline, 3, 6, 9 and 12 months.1501 patients were enrolled and 99.8%, 95%, 94%, 93%, and 93% responded to the questionnaire at baseline, 3, 6, 9 and 12 months, respectively. 90% reported a current or previous history of cigarette smoking. 60% of non-smokers at enrollment reported smoking after diagnosis (before randomization); however, 1% of them reported smoking at 12 months. 94% of respondents smoked none/fewer cigarettes daily at 12 months. The incidence of grades 3-5 toxicity on treatment was 68%, 76%, and 72% in never, former, and current smokers, respectively (p=0.05). The disease-free survival (DFS) for never-smokers relative to current and former smokers was (HR 0.93, p=0.64, HR 1.05, p=0.72), and OS was (adjusted HR for death 0.54, p=0.005, adjusted HR for death 0.68, p=0.03), respectively.This is the first comprehensive, prospective report of smoking habits in NSCLC patients from a phase III early stage trial. There was a high rate of smoking reduction and cessation following study entry. DFS did not differ significantly between smokers and never smokers, though there were less grade 3-5 toxicities and more favorable OS in never-smokers.
View details for DOI 10.1016/j.jtho.2020.12.017
View details for PubMedID 33539971
-
Durvalumab for Patients with Stage III EGFR-Mutated Non-Small Cell Lung Cancer Receiving Definitive Chemoradiotherapy
ELSEVIER SCIENCE INC. 2021: S15
View details for Web of Science ID 000610079600029
-
Improved survival and disease control following pembrolizumab-induced immune-related adverse events in high PD-L1 expressing non-small cell lung cancer with brain metastases.
Journal of neuro-oncology
2021
Abstract
Immune checkpoint inhibitors have become standard of care for many patients with non-small cell lung cancer (NSCLC). These agents often cause immune-related adverse events (IRAEs), which have been associated with increased overall survival (OS). Intracranial disease control and OS for patients experiencing IRAEs with metastatic NSCLC and brain metastases have not yet been described.We performed a single-institution, retrospective review of patients with NSCLC and existing diagnosis of brain metastasis, who underwent pembrolizumab treatment and developed any grade IRAE. The primary outcome of the study was intracranial time to treatment failure (TTF), defined from time of pembrolizumab initiation to new intracranial disease progression or death. Kaplan-Meier and Cox proportional hazard analyses were performed.A total of 63 patients with NSCLC brain metastasis were identified, and 24 developed IRAEs. Patients with any grade IRAEs had longer OS (21 vs. 10 months, p = 0.004), systemic TTF (15 vs. 4 months, p < 0.001) and intracranial TTF (14 vs. 5 months, p = 0.001), relative to patients without IRAEs. Presence of IRAEs and high PD-L1 (≥ 50%), but not absent/moderate PD-L1 (0-49%), had a positive association for OS, systemic TTF, and intracranial TTF. Following multivariable analysis, IRAE experienced on pembrolizumab was an independent predictor of OS, systemic TTF, and intracranial TTF.In our series of patients with NSCLC and brain metastases treated with pembrolizumab, IRAE presence was associated with a significant increase in OS, systemic TTF, and intracranial TTF. Future studies with increased cohorts will clarify how IRAEs should be interpreted among molecular subtypes.
View details for DOI 10.1007/s11060-020-03686-3
View details for PubMedID 33415659
-
Combining Osimertinib With Chemotherapy in EGFR-Mutant NSCLC at Progression.
Clinical lung cancer
2021
Abstract
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor that has improved survival and central nervous system (CNS) outcomes in patients with non-small cell lung cancer (NSCLC) with activating EGFR mutations. However, little is known about the efficacy and safety of combining osimertinib with chemotherapy.This was a retrospective study performed at 3 institutions. Patients with advanced EGFR-mutated NSCLC who received concurrent osimertinib with chemotherapy in the third-line or beyond were identified by chart review. Efficacy outcomes including duration on treatment (DOT), overall survival (OS), and CNS outcomes were assessed. Safety outcomes were also evaluated.A total of 44 patients met inclusion criteria. Median DOT with osimertinib plus platinum doublet (n = 28) was 6.1 months (95% CI 4.1 months-not reached), and with osimertinib plus single-agent chemotherapy (n = 29) was 2.6 months (95% CI 1.8-4.8 months). Median OS from the start of osimertinib plus chemotherapy was 10.4 months (95% CI 7.0-13.2 months). At initiation of osimertinib plus chemotherapy, 37 patients (84%) had CNS metastases; 9 of these (24%) had CNS disease progression on osimertinib plus chemotherapy. Chemotherapy was delayed or dose reduced due to toxicity in 8 patients (18%); osimertinib was discontinued in 1 patient (2%) for reduced cardiac ejection fraction, and dose reduced in 2 patients (5%).The combination of osimertinib plus chemotherapy appeared safe and showed favorable control of CNS disease in this cohort of patients who had progressed systemically with multiple prior lines of therapy, with DOT and survival outcomes similar to historical chemotherapy controls.
View details for DOI 10.1016/j.cllc.2021.01.010
View details for PubMedID 33610453
-
Durvalumab for Stage III EGFR-Mutated Non-Small Cell Lung Cancer After Definitive Chemoradiotherapy.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2021
Abstract
In 2018, durvalumab was FDA approved as consolidation immunotherapy for patients with stage III non-small cell lung cancer (NSCLC) after definitive chemoradiotherapy (CRT). Whether durvalumab benefits patients with EGFR-mutated NSCLC remains unknown.We conducted a multi-institutional retrospective analysis of patients with unresectable stage III EGFR-mutated NSCLC who completed concurrent CRT. Kaplan-Meier analyses evaluated progression-free survival (PFS) between patients who completed CRT with or without durvalumab.Among 37 patients, 13 initiated durvalumab a median of 20 days after CRT completion. Two patients completed 12 months of treatment, with five patients discontinuing durvalumab due to progression and five due to immune-related adverse events (irAEs). Of 24 patients who completed CRT without durvalumab, 16 completed CRT alone and 8 completed CRT with induction or consolidation EGFR tyrosine kinase inhibitors (TKI). Median PFS was 10.3 months in patients who received CRT and durvalumab versus 6.9 months with CRT alone (log-rank P=0.993). CRT and EGFR TKI was associated with a significantly longer median PFS (26.1 months) compared to CRT and durvalumab or CRT alone (log-rank P=0.023). Six patients treated with durvalumab initiated EGFR TKIs after recurrence, with one developing grade 4 pneumonitis on osimertinib.In this study, patients with EGFR-mutated NSCLC did not benefit with consolidation durvalumab and experienced a high frequency of irAEs. Patients who initiate osimertinib after durvalumab may be susceptible to incident irAEs. Consolidation durvalumab should be approached with caution in this setting and concurrent CRT with induction and/or consolidation EGFR TKIs further investigated as definitive treatment.
View details for DOI 10.1016/j.jtho.2021.01.1628
View details for PubMedID 33588109
-
Safety of lorlatinib following alectinib-induced pneumonitis in two patients with ALK-rearranged non-small cell lung cancer: a case series.
Translational lung cancer research
2021; 10 (1): 487–95
Abstract
Drug-induced interstitial lung disease (DI-ILD) is a rare adverse event associated with targeted therapies that inhibit the anaplastic lymphoma kinase (ALK) protein. Although newer-generation ALK inhibitors such as alectinib significantly improve survival in metastatic ALK-rearranged non-small cell lung cancer (NSCLC), the risk of DI-ILD is similar to that of earlier-generation therapies. Lorlatinib is a third-generation ALK inhibitor that is active in patients with metastatic NSCLC whose tumors have developed secondary resistance to alectinib. While it is associated with low rates of DI-ILD in initial phase 1/2 clinical trials, the safety of lorlatinib in patients with a history of DI-ILD has not been well-described. In this case series, we therefore report two patients with metastatic ALK-rearranged NSCLC who each tolerated lorlatinib following recovery from alectinib-related DI-ILD. Both cases were notable for the acute onset of dyspnea, hypoxia, and diffuse ground-glass opacities within one month of initiating alectinib. With no alternative etiology of pneumonitis identified, both patients were treated empirically for grade 3 DI-ILD with corticosteroids and discontinuation of alectinib. Following rapid clinical recovery and eventual radiographic resolution of opacities, each patient was started on lorlatinib at the time of cancer progression, with neither person developing symptoms or radiographic findings consistent with recurrent DI-ILD. In the following series, we describe these two cases in greater detail and discuss their significance within the context of the prior literature. While further descriptions are needed, our experience suggests that lorlatinib may be a safe therapeutic option in some patients who have recovered from DI-ILD.
View details for DOI 10.21037/tlcr-20-564
View details for PubMedID 33569330
-
Smoking Cessation After Lung Cancer Diagnosis and Risk of Second Primary Lung Cancer: The Multiethnic Cohort Study
ELSEVIER SCIENCE INC. 2021: S40–S41
View details for Web of Science ID 000610079600083
-
Giant Magnetoresistive Nanosensor Analysis of Circulating Tumor DNA Epidermal Growth Factor Receptor Mutations for Diagnosis and Therapy Response Monitoring.
Clinical chemistry
2021
Abstract
Liquid biopsy circulating tumor DNA (ctDNA) mutational analysis holds great promises for precision medicine targeted therapy and more effective cancer management. However, its wide adoption is hampered by high cost and long turnaround time of sequencing assays, or by inadequate analytical sensitivity of existing portable nucleic acid tests to mutant allelic fraction in ctDNA.We developed a ctDNA Epidermal Growth Factor Receptor (EGFR) mutational assay using giant magnetoresistive (GMR) nanosensors. This assay was validated in 36 plasma samples of non-small cell lung cancer patients with known EGFR mutations. We assessed therapy response through follow-up blood draws, determined concordance between the GMR assay and radiographic response, and ascertained progression-free survival of patients.The GMR assay achieved analytical sensitivities of 0.01% mutant allelic fraction. In clinical samples, the assay had 87.5% sensitivity (95% CI = 64.0-97.8%) for Exon19 deletion and 90% sensitivity (95% CI = 69.9-98.2%) for L858R mutation with 100% specificity; our assay detected T790M resistance with 96.3% specificity (95% CI = 81.7-99.8%) with 100% sensitivity. After 2 weeks of therapy, 10 patients showed disappearance of ctDNA by GMR (predicted responders), whereas 3 patients did not (predicted nonresponders). These predictions were 100% concordant with radiographic response. Kaplan-Meier analysis showed responders had significantly (P < 0.0001) longer PFS compared to nonresponders (N/A vs. 12 weeks, respectively).The GMR assay has high diagnostic sensitivity and specificity and is well suited for detecting EGFR mutations at diagnosis and noninvasively monitoring treatment response at the point-of-care.
View details for DOI 10.1093/clinchem/hvaa307
View details for PubMedID 33393992
-
Tobacco Smoking and Risk of Second Primary Lung Cancer.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2021
Abstract
Lung cancer survivors are at high risk of a second primary lung cancer (SPLC). However, SPLC risk factors have not been established and the impact of tobacco smoking remains controversial. We examined risk factors for SPLC across multiple epidemiologic cohorts and assessed the impact of smoking cessation on reducing SPLC risk.We analyzed data from 7,059 participants in the Multiethnic Cohort (MEC) diagnosed with an initial primary lung cancer (IPLC) between 1993 and 2017. Cause-specific proportional hazards models estimated SPLC risk. We conducted validation studies using the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, N=3,423 IPLC cases) and European Prospective Investigation into Cancer and Nutrition (EPIC, N=4,731 IPLC cases) cohorts and pooled the SPLC risk estimates using random effects meta-analysis.Overall, 163 (2.3%) MEC cases developed a SPLC. Smoking pack-years (HR 1.18 per 10 pack-years; P<0.001) and smoking intensity (HR 1.30 per 10 cigarettes per day (CPD); P<0.001) were significantly associated with increased SPLC risk. Individuals who met the 2013 U.S. Preventive Services Task Force's (USPSTF) screening criteria at IPLC diagnosis also had an increased SPLC risk (HR 1.92; P<0.001). Validation studies with PLCO and EPIC showed consistent results. Meta-analysis yielded pooled HRs of 1.16 per 10 pack-years (Pmeta<0.001), 1.25 per 10 CPD (Pmeta<0.001), and 1.99 (Pmeta<0.001) for meeting the USPSTF criteria. In MEC, smoking cessation after IPLC diagnosis was associated with an 83% reduction in SPLC risk (HR 0.17; P<0.001).Tobacco smoking is a risk factor for SPLC. Smoking cessation after IPLC diagnosis may reduce the risk of SPLC. Additional strategies for SPLC surveillance and screening are warranted.
View details for DOI 10.1016/j.jtho.2021.02.024
View details for PubMedID 33722709
-
Two Cases of Pulmonary Tumor Thrombotic Microangiopathy Associated with ROS1-Rearranged Non-Small-Cell Lung Cancer.
Clinical lung cancer
2020
View details for DOI 10.1016/j.cllc.2020.09.020
View details for PubMedID 33153897
-
Opportunistic Invasive Fungal Infections Mimicking Progression of Non-Small-Cell Lung Cancer.
Clinical lung cancer
2020
Abstract
BACKGROUND: Many studies have shown that invasive pulmonary aspergillosis, cryptococcosis, and mucormycosis can mimic radiographic and clinical features of primary lung cancer. However, more research surveying the incidence and outcomes of these fungal infections among patients with a history of lung cancer is needed. The aim of this study was to describe the occurrence and clinical outcomes of opportunistic invasive fungal infections that can mimic tumors in non-small-cell lung cancer patients.PATIENTS AND METHODS: Patients seen at Stanford University Medical Center from January 1, 2007, to May 1, 2020, with pulmonary aspergillosis, cryptococcosis, or mucormycosis after non-small-cell lung cancer (NSCLC) diagnosis were reviewed. The European Organization for Research and Treatment of Cancer National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria was used to classify patients with evidence of proven or probable invasive fungal infection within our cohort.RESULTS: A total of 12 patients with proven or probable invasive mold infection (including 8 cases of aspergillosis) and 1 patient with proven cryptococcosis were identified, without any cases of mucormycosis. Of this cohort, 6 patients (46%) showed radiographic findings that were found to be most consistent with lung cancer by radiologists. Eight cases (62%) were suspected of cancer recurrence or progression by the treatment team on the basis of additional considerations of medical history and clinical symptoms. Most patients had active NSCLC or had a history of recurrence without active NSCLC at the time of fungal discovery (11 patients; 85%). Most patients died without full recovery (7 patients; 54%).CONCLUSIONS: Invasive pulmonary aspergillosis and cryptococcosis can often be mistaken as cancer recurrence or progression in patients with a history of NSCLC because of mimicking radiographic and clinical characteristics.
View details for DOI 10.1016/j.cllc.2020.10.001
View details for PubMedID 33168426
-
Phase III Randomized Study of Ensartinib vs Crizotinib in Anaplastic Lymphoma Kinase (ALK) POSITIVE NSCLC Patients: eXalt3
ELSEVIER SCIENCE INC. 2020: E41–E42
View details for Web of Science ID 000569266100003
-
Late Breaking Abstract - Thoracic Cancers International COVID-19 Collaboration (TERAVOLT): Impact of type of cancer therapy and COVID therapy on survival
EUROPEAN RESPIRATORY SOC JOURNALS LTD. 2020
View details for DOI 10.1183/13993003.congress-2020.3584
View details for Web of Science ID 000606501407115
-
Thoracic cancers international COVID-19 collaboration (TERAVOLT): Small-cell lung cancer and other rare thoracic malignancies.
AMER ASSOC CANCER RESEARCH. 2020
View details for Web of Science ID 000572825800122
-
Perioperative pembrolizumab plus platinum-based chemotherapy for resectable locally advanced non-small cell lung cancer: The phase III KEYNOTE-671 study
ELSEVIER. 2020: S801–S802
View details for DOI 10.1016/j.annonc.2020.08.1437
View details for Web of Science ID 000573469101522
-
Defining COVID-19 outcomes in thoracic cancer patients: TERAVOLT (Thoracic cancERs international coVid 19 cOLlaboraTion)
ELSEVIER. 2020: S1204–S1205
View details for DOI 10.1016/j.annonc.2020.08.2316
View details for Web of Science ID 000573469102714
-
A noninvasive approach for early prediction of therapeutic benefit from immune checkpoint inhibition for lung cancer
AMER ASSOC CANCER RESEARCH. 2020
View details for DOI 10.1158/1538-7445.AM2020-5666
View details for Web of Science ID 000590059306446
-
Association of baseline systemic corticosteroid use with time to next treatment in patients with advanced melanoma, non-small cell lung cancer or urothelial cancer receiving cancer immunotherapy in US clinical practice
AMER ASSOC CANCER RESEARCH. 2020
View details for Web of Science ID 000590059306347
-
Association of baseline systemic corticosteroid use with time to next treatment in patients with advanced melanoma, non-small cell lung cancer or urothelial cancer receiving cancer immunotherapy in US clinical practice
AMER ASSOC CANCER RESEARCH. 2020
View details for DOI 10.1158/1538-7445.AM2020-5388
View details for Web of Science ID 000590059301372
-
Is smoking a risk factor for second primary lung cancer
AMER ASSOC CANCER RESEARCH. 2020
View details for DOI 10.1158/1538-7445.AM2020-2298
View details for Web of Science ID 000590059304293
-
Thoracic Cancers International COVID-19 Collaboration (TERAVOLT): Impact of type of cancer therapy and COVID therapy on survival
LIPPINCOTT WILLIAMS & WILKINS. 2020
View details for DOI 10.1200/JCO.2020.38.18_suppl.LBA111
View details for Web of Science ID 000572436700005
-
Lung cancer incidence and risk factors in never-smoking Asian American, Native Hawaiian, and Pacific Islander women: The development of a multilevel integrated dataset of EHR, cancer registry, and environmental data
AMER ASSOC CANCER RESEARCH. 2020
View details for DOI 10.1158/1538-7755.DISP18-IA37
View details for Web of Science ID 000577495000725
-
Lung cancer incidence and risk factors in never-smoking Asian American, Native Hawaiian, and Pacific Islander women: A multilevel dataset of electronic health record, cancer registry, and environmental data
AMER ASSOC CANCER RESEARCH. 2020
View details for DOI 10.1158/1538-7755.DISP19-PR07
View details for Web of Science ID 000580647800528
-
Phase I/II study of vorolanib plus nivolumab in patients with thoracic malignancies: immunotherapy (IO) correlatives to differentiate responders from nonresponders.
LIPPINCOTT WILLIAMS & WILKINS. 2020
View details for Web of Science ID 000560368307512
-
High-dose osimertinib for CNS progression in EGFR plus non-small cell lung cancer (NSCLC): A multi-institutional experience.
AMER SOC CLINICAL ONCOLOGY. 2020
View details for Web of Science ID 000560368303485
-
Osimertinib in non-small cell lung cancer (NSCLC) with atypical EGFR activating mutations: A retrospective multicenter study.
AMER SOC CLINICAL ONCOLOGY. 2020
View details for Web of Science ID 000560368303469
-
A mid-chemoradiation dynamic risk model integrating tumor features and ctDNA analysis for lung cancer outcome prediction.
AMER SOC CLINICAL ONCOLOGY. 2020
View details for Web of Science ID 000560368303378
-
KEAP1/NFE2L2 mutations to predict local recurrence after radiotherapy but not surgery in localized non-small cell lung cancer.
AMER SOC CLINICAL ONCOLOGY. 2020
View details for Web of Science ID 000560368303348
-
Discovery of a novel shared tumor antigen in human lung cancer.
AMER SOC CLINICAL ONCOLOGY. 2020
View details for Web of Science ID 000560368301343
-
Phase II randomized trial of carboplatin plus pemetrexed plus bevacizumab, plus /- atezolizumab in stage IV non-squamous non-small lung cancer (NSCLC) patients who harbor a sensitizing EGFR mutation or have never smoked.
LIPPINCOTT WILLIAMS & WILKINS. 2020
View details for Web of Science ID 000560368309251
-
TERAVOLT: Thoracic Cancers International COVID-19 Collaboration.
Cancer cell
2020
Abstract
Prior publications on small subsets of cancer patients infected with SARS CoV-2 have shown an increased risk of mortality compared to the general population. Furthermore, patients with thoracic malignancies are thought to be at particularly high risk given their older age, smoking habits, and pre-existing cardio-pulmonary comorbidities. For this reason, physicians around the world have formed TERAVOLT, a global consortium dedicated to understanding the impact of COVID-19 on patients with thoracic malignancies.
View details for DOI 10.1016/j.ccell.2020.05.008
View details for PubMedID 32425702
-
Integrating genomic features for non-invasive early lung cancer detection.
Nature
2020; 580 (7802): 245-251
Abstract
Radiologic screening of high-risk adults reduces lung-cancer-related mortality1,2; however, a small minority of eligible individuals undergo such screening in the United States3,4. The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)5, a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed 'lung cancer likelihood in plasma' (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.
View details for DOI 10.1038/s41586-020-2140-0
View details for PubMedID 32269342
-
Circulating Tumor DNA Dynamics Predict Benefit from Consolidation Immunotherapy in Locally Advanced Non-Small Cell Lung Cancer.
Nature cancer
2020; 1 (2): 176-183
Abstract
Circulating tumor DNA (ctDNA) molecular residual disease (MRD) following curative-intent treatment strongly predicts recurrence in multiple tumor types, but whether further treatment can improve outcomes in patients with MRD remains unclear. We applied CAPP-Seq ctDNA analysis to 218 samples from 65 patients receiving chemoradiation therapy (CRT) for locally advanced NSCLC, including 28 patients receiving consolidation immune checkpoint inhibition (CICI). Patients with undetectable ctDNA after CRT had excellent outcomes whether or not they received CICI. Among such patients, one died from CICI-related pneumonitis, highlighting the potential utility of only treating patients with MRD. In contrast, patients with MRD after CRT who received CICI had significantly better outcomes than patients who did not receive CICI. Furthermore, the ctDNA response pattern early during CICI identified patients responding to consolidation therapy. Our results suggest that CICI improves outcomes for NSCLC patients with MRD and that ctDNA analysis may facilitate personalization of consolidation therapy.
View details for DOI 10.1038/s43018-019-0011-0
View details for PubMedID 34505064
View details for PubMedCentralID PMC8425388
-
US phase 1 first-in-human study of taletrectinib (DS-6051b/AB-106), a ROS1/TRK inhibitor, in patients with advanced solid tumors.
Clinical cancer research : an official journal of the American Association for Cancer Research
2020
Abstract
Taletrectinib (DS-6051b/AB-106) is an oral, tyrosine kinase inhibitor of ROS1 and NTRK with potent pre-clinical activity against ROS1 G2032R solvent-front mutation among others. We report the first-in-human US-phase 1 results of taletrectinib.Patients ≥18 years old with neuroendocrine tumors, with tumor-induced pain, or tumors harboring ROS1/NTRK rearrangements were eligible. Accelerated titration followed by modified continuous reassessment method and escalation with overdose control was used (50-1200 mg once daily [QD] or 400 mg twice daily). Primary objectives were safety/tolerability, and maximum tolerated dose (MTD) determination. Secondary objectives were food-effect pharmacokinetics and antitumor activity.A total of 46 patients were enrolled. Steady-state peak concentration (Cmax) and exposure (AUC0-8) increased dose dependently from 50 mg to 800 mg QD doses. The ratio of the geometric mean of AUC0-24 between low-fat-diet-fed/fasted state was 123% (90% confidence interval: 104% - 149%). Dose-limiting toxicities (grade 3 transaminases increase) occurred in 2 patients (1200 mg QD dose). MTD was 800 mg QD. Most common treatment-related adverse events (TRAEs) were nausea (47.8%), diarrhea (43.5%), and vomiting (32.6%). Pain score reductions were observed in the 800 mg QD-dose cohort. Confirmed ORR was 33.3% among the 6 RECIST-evaluable crizotinib-refractory ROS1+ NSCLC patients. One TPM3-NTRK1 differentiated thyroid cancer patient achieving a confirmed partial response (PR) of 27 months at data cutoff. We identified a cabozantinib-sensitive ROS1 L2086F as an acquired taletrectinib-resistance mutation.Taletrectinib has manageable toxicities at the MTD of 800 mg daily. Preliminary efficacy was observed in crizotinib-refractory ROS1+ NSCLC patients.
View details for DOI 10.1158/1078-0432.CCR-20-1630
View details for PubMedID 32591465
-
The International Association for the Study of Lung Cancer (IASLC) Global Survey on Molecular Testing in Lung Cancer.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2020
Abstract
Access to targeted therapies for lung cancer depends on accurate identification of patients' biomarkers through molecular testing. IASLC conducted an international survey to evaluate perceptions on current practice and barriers to implementation of molecular testing.We distributed the survey to IASLC members and other healthcare professionals around the world. The survey included a 7-question introduction for all respondents, who then answered according to one of three tracks: requesting tests/treating patients, performing/interpreting assays, or tissue acquisition. Barriers to implementing molecular testing were provided in free-response fields. The Chi-squared test was used for regional comparisons.2,537 respondents from 102 countries participated. Most respondents testing/treating patients believe <50% of lung cancer patients in their country receive molecular testing, but report higher rates within their own practice. Although many results varied by region, the five most frequent barriers cited in all regions were cost, quality/standards, access, awareness, and turnaround time. Many respondents expressed dissatisfaction with the current state of molecular testing for lung cancer, including 41% of those performing/interpreting assays. Issues identified included trouble understanding results (37%) and quality of the samples (23% report >10% rejection rate). Despite concerns regarding quality of testing, 47% in the performing/interpreting track stated there is no policy or strategy to improve quality in their country. Additionally, 33% of respondents who request tests/treat patients were unaware of the most recent CAP/IASLC/AMP guidelines for molecular testing.Adoption of molecular testing for lung cancer is relatively low across the world; barriers include cost, access, quality, turn-around time, and lack of awareness.
View details for DOI 10.1016/j.jtho.2020.05.002
View details for PubMedID 32445813
-
Adjuvant Chemotherapy.
Thoracic surgery clinics
2020; 30 (2): 179–85
Abstract
Five-year survival rates for patients with early-stage non-small cell lung cancer have room for improvement. Adjuvant chemotherapy results in a small but significant increase in overall survival at 5 years. Efforts to improve outcomes by intensifying adjuvant treatment, utilizing cancer-specific vaccines or tyrosine kinase inhibitors in unselected patients, have been unsuccessful. In addition to research with immune checkpoint inhibitors that are addressed in a separate article, ongoing studies to personalize adjuvant therapy either by selecting only patients with evidence of minimal residual disease or targeting tumor driver mutations are promising.
View details for DOI 10.1016/j.thorsurg.2020.01.003
View details for PubMedID 32327176
-
Targeted Treatment of Multiple Primary Lung Cancers Harboring Distinct EGFR or RET Alterations: A Case Report.
Clinical lung cancer
2020
View details for DOI 10.1016/j.cllc.2020.12.005
View details for PubMedID 33451914
-
Circulating tumor DNA analysis to assess risk of progression after long-term response to PD-(L)1 blockade in NSCLC.
Clinical cancer research : an official journal of the American Association for Cancer Research
2020
Abstract
Treatment with PD-(L)1 blockade can produce remarkably durable responses in non-small cell lung cancer (NSCLC) patients. However, a significant fraction of long-term responders ultimately progress and predictors of late progression are unknown. We hypothesized that circulating tumor DNA (ctDNA) analysis of long-term responders to PD-(L)1 blockade may differentiate those who will achieve ongoing benefit from those at risk of eventual progression.In patients with advanced NSCLC achieving long-term benefit from PD-(L)1 blockade (PFS≥12 months), plasma was collected at a surveillance timepoint late during/after treatment to interrogate ctDNA by Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq). Tumor tissue was available for 24 patients and was profiled by whole-exome sequencing (n=18) or by targeted sequencing (n=6).31 NSCLC patients with long-term benefit to PD-(L)1 blockade were identified and ctDNA was analyzed in surveillance blood samples collected at a median of 26.7 months after initiation of therapy. Nine patients also had baseline plasma samples available, and all had detectable ctDNA prior to therapy initiation. At the surveillance timepoint, 27 patients had undetectable ctDNA and 25 (93%) have remained progression-free; by contrast, all four patients with detectable ctDNA eventually progressed (Fisher's p<0.0001; PPV 1 [95% CI 0.51-1]; NPV 0.93 [95% CI 0.80-0.99]).ctDNA analysis can noninvasively identify minimal residual disease in patients with long-term responses to PD-(L)1 and predict the risk of eventual progression. If validated, ctDNA surveillance may facilitate personalization of the duration of immune checkpoint blockade and enable early intervention in patients at high risk for progression.
View details for DOI 10.1158/1078-0432.CCR-19-3418
View details for PubMedID 32046999
-
A PHASE IIA STUDY REPOSITIONING DESIPRAMINE IN SMALL CELL LUNG CANCER AND OTHER HIGH-GRADE NEUROENDOCRINE TUMORS.
Cancer treatment and research communications
2020; 23: 100174
Abstract
A bioinformatics approach identified antitumor effects of tricyclic antidepressants (TCAs) in small cell lung cancer (SCLC) and other high-grade neuroendocrine carcinomas (grade 3 neuroendocrine carcinomas) (G3NEC) that was subsequently validated in preclinical models with a putative mechanism of action via inhibition of neuroendocrine signaling pathways. This study was undertaken to reposition the candidate TCA desipramine in a clinical trial in SCLC and G3NEC.In this prospective, phase IIa intrapatient dose escalation clinical trial, patients were required to have failed at least one prior chemotherapy for metastatic SCLC or G3NEC. Treatment with desipramine began at 75 mg nightly with escalation in increments of 75 mg weekly to a maximum of 450 mg daily.Six patients were enrolled, 3 with SCLC, and 3 with G3NEC (lung, rectal, and pancreas). Tolerability of desipramine was worse than predicted. Of the 6 patients enrolled: 1 patient achieved 300 mg daily, 2 patients reached 150 mg daily, 1 patient reached 75 mg daily, and 2 patients were unable to tolerate any stable dose. Reasons for discontinuation included drug-related grade 3 colon pseudo-obstruction, unrelated GI bleed, and grade 1-2 neurocognitive adverse events. Median clinical or radiographic progression free survival was 1.2 months (range 0.2-3.3) and median overall survival from study entry was 2.7 months (range 1.3-5.6).No clinical or radiographic benefit was observed using desipramine to treat SCLC and G3NEC, so this trial was terminated. Intolerable low and medium grade neurocognitive side effects led to intermittent treatment and early discontinuation in most patients; given this limitation, doses achieved may be inadequate compared to the preclinical studies.A bioinformatics approach previously identified a potential antitumor effect of tricyclic antidepressants (TCAs) in small cell lung cancer (SCLC) and other high-grade neuroendocrine carcinomas (grade 3 neuroendocrine carcinoma) (G3NEC), which was validated in preclinical models. In this prospective, phase IIa clinical trial, patients were required to have failed at least one prior chemotherapy for metastatic SCLC or G3NEC (Ki-67 ≥ 20% or ≥ 20 mitoses/10 HPF). Treatment with desipramine began at 75 mg nightly with escalation by 75 mg weekly to a maximum dose of 450 mg daily. Six patients were enrolled on this clinical trial, 3 with SCLC, and 3 with G3NEC (lung, rectal, and pancreatic). Tolerability of desipramine was worse than predicted. In the 6 patients enrolled: 1 patient achieved 300 mg daily, 2 patients reached 150 mg daily, 1 patient reached 75 mg daily, and 2 patients were unable to tolerate any stable dose. Reasons for discontinuation included drug-related grade 3 colon pseudo-obstruction, unrelated GI bleed, and grade 1-2 drug related dizziness, confusion, and somnolence. Though numbers are small, median clinical or radiographic progression free survival was 1.2 months (range 0.2-3.3) and median overall survival from study entry was 2.7 months (range 1.3-5.6). Although preclinical evidence was promising, no clinical or radiographic benefit was observed using desipramine to treat SCLC and G3NEC, so this trial was terminated.
View details for DOI 10.1016/j.ctarc.2020.100174
View details for PubMedID 32413603
-
KEAP1/NFE2L2 mutations predict lung cancer radiation resistance that can be targeted by glutaminase inhibition.
Cancer discovery
2020
Abstract
Tumor genotyping is not routinely performed in localized non-small cell lung cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we analyze 232 consecutive patients with localized NSCLC and demonstrate that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence (LR) after radiotherapy but not surgery. Half of LRs occurred in KEAP1/NFE2L2 mutation tumors, indicating they are major molecular drivers of clinical radioresistance. Next, we functionally evaluate KEAP1/NFE2L2 mutations in our radiotherapy cohort and demonstrate that only pathogenic mutations are associated with radioresistance. Furthermore, expression of NFE2L2 target genes does not predict LR, underscoring the utility of tumor genotyping. Finally, we show that glutaminase inhibition preferentially radiosensitizes KEAP1 mutant cells via depletion of glutathione and increased radiation-induced DNA damage. Our findings suggest that genotyping for KEAP1/NFE2L2 mutations could facilitate treatment personalization and provide a potential strategy for overcoming radioresistance conferred by these mutations.
View details for DOI 10.1158/2159-8290.CD-20-0282
View details for PubMedID 33071215
-
Supporting Clinical Decision-Making during the SARS-CoV-2 Pandemic through a Global Research Commitment: The TERAVOLT Experience.
Cancer cell
2020
Abstract
To understand the real impact of COVID-19 on cancer patients, an entirely new data collection effort was initiated within the Thoracic Cancers International COVID-19 Collaboration (TERAVOLT). TERAVOLT reported high mortality related to COVID-19 infection in thoracic cancer patients and identified several negative prognostic factors. In this commentary, we discuss the importance and limits of patient registries to support decision-making in thoracic cancer during the SARS-CoV-2 pandemic.
View details for DOI 10.1016/j.ccell.2020.10.002
View details for PubMedID 33091381
View details for PubMedCentralID PMC7534826
-
Association of baseline systemic corticosteroid use with overall survival and time to next treatment in patients receiving immune checkpoint inhibitor therapy in real-world US oncology practice for advanced non-small cell lung cancer, melanoma, or urothelial carcinoma
ONCOIMMUNOLOGY
2020; 9 (1)
View details for DOI 10.1080/2162402X.2020.1824645
View details for Web of Science ID 000576987400001
-
Circulating tumor DNA dynamics predict benefit from consolidation immunotherapy in locally advanced non-small-cell lung cancer
NATURE CANCER
2020; 1: 176–183
View details for DOI 10.1038/s43018-019-0011-0
-
Clinical implications of KEAP1-NFE2L2 mutations in non-small cell lung cancer.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2020
Abstract
The KEAP1-NFE2L2 pathway is an important modulator of cell homeostasis. Mutations in this pathway are common in non-small cell lung cancer (NSCLC) and have been associated with enhanced tumor growth and aggressiveness. In addition, tumors with mutations in the KEAP1-NFE2L2 pathway have been shown in pre-clinical and clinical studies to convey refractoriness to cancer-directed therapy such as radiation, chemotherapy and targeted therapy. The role of immunotherapy in this patient population is less clear and there are conflicting studies on the efficacy of immune checkpoint inhibitors in KEAP1-NFE2L2 mutant NSCLC. Here we review the current clinical evidence on several classes of anti-cancer therapeutics in KEAP1 -NFE2L2 mutant tumors. We also provide an overview of the landscape of the current clinical trials in this patient population, highlighting work being done with mTORC1/2 and glutaminase inhibition.
View details for DOI 10.1016/j.jtho.2020.11.015
View details for PubMedID 33307193
-
PD-1/PD-L1 Checkpoint Inhibitor Immunotherapy for Malignant Pleural Mesothelioma: Case Series and Literature Review.
Clinical lung cancer
2020
View details for DOI 10.1016/j.cllc.2020.05.012
View details for PubMedID 32624413
-
Everolimus in the treatment of metastatic thymic epithelial tumors.
Lung cancer (Amsterdam, Netherlands)
2020; 149: 97–102
Abstract
There is emerging evidence to support the use of mTOR inhibitor everolimus in patients with advanced, relapsed-refractory thymic epithelial tumors (TETs). However, patient selection and identifying predictive biomarkers of response remains a challenge. Here, we describe a single-center experience with everolimus in patients with TETs and provide detailed molecular analysis of their thymic tumors.Data on all patients with advanced TETs who were prescribed everolimus at Stanford University were retrospectively assessed. Time to treatment failure (TTF) and overall survival (OS) were calculated. STAMP, a 130-gene targeted next generation sequencing (NGS) panel, was performed on each tumor sample.Twelve patients with thymoma (T) and three with thymic carcinoma (TC) treated with everolimus were included. Patients had been heavily pre-treated with an average of three prior lines of therapy. Three patients discontinued treatment due to adverse events. The average TTF was 14.7 months in T and 2.6 months in TC with median OS of 27.6 months in the entire cohort (NR T and 5.3 months TC). Two patients with paraneoplastic autoimmune diseases had improvement in autoimmunity on everolimus. Pathogenic mutations were observed in 4/15 (27 %) of patients and includedTP53, KEAP1 and CDKN2A. Several variants of unknown significance in key genes responsible for modulating tumor response to mTOR inhibition were also found.As previously reported in a prospective trial, patients with previously treated advanced TETs appear to benefit from everolimus in this single institution cohort. Moreover, there was a manageable toxicity profile and no cases of everolimus-induced pneumonitis. A targeted NGS panel revealed several pathogenic mutations but there was no association between detectable tumor mutations and time to treatment failure in this cohort.
View details for DOI 10.1016/j.lungcan.2020.09.006
View details for PubMedID 33007678
-
Noninvasive Early Identification of Therapeutic Benefit from Immune Checkpoint Inhibition.
Cell
2020
Abstract
Although treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs) can produce remarkably durable responses, most patients develop early disease progression. Furthermore, initial response assessment by conventional imaging is often unable to identify which patients will achieve durable clinical benefit (DCB). Here, we demonstrate that pre-treatment circulating tumor DNA (ctDNA) and peripheral CD8 T cell levels are independently associated with DCB. We further show that ctDNA dynamics after a single infusion can aid in identification of patients who will achieve DCB. Integrating these determinants, we developed and validated an entirely noninvasive multiparameter assay (DIREct-On, Durable Immunotherapy Response Estimation by immune profiling and ctDNA-On-treatment) that robustly predicts which patients will achieve DCB with higher accuracy than any individual feature. Taken together, these results demonstrate that integrated ctDNA and circulating immune cell profiling can provide accurate, noninvasive, and early forecasting of ultimate outcomes for NSCLC patients receiving ICIs.
View details for DOI 10.1016/j.cell.2020.09.001
View details for PubMedID 33007267
-
Association of systemic corticosteroids with overall survival in patients receiving cancer immunotherapy for advanced melanoma, non-small cell lung cancer or urothelial cancer in routine clinical practice
OXFORD UNIV PRESS. 2019: 16–17
View details for Web of Science ID 000506799900046
-
Evaluating the Role of Targeted Therapy in Lung Cancer
ONCOLOGY-NEW YORK
2019; 33 (12): 482–86
View details for Web of Science ID 000608683300002
-
Checkpoint Inhibitor Combinations Among Themselves and with Chemotherapy
ELSEVIER SCIENCE INC. 2019: S1166
View details for DOI 10.1016/j.jtho.2019.09.119
View details for Web of Science ID 000494945000032
-
Evaluating Racial Differences in KRAS-Mutant Non-Small Cell Lung Cancer
ELSEVIER SCIENCE INC. 2019: S1133
View details for Web of Science ID 000493094100023
-
Long Term Efficacy and Safety of Ensartinib in Pre-Treated Anaplastic Lymphoma Kinase (ALK) Positive Non-Small Cell Lung Cancer (NSCLC) Patients (eXalt2)
ELSEVIER SCIENCE INC. 2019: S1171–S1172
View details for DOI 10.1016/j.jtho.2019.09.131
View details for Web of Science ID 000494945000043
-
Adjuvant PD-(L)1 Checkpoint Inhibitors
ELSEVIER SCIENCE INC. 2019: S156–S157
View details for Web of Science ID 000492162201001
-
Making the Most of WCLC: A Guide for First Time Attendees
ELSEVIER SCIENCE INC. 2019: S1115–S1116
View details for Web of Science ID 000492162206054
-
Results of the ASCEND-7 phase II study evaluating ALK inhibitor (ALKi) ceritinib in patients (pts) with ALK plus non-small cell lung cancer (NSCLC) metastatic to the brain
OXFORD UNIV PRESS. 2019: 602–3
View details for Web of Science ID 000491295504141
-
Outcome Disparities in American Indian/Alaskan Natives with Advanced Stage Lung Cancer
ELSEVIER SCIENCE INC. 2019: S668
View details for Web of Science ID 000492162203331
-
E1505: Adjuvant Chemotherapy plus /- Bevacizumab for Early Stage NSCLC: Updated Chemotherapy Subset Analysis
ELSEVIER SCIENCE INC. 2019: S271
View details for Web of Science ID 000492162201228
-
Efficacy and safety of ceritinib in ALK-positive non-small cell lung cancer (NSCLC) patients with leptomeningeal metastases (LW: Results from the phase II, ASCEND-7 study
OXFORD UNIV PRESS. 2019: 143-+
View details for Web of Science ID 000491295501207
-
Role of mTOR Inhibitor Everolimus in the Treatment of Metastatic Thymic Epithelial Tumors
ELSEVIER SCIENCE INC. 2019: S580
View details for Web of Science ID 000492162203131
-
A Single-Cell Resolution Map of EMT and Drug Resistance States for Evaluating NSCLC Clinical Specimens
ELSEVIER SCIENCE INC. 2019: S226–S227
View details for Web of Science ID 000492162201134
-
Phase I/II Study of Nivolumab and Vorolanib in Patients with Refractory Thoracic Tumors
ELSEVIER SCIENCE INC. 2019: S445–S446
View details for Web of Science ID 000492162202249
-
STK11/LKB1 Genomic Alterations Are Associated with Inferior Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC
ELSEVIER SCIENCE INC. 2019: S294–S295
View details for Web of Science ID 000492162201276
-
Rash and Efficacy in Anaplastic Lymphoma Kinase Positive (ALK plus ) Non-Small Cell Lung Cancer Patients Treated with Ensartinib
ELSEVIER SCIENCE INC. 2019: S566
View details for Web of Science ID 000492162203099
-
Feasibility and design of a cloud-based digital platform in patients with advanced cancer.
AMER SOC CLINICAL ONCOLOGY. 2019
View details for DOI 10.1200/JCO.2019.37.27_suppl.211
View details for Web of Science ID 000518223100208
-
Impact of dual-eligible status on survival in Medicare patients with lung cancer.
AMER SOC CLINICAL ONCOLOGY. 2019
View details for DOI 10.1200/JCO.2019.37.27_suppl.149
View details for Web of Science ID 000518223100147
-
Monitoring therapeutic response and resistance: analysis of circulating tumor DNA in patients with ALK+ lung cancer.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2019
Abstract
INTRODUCTION: Despite initial effectiveness of ALK tyrosine kinase inhibitors (TKIs) in patients with ALK+ non-small cell lung cancer (NSCLC), therapeutic resistance will ultimately develop. Serial tracking of genetic alterations detected in circulating tumor DNA (ctDNA) can be an informative strategy to identify response and resistance. This study evaluated the utility of analyzing ctDNA as a function of response to ensartinib, a potent second-generation ALK TKI.METHODS: Pre-treatment plasma was collected from 76 patients with ALK+ NSCLC who were ALK TKI naive or had received prior ALK TKI, and analyzed for specific genetic alterations. Longitudinal plasma samples were analyzed from a subset (N=11) of patients. Analysis of pre-treatment tumor biopsies from 22 patients was compared with plasma.RESULTS: Disease-associated genetic alterations were detected in 74% (56/76) of patients, the most common being EML4-ALK. Concordance of ALK fusion between plasma and tissue was 91% (20/22). Twenty-four ALK kinase domain mutations were detected in 15 patients, all had previously received an ALK TKI; G1269A was the most prevalent (4/24). Patients with a detectable EML4-ALK variant 1 (V1) fusion had improved response (9/17, 53%) to ensartinib compared to patients with EML4-ALK V3 fusion (1/7, 14%). Serial changes in ALK alterations were observed during therapy.CONCLUSIONS: Clinical utility of ctDNA was demonstrated, both at pre-treatment by identifying a potential subgroup of ALK+ NSCLC patients that may derive more benefit from ensartinib and longitudinally by tracking resistance. Prospective application of this technology may translate to improved outcomes for NSCLC patients treated with ALK TKIs.
View details for DOI 10.1016/j.jtho.2019.08.003
View details for PubMedID 31446141
-
Phase I/II study to evaluate the safety and preliminary activity of nivolumab in combination with vorolanib in patients with refractory thoracic tumors
AMER ASSOC CANCER RESEARCH. 2019
View details for DOI 10.1158/1538-7445.AM2019-CT171
View details for Web of Science ID 000488129900153
-
Characterization of circulating tumor cells and its PD-L1 expression with high-sensitivity liquid biopsy panel in non-small cell lung cancer patients
AMER ASSOC CANCER RESEARCH. 2019
View details for DOI 10.1158/1538-7445.AM2019-LB-238
View details for Web of Science ID 000488129900417
-
Osimertinib for EGFR-Mutant Lung Cancer with Brain Metastases: Results from a Single-Center Retrospective Study
ONCOLOGIST
2019; 24 (6): 836–43
View details for DOI 10.1634/theoncologist.2018-0264
View details for Web of Science ID 000471906300044
-
Case series of MET exon 14 skipping mutation-positive non-small-cell lung cancers with response to crizotinib and cabozantinib
ANTI-CANCER DRUGS
2019; 30 (5): 537–41
View details for DOI 10.1097/CAD.0000000000000765
View details for Web of Science ID 000466009600014
-
Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry.
Annals of oncology : official journal of the European Society for Medical Oncology
2019
Abstract
BACKGROUND: Anti-PD1/PD-L1 directed immune-checkpoint-inhibitors (ICI) are widely used to treat patients with advanced non-small cell lung cancer (NSCLC). The activity of ICI across NSCLC harboring oncogenic alterations is poorly characterized. The aim of our study was to address the efficacy of ICI in the context of oncogenic addiction.PATIENTS AND METHODS: We conducted a retrospective study for patients receiving ICI monotherapy for advanced NSCLC with at least one oncogenic driver alteration. Anonymized data were evaluated for clinicopathologic characteristics and outcomes for ICI therapy: best response (RECIST 1.1), progression-free survival (PFS) and overall survival (OS) from ICI initiation. The primary endpoint was PFS under ICI. Secondary endpoints were best response (RECIST 1.1) and overall survival (OS) from ICI initiation.RESULTS: We studied 551 patients treated in 24 centers from 10 countries. The molecular alterations involved KRAS (n=271), EGFR (n=125), BRAF (n=43), MET (n=36), HER2 (n=29), ALK (n=23), RET (n=16), ROS1 (n=7), and multiple drivers (n=1). Median age was 60 years, gender-ratio was 1:1, never/former/current smokers were 28/51/21% respectively, and the majority of tumors were adenocarcinoma. The objective response rate by driver alteration was: KRAS=26%, BRAF=24%, ROS1=17%, MET=16%, EGFR=12%, HER2=7%, RET=6%, ALK=0%. In the entire cohort, median PFS was 2.8 months, OS 13.3 months and the best response rate 19%. In a subgroup analysis, median PFS (in months) was 2.1 for EGFR, 3.2 for KRAS, 2.5 for ALK, 3.1 for BRAF, 2.5 for HER2, 2.1 for RET, and 3.4 for MET. In certain subgroups, PFS was positively associated with PD-L1 expression (KRAS, EGFR) and with smoking status (BRAF, HER2).CONCLUSIONS: ICI induced regression in some tumors with actionable driver alterations, but clinical activity was lower compared to the KRAS group and the lack of response in the ALK group was notable. Patients with actionable tumor alterations should receive targeted therapies and chemotherapy before considering immunotherapy.
View details for DOI 10.1093/annonc/mdz167
View details for PubMedID 31125062
-
ctDNA analysis for personalization of consolidation immunotherapy in localized non-small cell lung cancer.
AMER SOC CLINICAL ONCOLOGY. 2019
View details for DOI 10.1200/JCO.2019.37.15_suppl.2547
View details for Web of Science ID 000487345804497
-
Osimertinib (Osi) plus necitumumab (Neci) in EGFR-mutant NSCLC:An ETCTN California cancer consortium phase I study.
AMER SOC CLINICAL ONCOLOGY. 2019
View details for Web of Science ID 000487345806498
-
Osimertinib with chemotherapy for EGFR-mutant NSCLC at progression: Safety profile and survival analysis.
AMER SOC CLINICAL ONCOLOGY. 2019
View details for Web of Science ID 000487345806523
-
Role of mTOR Inhibitor Everolimus in the Treatment of Metastatic Thymic Epithelial Tumors
ELSEVIER SCIENCE INC. 2019: 239
View details for Web of Science ID 000463830100062
-
Increased Galectin-1 Expression in Thymic Epithelial Tumors
CLINICAL LUNG CANCER
2019; 20 (3): E356–E361
View details for DOI 10.1016/j.cllc.2018.12.005
View details for Web of Science ID 000467981200020
-
First-in-Human, First-in-Class Phase I Trial of the Anti-CD47 Antibody Hu5F9-G4 in Patients With Advanced Cancers
JOURNAL OF CLINICAL ONCOLOGY
2019; 37 (12): 946-+
View details for DOI 10.1200/JCO.18.02018
View details for Web of Science ID 000466717700002
-
Circulating tumor (ct) DNA analysis to monitor response and resistance to ensartinib in patients (pts) with ALK plus non-small cell lung cancer (NSCLC)
OXFORD UNIV PRESS. 2019: 44
View details for Web of Science ID 000478089000111
-
Circulating tumor (ct) DNA analysis to monitor response and resistance to ensartinib in patients (pts) with ALK+ non-small cell lung cancer (NSCLC).
Annals of oncology : official journal of the European Society for Medical Oncology
2019; 30 Suppl 2: ii48
View details for DOI 10.1093/annonc/mdz063.010
View details for PubMedID 32131242
-
Tumor heterogeneity and testing discrepancy confound ROS1 detection in NSCLC.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2019
View details for DOI 10.1016/j.jtho.2019.03.011
View details for PubMedID 30914313
-
Natural Disease History, Outcomes, and Co-mutations in a Series of Patients With BRAF-Mutated Non-small-cell Lung Cancer
CLINICAL LUNG CANCER
2019; 20 (2): E208–E217
View details for DOI 10.1016/j.cllc.2018.10.003
View details for Web of Science ID 000459793100012
-
First-in-Human, First-in-Class Phase I Trial of the Anti-CD47 Antibody Hu5F9-G4 in Patients With Advanced Cancers.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
2019: JCO1802018
Abstract
PURPOSE: To evaluate the safety, pharmacokinetics, and pharmacodynamics of Hu5F9-G4 (5F9), a humanized IgG4 antibody that targets CD47 to enable phagocytosis.PATIENTS AND METHODS: Adult patients with solid tumors were treated in four cohorts: part A, to determine a priming dose; part B, to determine a weekly maintenance dose; part C, to study a loading dose in week 2; and a tumor biopsy cohort.RESULTS: Sixty-two patients were treated: 11 in part A, 14 in B, 22 in C, and 15 in the biopsy cohort. Part A used doses that ranged from 0.1 to 3 mg/kg. On the basis of tolerability and receptor occupancy studies that showed 100% CD47 saturation on RBCs, 1 mg/kg was selected as the priming dose. In subsequent groups, patients were treated with maintenance doses that ranged from 3 to 45 mg/kg, and most toxicities were mild to moderate. These included transient anemia (57% of patients), hemagglutination on peripheral blood smear (36%), fatigue (64%), headaches (50%), fever (45%), chills (45%), hyperbilirubinemia (34%), lymphopenia (34%), infusion-related reactions (34%), and arthralgias (18%). No maximum tolerated dose was reached with maintenance doses up to 45 mg/kg. At doses of 10 mg/kg or more, the CD47 antigen sink was saturated by 5F9, and a 5F9 half-life of approximately 13 days was observed. Strong antibody staining of tumor tissue was observed in a patient at 30 mg/kg. Two patients with ovarian/fallopian tube cancers had partial remissions for 5.2 and 9.2 months.CONCLUSION: 5F9 is well tolerated using a priming dose at 1 mg/kg on day 1 followed by maintenance doses of up to 45 mg/kg weekly.
View details for PubMedID 30811285
-
Case series of MET exon 14 skipping mutation-positive non-small-cell lung cancers with response to crizotinib and cabozantinib.
Anti-cancer drugs
2019
Abstract
The mesenchymal-to-epithelial transition (MET) gene is altered and becomes a driver mutation in up to 5% of non-small-cell lung cancer (NSCLC). We report our institutional experience treating patients with MET exon 14 skipping (METex14) mutations, including responses to the MET inhibitors crizotinib and cabozantinib. We identified cases of NSCLC with METex14 mutations using an institutionally developed or commercial next-generation sequencing assay. We assessed patient and disease characteristics by retrospective chart review. Some patients were treated off-label by the physician with crizotinib or cabozantinib, and tumor responses to these agents were assessed. A total of 15 patients with METex14-mutated NSCLC were identified, predominantly male (n=10) with a smoking history (60%) and a median age of 74.0 years. No other actionable somatic mutations were detected. Stage distribution included 26.7% stage I, 6.7% stage II, 6.7% stage III, and 60.0% stage IV. Among patients treated with crizotinib or cabozantinib (n=6), three patients showed partial response and one patient showed stable disease on the basis of RECIST criteria. Four patients experienced side effects requiring drug holiday, reduction, or cessation. Our findings highlight the diversity in presentation and histology of NSCLC with METex14 mutations, which were found in the absence of other actionable driver mutations. We observed evidence of tumor response to crizotinib and cabozantinib, supporting the previous reports that METex14 mutations in NSCLC are actionable driver events.
View details for PubMedID 30762593
-
Real-world treatment patterns and survival of patients with BRAF V600-mutated metastatic non-small cell lung cancer.
Lung cancer (Amsterdam, Netherlands)
2019; 128: 74–90
Abstract
INTRODUCTION: Clinical outcomes data on BRAF-mutated non-small cell lung cancer (NSCLC) patients treated in routine practice is limited. To address this gap, we described treatment patterns and survival in a cohort of these patients evaluated/treated at 7 US academic cancer centers during 2009-2016.METHODS: This was a retrospective chart review. Patients with BRAF V600-mutated metastatic NSCLC were selected. Current/previous participants in BRAF-related trials were excluded. Onset of metastatic NSCLC defined a patient's index date, which had to occur ≥6 months before the chart review date. Analyses were descriptive, including Kaplan-Meier analyses for overall survival (OS).RESULTS: The study included 72 patients. At index, median age (range) was 65 (44-90) years; 61.1% were female. Fifty-two patients received ≥1 line of systemic therapy for metastatic disease. Platinum-based doublet chemotherapy was the most common first-line (1L) regimen (76.9% of 1l recipients); no patient received 1l targeted therapy (TT) with a BRAF/MEK inhibitor. In total, 20 patients received TT in any treatment line (2l or later). At time of review, 38 patients were deceased. Median (95%CI) OS from index for all patients was 31.0 (14.5, 63.8) months. Median (95%CI) OS was 56.5 (13.4, 89.1) months from index for TT recipients and 27.2 (10.6, 64.6) months in patients not treated with TT.CONCLUSION: Survival time in BRAF V600-mutated metastatic NSCLC patients studied here was higher than expected based on indirect comparisons with historical NSCLC cohorts for whom no oncogenic driver (BRAF or otherwise) was present. TT recipients had a numerically longer OS from metastatic onset than patients receiving usual care, further highlighting the importance of TT in BRAF V600-mutant NSCLC.
View details for PubMedID 30642457
-
Lengthy Progression-Free Survival and Intracranial Activity of Cabozantinib in Patients with Crizotinib and Ceritinib-Resistant ROS1-Positive Non-Small Cell Lung Cancer
JOURNAL OF THORACIC ONCOLOGY
2019; 14 (2): E21–E24
View details for DOI 10.1016/j.jtho.2018.08.2030
View details for Web of Science ID 000456410800001
-
Real-world treatment patterns and survival of patients with BRAF V600-mutated metastatic non-small cell lung cancer
LUNG CANCER
2019; 128: 74–90
View details for DOI 10.1016/j.lungcan.2018.12.003
View details for Web of Science ID 000457504800012
-
Response to comment on "Impact of KRAS mutation subtype and concurrent pathogenic mutations on non-small cell lung cancer outcomes".
Lung cancer (Amsterdam, Netherlands)
2019
View details for DOI 10.1016/j.lungcan.2019.08.020
View details for PubMedID 31492438
-
A Phase 1b/2 Study of the Bruton Tyrosine Kinase Inhibitor Ibrutinib and the PD-L1 Inhibitor Durvalumab in Patients with Pretreated Solid Tumors.
Oncology
2019: 1–10
Abstract
Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the United States for the treatment of various B-cell malignancies. Preclinical data suggest synergistic antitumor activity of ibrutinib with programmed death-ligand 1 (PD-L1) inhibitors in solid tumors. This study evaluated ibrutinib plus durvalumab, a PD-L1-targeting antibody, in patients with relapsed/refractory solid tumors.This open-label, multicenter, phase 1b/2 study enrolled previously treated patients with stage III/IV pancreatic adenocarcinoma, breast cancer, or non-small cell lung cancer (NSCLC). Phase 1b determined the recommended phase 2 dose (RP2D). In phase 2, patients were treated at the RP2D to evaluate the safety and antitumor activity of ibrutinib plus durvalumab.The RP2D was identified as ibrutinib 560 mg p.o. daily and durvalumab 10 mg/kg i.v. every 2 weeks, with 122 patients treated at the RP2D. Median age was 61 years, and the majority of patients (94%) had stage IV disease. Overall response rates (complete or partial responses) were 2% for pancreatic cancer, 3% for breast cancer, and 0% for NSCLC. Median progression-free survival was 1.7, 1.7, and 2.0 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. Median overall survival was 4.2, 4.2, and 7.9 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. The safety profiles observed across tumor types were consistent with the known safety profiles for ibrutinib and durvalumab. Grade ≥3 adverse events in ≥5% of all patients were hyponatremia (10%), dyspnea (7%), maculopapular rash (7%), pneumonia (7%), anemia (6%), and diarrhea (6%).The combination of ibrutinib 560 mg daily and durvalumab 10 mg/kg every 2 weeks had an acceptable safety profile. The antitumor activity of the ibrutinib-durvalumab combination was limited in our study population.
View details for DOI 10.1159/000500571
View details for PubMedID 31230047
-
Role of Immunotherapy in Small Cell Lung Cancer, Thymic Epithelial Tumors, and Mesothelioma.
American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting
2019: 543–52
Abstract
The introduction of programmed death receptor ligand-1 (PD-L1) and programmed death receptor-1 (PD-1) inhibitors into the field of non-small cell lung cancer (NSCLC) was practice changing. The pivotal trials consistently showed a clinically meaningful improvement in overall survival (OS) for patients with driver mutation-negative NSCLC, a field in which outcomes had been stagnant for decades. The success of immune checkpoint inhibitor (ICI) therapy in NSCLC has led to enthusiasm to expand the reach of these drugs into other thoracic malignancies such as thymic epithelial tumors (TETs), mesothelioma, and small cell lung cancer (SCLC). Unfortunately, the improvement in outcomes with ICI therapy in these rarer thoracic tumors has been somewhat modest, and in the case of thymoma, rates of adverse events are too high to routinely justify their use. Although the response rates seen in ICI therapy in these tumor types are similar to those seen with other available single-agent therapies for advanced disease, ICIs do present another option for clinicians treating patients with mesothelioma, small cell carcinoma, and thymic carcinoma (TC), diseases in which approved treatment options are limited. Here we review the latest trials of ICI therapy in mesothelioma, SCLC, and TETs.
View details for DOI 10.1200/EDBK_237847
View details for PubMedID 31099677
-
Impact of KRAS mutation subtype and concurrent pathogenic mutations on non-small cell lung cancer outcomes.
Lung cancer (Amsterdam, Netherlands)
2019; 133: 144–50
Abstract
Concurrent genetic mutations are prevalent in KRAS-mutant non-small cell lung cancer (NSCLC) and may differentially influence patient outcomes. We sought to characterize the effects of KRAS mutation subtypes and concurrent pathogenic mutations on overall survival (OS) and PD-L1 expression, a predictive biomarker for anti-PD-1/PD-L1 immunotherapy.We retrospectively identified patients with KRAS-mutant NSCLC at a single institution and abstracted clinical, molecular, and pathologic data from electronic health records. Cox regression and multinomial logistic regression were used to determine how KRAS mutation subtypes and concurrent pathogenic mutations are associated with OS and tumor PD-L1 expression, respectively.A total 186 patients were included. Common KRAS mutation subtypes included G12C (35%) and G12D (17%). Concurrent pathogenic mutations were identified in TP53 (39%), STK11 (12%), KEAP1 (8%), and PIK3CA (4%). On multivariable analysis, KRAS G12D mutations were significantly associated with poor OS (hazard ratio [HR] 2.43, 95% confidence interval [CI] 1.15-5.16; P = 0.021), as were STK11 co-mutations (HR 2.95, 95% CI 1.27-6.88; P = 0.012). Compared to no (<1%) PD-L1 expression, KRAS G12C mutations were significantly associated with positive yet low (1-49%) PD-L1 expression (odds ratio [OR] 4.94, 95% CI 1.07-22.85; P = 0.041), and TP53 co-mutations with high (≥50%) PD-L1 expression (OR 6.36, 95% CI 1.84-22.02; P = 0.004).KRAS G12D and STK11 mutations confer poor prognoses for patients with KRAS-mutant NSCLC. KRAS G12C and TP53 mutations correlate with a biomarker that predicts benefit from immunotherapy. Concurrent mutations may represent distinct subsets of KRAS-mutant NSCLC; further investigation is warranted to elucidate their role in guiding treatment.
View details for DOI 10.1016/j.lungcan.2019.05.015
View details for PubMedID 31200821
-
Impact of KEAP1/NFE2L2/CUL3 mutations on duration of response to EGFR tyrosine kinase inhibitors in EGFR mutated non-small cell lung cancer.
Lung cancer (Amsterdam, Netherlands)
2019; 134: 42–45
Abstract
For patients with Epidermal Growth Factor Receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), frontline EGFR-tyrosine kinase inhibitor (TKI) therapy compared to chemotherapy improves outcomes. However, resistance to these agents uniformly develops. Recently, mutations in the KEAP1-NFE2L2 pathway have been implicated as a potential mechanism of acquired EGFR TKI resistance.We examined all patients with metastatic NSCLC with mutations in both EGFR and KEAP1/NFE2L2/CUL3 identified on next generation sequencing from 2015 - 2018. These patients were compared to a NSCLC control cohort with mutations in EGFR and wild type in KEAP1/NFE2L2/CUL3 matched on the basis of sex, smoking status, age and race. Time to treatment failure on EGFR TKI therapy and overall survival were examined.Among 228 EGFR mutant NSCLCs, 17 (7%) also carried mutations in KEAP1, NFE2L2, or CUL3. The most common co-mutation in both the KEAP1/NFE2L2/CUL3 mutant and wild-type cohort was TP53. Patients with KEAP1/NFE2L2/CUL3 mutations had a shorter median time to treatment failure on EGFR TKI (4.7 months) compared with the wild-type matched cohort (13.0 months), p= 0.0014. There was no difference in overall survival.For NSCLC patients with mutations in EGFR, co-mutations in KEAP1/NFE2L2/CUL3 are associated with significantly decreased time to treatment failure. Our results suggest that these mutations represent a mechanism of intrinsic resistance to TKI treatment.
View details for DOI 10.1016/j.lungcan.2019.05.002
View details for PubMedID 31319993
-
Increased Galectin-1 Expression in Thymic Epithelial Tumors.
Clinical lung cancer
2018
Abstract
INTRODUCTION: Thymic epithelial tumors (TET) are rare malignancies with a paucity of data on biology and therapeutics. Galectin-1 is a member of the beta-galactoside binding protein family and has been shown to mediate tumor growth via modulation of immune cell function. This study examined galectin-1 expression in TET.PATIENTS AND METHODS: A tissue microarray of 68 patients with TET and 8 benign thymus controls were stained for galectin-1 expression and scored by a pathologist blinded to patient clinical and pathologic data. Galectin-1 expression+1 or greater staining intensity was considered positive. Clinical and pathologic data were abstracted from institutional databases. Expression of galectin-1 in thymic tumor was compared to benign thymus controls and correlated with pertinent clinical and pathologic data.RESULTS: Galectin-1 expression was higher in TET compared to benign thymus controls (65% vs. 0%). No significant association between galectin-1 expression and the development of recurrent disease, paraneoplastic syndromes, or overall survival was noted.CONCLUSION: Galectin-1 is overexpressed in the majority of TET. Detection of galectin-1 may differentiate benign from neoplastic thymic processes. Additional studies are needed to assess the role of galectin-1 in the development of TET.
View details for PubMedID 30773448
-
EGFR-Mutant Adenocarcinomas That Transform to Small-Cell Lung Cancer and Other Neuroendocrine Carcinomas: Clinical Outcomes.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
2018: JCO1801585
Abstract
PURPOSE: Approximately 3% to 10% of EGFR (epidermal growth factor receptor) -mutant non-small cell lung cancers (NSCLCs) undergo transformation to small-cell lung cancer (SCLC), but their clinical course is poorly characterized.METHODS: We retrospectively identified patients with EGFR-mutant SCLC and other high-grade neuroendocrine carcinomas seen at our eight institutions. Demographics, disease features, and outcomes were analyzed.RESULTS: We included 67 patients-38 women and 29 men; EGFR mutations included exon 19 deletion (69%), L858R (25%), and other (6%). At the initial lung cancer diagnosis, 58 patients had NSCLC and nine had de novo SCLC or mixed histology. All but these nine patients received one or more EGFR tyrosine kinase inhibitor before SCLC transformation. Median time to transformation was 17.8 months (95% CI, 14.3 to 26.2 months). After transformation, both platinum-etoposide and taxanes yielded high response rates, but none of 17 patients who received immunotherapy experienced a response. Median overall survival since diagnosis was 31.5 months (95% CI, 24.8 to 41.3 months), whereas median survival since the time of SCLC transformation was 10.9 months (95% CI, 8.0 to 13.7 months). Fifty-nine patients had tissue genotyping at first evidence of SCLC. All maintained their founder EGFR mutation, and 15 of 19 with prior EGFR T790M positivity were T790 wild-type at transformation. Other recurrent mutations included TP53, Rb1, and PIK3CA. Re-emergence of NSCLC clones was identified in some cases. CNS metastases were frequent after transformation.CONCLUSION: There is a growing appreciation that EGFR-mutant NSCLCs can undergo SCLC transformation. We demonstrate that this occurs at an average of 17.8 months after diagnosis and cases are often characterized by Rb1, TP53, and PIK3CA mutations. Responses to platinum-etoposide and taxanes are frequent, but checkpoint inhibitors yielded no responses. Additional investigation is needed to better elucidate optimal strategies for this group.
View details for DOI 10.1200/JCO.18.01585
View details for PubMedID 30550363
-
Case closed: another prophylactic cranial irradiation trial for stage 3 non-small cell lung cancer fails to improve overall survival.
Annals of translational medicine
2018; 6 (Suppl 2): S118
View details for DOI 10.21037/atm.2018.12.24
View details for PubMedID 30740439
View details for PubMedCentralID PMC6330621
-
Case closed: another prophylactic cranial irradiation trial for stage 3 non-small cell lung cancer fails to improve overall survival
ANNALS OF TRANSLATIONAL MEDICINE
2018; 6
View details for DOI 10.21037/atm.2018.12.24
View details for Web of Science ID 000454556000033
-
SELECT: A Phase II Trial of Adjuvant Erlotinib in Patients With Resected Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
2018: JCO1800131
Abstract
PURPOSE: Given the pivotal role of epidermal growth factor receptor (EGFR) inhibitors in advanced EGFR-mutant non-small-cell lung cancer (NSCLC), we tested adjuvant erlotinib in patients with EGFR-mutant early-stage NSCLC.MATERIALS AND METHODS: In this open-label phase II trial, patients with resected stage IA to IIIA (7th edition of the American Joint Committee on Cancer staging system) EGFR-mutant NSCLC were treated with erlotinib 150 mg per day for 2 years after standard adjuvant chemotherapy with or without radiotherapy. The study was designed for 100 patients and powered to demonstrate a primary end point of 2-year disease-free survival (DFS) greater than 85%, improving on historic data of 76%.RESULTS: Patients (N = 100) were enrolled at seven sites from January 2008 to May 2012; 13% had stage IA disease, 32% had stage IB disease, 11% had stage IIA disease, 16% had stage IIB disease, and 28% had stage IIIA disease. Toxicities were typical of erlotinib; there were no grade 4 or 5 adverse events. Forty percent of patients required erlotinib dose reduction to 100 mg per day and 16% to 50 mg per day. The intended 2-year course was achieved in 69% of patients. The median follow-up was 5.2 years, and 2-year DFS was 88% (96% stage I, 78% stage II, 91% stage III). Median DFS and overall survival have not been reached; 5-year DFS was 56% (95% CI, 45% to 66%), 5-year overall survival was 86% (95% CI, 77% to 92%). Disease recurred in 40 patients, with only four recurrences during erlotinib treatment. The median time to recurrence was 25 months after stopping erlotinib. Of patients with recurrence who underwent rebiopsy (n = 24; 60%), only one had T790M mutation detected. The majority of patients with recurrence were retreated with erlotinib (n = 26; 65%) for a median duration of 13 months.CONCLUSION: Patients with EGFR-mutant NSCLC treated with adjuvant erlotinib had an improved 2-year DFS compared with historic genotype-matched controls. Recurrences were rare for patients receiving adjuvant erlotinib, and patients rechallenged with erlotinib after recurrence experienced durable benefit.
View details for DOI 10.1200/JCO.18.00131
View details for PubMedID 30444685
-
Comparison of Genomic Driver Oncogenes in Vietnamese Patients With Non-Small-Cell Lung Cancer in the United States and Vietnam
JOURNAL OF GLOBAL ONCOLOGY
2018; 4
View details for DOI 10.1200/JGO.18.00086
View details for Web of Science ID 000462471900001
-
Comparison of Genomic Driver Oncogenes in Vietnamese Patients With Non-Small-Cell Lung Cancer in the United States and Vietnam.
Journal of global oncology
2018: 1–9
Abstract
PURPOSE: Discoveries of oncogenic driver alterations in non-small-cell lung cancer (NSCLC) have been accompanied by the development of effective targeted therapies. The frequencies of these mutations vary between populations but are less well characterized in the Vietnamese population. In this study, we analyzed the frequencies of lung cancer driver oncogenic alterations in Vietnamese patients compared with Vietnamese patients treated in the United States.METHODS: We collected data on tumor and disease characteristics of Vietnamese patients with NSCLC treated at Stanford. In addition, we collected NSCLC tumor specimens from patients with NSCLC diagnosed in Hue, Vietnam, and performed next-generation-based genotyping on these samples. The molecular and clinical characteristics of these groups were compared.RESULTS: Fifty-nine Vietnamese patients were identified at Stanford. Of the 44 patients with molecular testing results, there were 21 (47.7%) with EGFR alterations, six (13.6%) with ALK alterations, two (4.5%) with KRAS alterations, one (2.3%) with BRAF alterations, and no ROS1 or RET alterations. Across all stages, the median overall survival for patients with a tumor having a targetable genomic alteration driver mutation was 42.4 months, compared with 27.1 months for patients without such alterations. In the 45 genotyped samples from Vietnam, there were 26 (57.8%) with EGFR, 11 (24.4%) with KRAS, and one each (2.2%) with ALK, ROS1, and RET.CONCLUSION: The majority of tumors from both Stanford and Vietnam had targetable oncogenic alterations. This suggests that routine implementation of molecular testing may have a significant, positive impact on the treatment of Vietnamese patients with NSCLC, but affordability of testing and treatments remains a barrier to adoption.
View details for PubMedID 30422746
-
EGFR Genotyping of Matched Urine, Plasma, and Tumor Tissue in Patients With Non-Small-Cell Lung Cancer Treated With Rociletinib, an EGFR Tyrosine Kinase Inhibitor.
JCO precision oncology
2018; 2: 1-13
Abstract
Liquid biopsies represent an attractive alternative to tissue biopsies, particularly rebiopsies, in determining patient eligibility for targeted therapies. Clinical utility of urine genotyping, however, has not been explored extensively. We evaluated epidermal growth factor receptor (EGFR) T790M detection in matched urine, plasma, and tissue and the clinical outcomes of patients with advanced non-small-cell lung cancer treated with rociletinib.Tissue (n = 540), plasma (n = 482), and urine (n = 213) were collected from evaluable patients enrolled in TIGER-X, a phase I/II study. Genotyping was performed by therascreen EGFR testing in tissue, BEAMing in plasma, and a quantitative short footprint assay (Trovera) in urine, which was used to further examine discordant samples.Positive percent agreement with tissue T790M results was similar for urine (82%; 142 of 173) and plasma (81%; 313 of 387) genotyping. Urine and plasma together identified more patients who were T790M positive (92%) than tissue alone (83%) among matched samples (n = 177). The ability to identify mutations in plasma was strongly associated with M stage (P < .001); rate of T790M detection for patients with M1a/M0 disease increased from 54% for plasma alone to 85% when urine and plasma were both examined. Objective response rates of patients who were T790M positive were comparable between tumor (34%), plasma (32%), and urine (37%).Clinical response to rociletinib was comparable irrespective of whether T790M status was identified by liquid or tissue biopsy. Combined, urine and plasma identified a higher percentage of patients who were T790M positive than tumor genotyping alone and improved detection of T790M, particularly in the absence of distant metastases. These findings support the noninvasive analysis of urine and plasma before tumor rebiopsy when assessing T790M status.
View details for DOI 10.1200/PO.17.00116
View details for PubMedID 35135111
-
Natural Disease History, Outcomes, and Co-mutations in a Series of Patients With BRAF-Mutated Non-small-cell Lung Cancer.
Clinical lung cancer
2018
Abstract
BACKGROUND: BRAF mutations occur in 1% to 4% of non-small-cell lung cancer (NSCLC) cases. Previous retrospective studies have reported similar outcomes for BRAF-mutated NSCLC as compared with wild-type tumors without a known driver mutation or tumors harboring other mutations. However, select cases of prolonged survival have also been described, and thus, the natural history of BRAF-mutated NSCLC remains an area of ongoing study. The aim of this series was to describe the natural history, clinical outcomes, and occurrence of co-mutations in patients with BRAF-mutated NSCLC.PATIENTS AND METHODS: Patients with BRAF-mutated NSCLC seen at Stanford University Medical Center from January 1, 2006 through July 31, 2015 were reviewed. The Kaplan-Meier method was used to calculate median overall survival, and the generalized Wilcoxon test was used to compare median survivals across subgroups of patients.RESULTS: Within a cohort of 18 patients with BRAF-mutated NSCLC, V600E mutations were most common (72%; 13/18). Clinicopathologic features were similar between patients with V600E versus non-V600E mutations, although there was a trend toward more patients with non-V600E mutations being heavy smokers (80% vs. 31%; P= .12). Co-occurring mutations in TP53 were identified most commonly (28%; 5/18). The median overall survival for the entire cohort was 40.1 months, and the median survival from the onset of metastases (n= 16) was 28.1 months. Survival rates at 2 and 5 years from the onset of metastases were 56% and 13%, respectively.CONCLUSION: The clinical behavior of BRAF-mutated NSCLC is variable, but favorable outcomes can be seen in a subset of patients.
View details for PubMedID 30442523
-
How I Treat Advanced Stage Thymic Malignancy Patients
ELSEVIER SCIENCE INC. 2018: S222–S223
View details for DOI 10.1016/j.jtho.2018.08.074
View details for Web of Science ID 000454014500064
-
eXalt3: Phase III randomized study comparing ensartinib to crizotinib in anaplastic lymphoma kinase positive non-small cell lung cancer patients.
Annals of oncology : official journal of the European Society for Medical Oncology
2018; 29 Suppl 8: viii543
View details for DOI 10.1093/annonc/mdy292.121
View details for PubMedID 32137417
-
Intracranial activity of ensartinib in patients with anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC).
Annals of oncology : official journal of the European Society for Medical Oncology
2018; 29 Suppl 8: viii541–viii542
View details for DOI 10.1093/annonc/mdy292.117
View details for PubMedID 32137409
-
Prediction of PD-1 immunotherapy (IO) response for KRAS mutated non-small cell lung cancer (NSCLC) based on co-mutations using a computational biological model.
Annals of oncology : official journal of the European Society for Medical Oncology
2018; 29 Suppl 8: viii510–viii511
View details for DOI 10.1093/annonc/mdy292.036
View details for PubMedID 32137320
-
Intracranial activity of ensartinib in patients with anaplastic lymphoma kinase positive (ALK plus ) non-small cell lung cancer (NSCLC)
OXFORD UNIV PRESS. 2018
View details for Web of Science ID 000459277303266
-
eXalt3: Phase III randomized study comparing ensartinib to crizotinib in anaplastic lymphoma kinase positive non-small cell lung cancer patients
OXFORD UNIV PRESS. 2018
View details for Web of Science ID 000459277303270
-
Prediction of PD-1 immunotherapy (IO) response for KRAS mutated non-small cell lung cancer (NSCLC) based on co-mutations using a computational biological model
OXFORD UNIV PRESS. 2018
View details for Web of Science ID 000459277303184
-
Improved EGFR mutation detection using combined exosomal RNA and circulating tumor DNA in NSCLC patient plasma
ANNALS OF ONCOLOGY
2018; 29 (10): 2143
View details for PubMedID 30060089
-
Identification of Molecular Subtypes of Thymic Epithelial Tumors and Novel Treatments Using a Computational Biological Model
ELSEVIER SCIENCE INC. 2018: S606
View details for DOI 10.1016/j.jtho.2018.08.919
View details for Web of Science ID 000454014502074
-
Computational Biological Model Prediction of PD-L1 Expression and Immunotherapy Response for KRAS Mutated Lung Cancer Based on Co-Mutations
ELSEVIER SCIENCE INC. 2018: S533
View details for DOI 10.1016/j.jtho.2018.08.735
View details for Web of Science ID 000454014501368
-
Co-Mutations, Natural History, and Outcomes of BRAF-Mutated Non-Small Cell Lung Cancer at a Single Academic Cancer Center
ELSEVIER SCIENCE INC. 2018: S489–S490
View details for DOI 10.1016/j.jtho.2018.08.627
View details for Web of Science ID 000454014501261
-
Evolving Immunotherapy Practice Patterns in Advanced NSCLC: Analysis of an Online Treatment Decision Tool
ELSEVIER SCIENCE INC. 2018: S421
View details for DOI 10.1016/j.jtho.2018.08.472
View details for Web of Science ID 000454014501109
-
Ensartinib Treatment Beyond Disease Progression in Stage IV ALK plus Non-Small Cell Lung Cancer
ELSEVIER SCIENCE INC. 2018: S583
View details for DOI 10.1016/j.jtho.2018.08.860
View details for Web of Science ID 000454014502015
-
Immunotherapy for Non-Small Cell Lung Cancers (NSCLC) with Oncogenic Driver Mutations: New Results from the Global IMMUNOTARGET Registry
ELSEVIER SCIENCE INC. 2018: S367
View details for DOI 10.1016/j.jtho.2018.08.342
View details for Web of Science ID 000454014500323
-
Effect of Induction Chemotherapy in the PACIFIC Study
ELSEVIER SCIENCE INC. 2018: S629
View details for DOI 10.1016/j.jtho.2018.08.974
View details for Web of Science ID 000454014502127
-
Metabolomic Profiling for Second Primary Lung Cancer Among Lung Cancer Survivors
ELSEVIER SCIENCE INC. 2018: S567
View details for DOI 10.1016/j.jtho.2018.08.821
View details for Web of Science ID 000454014501453
-
eXalt3: Phase 3 Randomized Study Comparing Ensartinib to Crizotinib in Anaplastic Lymphoma Kinase Positive Non-Small Cell Lung Cancer Patients
ELSEVIER SCIENCE INC. 2018: S582
View details for DOI 10.1016/j.jtho.2018.08.858
View details for Web of Science ID 000454014502014
-
Lengthy progression-free survival and intracranial activity of cabozantinib in patients with crizotinib and ceritinib-resistant ROS1-positive non-small-cell lung cancer.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2018
View details for PubMedID 30217491
-
Caution Needed for Analyzing the Risks of Second Cancers
JOURNAL OF THORACIC ONCOLOGY
2018; 13 (9): E172–E173
View details for DOI 10.1016/j.jtho.2018.04.018
View details for Web of Science ID 000444520200004
-
Three-dimensional organoid model for acquired drug resistance in non-small cell lung cancer
AMER ASSOC CANCER RESEARCH. 2018
View details for DOI 10.1158/1557-3265.AACRIASLC18-B30
View details for Web of Science ID 000582244900061
-
Update on International Cooperative Groups Studies in Thoracic Malignancies: The Emergence of Immunotherapy
CLINICAL LUNG CANCER
2018; 19 (5): 377–86
View details for DOI 10.1016/j.cllc.2018.03.004
View details for Web of Science ID 000442538700036
-
Prognostic Value of Pretreatment FDG-PET Parameters in High-dose Image-guided Radiotherapy for Oligometastatic Non-Small-cell Lung Cancer
CLINICAL LUNG CANCER
2018; 19 (5): E581–E588
View details for DOI 10.1016/j.cllc.2018.04.003
View details for Web of Science ID 000442538700007
-
A safety, tolerability, and pharmacokinetic analysis of two phase I studies of multitargeted small molecule tyrosine kinase inhibitor XL647 with an intermittent and continuous dosing schedule in patients with advanced solid malignancies
CANCER CHEMOTHERAPY AND PHARMACOLOGY
2018; 82 (3): 541–50
View details for DOI 10.1007/s00280-018-3646-0
View details for Web of Science ID 000442431600017
-
Caution Needed for Analyzing the Risks of Second Cancers.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2018; 13 (9): e172–e173
View details for PubMedID 30166015
-
Liquid Biopsy for Advanced Non-Small Cell Lung Cancer (NSCLC): A Statement Paper from the IASLC
JOURNAL OF THORACIC ONCOLOGY
2018; 13 (9): 1248–68
Abstract
The isolation and analysis of circulating cell-free tumor DNA in plasma is a powerful tool with considerable potential to improve clinical outcomes across multiple cancer types, including NSCLC. Assays of this nature that use blood as opposed to tumor samples are frequently referred to as liquid biopsies. An increasing number of innovative platforms have been recently developed that improve not only the fidelity of the molecular analysis but also the number of tests performed on a single specimen. Circulating tumor DNA assays for detection of both EGFR sensitizing and resistance mutations have already entered clinical practice and many other molecular tests - such as detection of resistance mutations for Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase rearrangements - are likely to do so in the near future. Due to an abundance of new evidence, an appraisal was warranted to review strengths and weaknesses, to describe what is already in clinical practice and what has yet to be implemented, and to highlight areas in need of further investigation. A multidisciplinary panel of experts in the field of thoracic oncology with interest and expertise in liquid biopsy and molecular pathology was convened by the International Association for the Study of Lung Cancer to evaluate current available evidence with the aim of producing a set of recommendations for the use of liquid biopsy for molecular analysis in guiding the clinical management of advanced NSCLC patients as well as identifying unmet needs. In summary, the panel concluded that liquid biopsy approaches have significant potential to improve patient care, and immediate implementation in the clinic is justified in a number of therapeutic settings relevant to NSCLC.
View details for PubMedID 29885479
-
Ensartinib in Anaplastic Lymphoma Kinase (ALK) Positive Non-Small Cell Lung Cancer (NSCLC) Patients: Updated Data
ELSEVIER SCIENCE INC. 2018: S156
View details for Web of Science ID 000444519200009
-
Predictive biomarkers for response to EGFR-directed monoclonal antibodies for advanced squamous cell lung cancer
ANNALS OF ONCOLOGY
2018; 29 (8): 1701–9
Abstract
Upregulated expression and aberrant activation of the epidermal growth-factor receptor (EGFR) are found in lung cancer, making EGFR a relevant target for non-small-cell lung cancer (NSCLC). Treatment with anti-EGFR monoclonal antibodies (mAbs) is associated with modest improvement in overall survival in patients with squamous cell lung cancer (SqCLC) who have a significant unmet need for effective treatment options. While there is evidence that using EGFR gene copy number, EGFR mutation, and EGFR protein expression as biomarkers can help select patients who respond to treatment, it is important to consider biomarkers for response in patients treated with combination therapies that include EGFR mAbs.Randomized trials of EGFR-directed mAbs cetuximab and necitumumab in combination with chemotherapy, immunotherapy, or antiangiogenic therapy in patients with advanced NSCLC, including SqCLC, were searched in the literature. Results of associations of potential biomarkers and outcomes were summarized.Data from phase III clinical trials indicate that patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein (H-score of ≥200) and/or gene copy numbers of EGFR (e.g. ≥40% cells with ≥4 EGFR copies as detected by fluorescence in situ hybridization; gene amplification in ≥10% of analyzed cells) derive greater therapeutic benefits from EGFR-directed mAbs. Biomarker data are limited for EGFR mAbs used in combination with immunotherapy and are absent when used in combination with antiangiogenic agents.Therapy with EGFR-directed mAbs in combination with chemotherapy is associated with greater clinical benefits in patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein and/or have increased EGFR gene copy number. These data support validating the role of these as biomarkers to identify those patients who derive the greatest clinical benefit from EGFR mAb therapy. However, data on biomarkers for EGFR-directed mAbs combined with immunotherapy or antiangiogenic agents remain limited.
View details for PubMedID 29905778
-
A safety, tolerability, and pharmacokinetic analysis of two phase I studies of multitargeted small molecule tyrosine kinase inhibitor XL647 with an intermittent and continuous dosing schedule in patients with advanced solid malignancies.
Cancer chemotherapy and pharmacology
2018
Abstract
PURPOSE: To evaluate the safety, tolerability, and pharmacokinetics of XL647 and determine the maximum tolerated dose (MTD) of oral XL647 once-daily using intermittent or continuous dosing schedules.METHODS: Patients with advanced solid malignancies were enrolled in successive cohorts to receive escalating dose levels of oral once-daily XL647 using two different dosing schedules: 5 consecutive days of every 14-day cycle (study XL647-001) or continuously over 28-day cycles (study XL647-002). PK sampling was performed to determine Cmax, and AUC. Patients remained on study until progressive disease or unacceptable AEs.RESULTS: In XL647-001, 42 individuals were enrolled across 9 dose levels. The most frequently occurring drug-related AEs were diarrhea, nausea, rash, and fatigue. Expansion of the 4.68mg/kg cohort to 6 patients occurred without further dose-limiting toxicities (DLTs) and this was considered the MTD. In XL647-002, 31 patients were enrolled across 5 dose levels. A DLT of grade 3 pneumonitis occurred in 1/6 patients at 300mg, which was declared the MTD. The most common AEs included grade 1/2 rash, diarrhea, fatigue, dysgeusia, and QTc prolongation. Levels of pharmacodynamic plasma markers were not consistently changed after XL647 and no conclusions could be drawn with this limited data set.CONCLUSIONS: For oral XL647, the MTD was 4.68mg/kg or 350mg fixed dose when administered once-daily for 5 consecutive days of every 14-day cycle and was 300mg when administered once-daily continuously. XL647 was well tolerated at doses up to the MTD.
View details for PubMedID 30030583
-
Development of a multilevel integrated dataset to study lung cancer incidence and risk factors in never-smoking Asian American, Native Hawaiian, and Pacific Islander females.
AMER ASSOC CANCER RESEARCH. 2018: 81–82
View details for Web of Science ID 000437526000094
-
Molecular and Immune Biomarker Testing in Squamous-Cell Lung Cancer: Effect of Current and Future Therapies and Technologies
CLINICAL LUNG CANCER
2018; 19 (4): 331–39
Abstract
Patients with non-small-cell lung cancer, including squamous-cell lung cancer (SqCLC), typically present at an advanced stage. The current treatment landscape, which includes chemotherapy, radiotherapy, surgery, immunotherapy, and targeted agents, is rapidly evolving, including for patients with SqCLC. Prompt molecular and immune biomarker testing can serve to guide optimal treatment choices, and immune biomarker testing is becoming more important for this patient population. In this review we provide an overview of current and emerging practices and technologies for molecular and immune biomarker testing in advanced non-small-cell lung cancer, with a focus on SqCLC.
View details for PubMedID 29773328
-
Ensartinib (X-396) in ALK-Positive Non-Small Cell Lung Cancer: Results from a First-in-Human Phase I/II, Multicenter Study
CLINICAL CANCER RESEARCH
2018; 24 (12): 2771–79
Abstract
Purpose: Evaluate safety and determine the recommended phase II dose (RP2D) of ensartinib (X-396), a potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), and evaluate preliminary pharmacokinetics and antitumor activity in a first-in-human, phase I/II clinical trial primarily in patients with non-small cell lung cancer (NSCLC).Patients and Methods: In dose escalation, ensartinib was administered at doses of 25 to 250 mg once daily in patients with advanced solid tumors; in dose expansion, patients with advanced ALK-positive NSCLC were administered 225 mg once daily. Patients who had received prior ALK TKI(s) and patients with brain metastases were eligible.Results: Thirty-seven patients enrolled in dose escalation, and 60 enrolled in dose expansion. The most common treatment-related toxicities were rash (56%), nausea (36%), pruritus (28%), vomiting (26%), and fatigue (22%); 23% of patients experienced a treatment-related grade 3 to 4 toxicity (primarily rash and pruritus). The maximum tolerated dose was not reached, but the RP2D was chosen as 225 mg based on the frequency of rash observed at 250 mg without improvement in activity. Among the ALK-positive efficacy evaluable patients treated at ≥200 mg, the response rate (RR) was 60%, and median progression-free survival (PFS) was 9.2 months. RR in ALK TKI-naïve patients was 80%, and median PFS was 26.2 months. In patients with prior crizotinib only, the RR was 69% and median PFS was 9.0 months. Responses were also observed in the central nervous system, with an intracranial RR of 64%.Conclusions: Ensartinib was active and generally well tolerated in patients with ALK-positive NSCLC. Clin Cancer Res; 24(12); 2771-9. ©2018 AACR.
View details for PubMedID 29563138
View details for PubMedCentralID PMC6004248
-
Oral bisphosphonate use and lung cancer incidence among postmenopausal women
ANNALS OF ONCOLOGY
2018; 29 (6): 1476–85
Abstract
Bisphosphonates are common medications for the treatment of osteoporosis in older populations. Several studies, including the Women's Health Initiative (WHI), have found inverse associations of bisphosphonate use with risk of breast and endometrial cancer, but little is known about its association with other common malignancies. The objective of this study was to evaluate the association of bisphosphonate use on the incidence of lung cancer in the WHI.The association between oral bisphosphonate use and lung cancer risk was examined in 151 432 postmenopausal women enrolled into the WHI in 1993-1998. At baseline and during follow-up, participants completed an inventory of regularly used medications including bisphosphonates.After a mean follow-up of 13.3 years, 2511 women were diagnosed with incident lung cancer. There was no evidence of a difference in lung cancer incidence between oral bisphosphonate users and never users (adjusted hazard ratio = 0.91; 95% confidence intervals, 0.80-1.04; P = 0.16). However, an inverse association was observed among those who were never smokers (hazard ratio = 0.57, 95% confidence interval, 0.39-0.84; P < 0.01).In this large prospective cohort of postmenopausal women, oral bisphosphonate use was associated with significantly lower lung cancer risk among never smokers, suggesting bisphosphonates may have a protective effect against lung cancer. Additional studies are needed to confirm our findings.
View details for PubMedID 29617712
View details for PubMedCentralID PMC6005043
-
Perspectives on Acquired Resistance to PD-1 Axis Inhibitors in Patients with Non-Small Cell Lung Cancer
JOURNAL OF THORACIC ONCOLOGY
2018; 13 (6): 741–44
View details for DOI 10.1016/j.jtho.2018.04.008
View details for Web of Science ID 000436559300009
-
Circulating Tumor DNA Quantitation for Early Response Assessment of Immune Checkpoint Inhibitors for Metastatic Non-Small Cell Lung Cancer
ELSEVIER SCIENCE INC. 2018: E1–E2
View details for Web of Science ID 000432447200003
-
Perspectives on Acquired Resistance to PD-1 AxisInhibitors in Patients with Non-Small Cell LungCancer.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2018; 13 (6): 741–44
View details for PubMedID 29793645
-
Incidence of lung cancer histologic cell-types according to neighborhood factors: A population based study in California
PLOS ONE
2018; 13 (5): e0197146
Abstract
The relationships between neighborhood factors (i.e., neighborhood socioeconomic status (nSES) and ethnic enclave) and histologic subtypes of lung cancer for racial/ethnic groups, particularly Hispanics and Asian American/Pacific Islanders (AAPIs), are poorly understood.We conducted a population-based study of 75,631 Californians diagnosed with lung cancer from 2008 through2012. We report incidence rate ratios (IRRs) for lung cancer histologic cell-types by nSES among racial/ethnic groups (non-Hispanic (NH) Whites, NH Blacks, Hispanics and AAPIs) and according to Hispanic or Asian neighborhood ethnic enclave status among Hispanics and AAPIs, respectively. In addition, we examined incidence jointly by nSES and ethnic enclave.Patterns of lung cancer incidence by nSES and ethnic enclave differed across race/ethnicity, sex, and histologic cell-type. For adenocarcinoma, Hispanic males and females, residing in both low nSES and high nSES neighborhoods that were low enclave, had higher incidence rates compared to those residing in low nSES, high enclave neighborhoods; males (IRR, 1.17 [95% CI, 1.04-1.32] and IRR, 1.15 [95% CI, 1.02-1.29], respectively) and females (IRR, 1.29 [95% CI, 1.15-1.44] and IRR, 1.51 [95% CI, 1.36-1.67], respectively). However, AAPI males residing in both low and high SES neighborhoods that were also low enclave had lower adenocarcinoma incidence.Neighborhood factors differentially influence the incidence of lung cancer histologic cell-types with heterogeneity in these associations by race/ethnicity and sex. For Hispanic males and females and AAPI males, neighborhood ethnic enclave status is strongly associated with lung adenocarcinoma incidence.
View details for PubMedID 29791458
-
eXalt3: Phase 3 randomized study comparing ensartinib to crizotinib in anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC) patients
AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.15_suppl.TPS9115
View details for Web of Science ID 000442916008019
-
Prognostic impact of KRAS mutation subtype and concurrent genetic mutations in non-small cell lung cancer.
AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.15_suppl.e21023
View details for Web of Science ID 000442916006490
-
Facile single cell profiling and clonotype analysis of NSCLC immune microenvironments.
AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.15_suppl.12014
View details for Web of Science ID 000442916004029
-
Outcomes of EGFR-mutant lung adenocarcinomas (AC) that transform to small cell lung cancer (SCLC).
AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.15_suppl.8573
View details for Web of Science ID 000442916003168
-
A multicenter study of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib plus durvalumab in patients with relapsed/refractory (R/R) solid tumors.
AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.15_suppl.2578
View details for Web of Science ID 000442916001357
-
Real-world treatment patterns and survival of BRAF V600-mutated metastatic non-small cell lung cancer patients.
AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.15_suppl.9096
View details for Web of Science ID 000442916003269
-
QUADRUPLE THREAT: A phase II trial of RRx-001 followed by etoposide-platinum re-challenge in previously treated small cell lung cancer.
AMER SOC CLINICAL ONCOLOGY. 2018
View details for DOI 10.1200/JCO.2018.36.15_suppl.e20575
View details for Web of Science ID 000442916006474
-
Computed Tomography Features associated With the Eighth Edition TNM Stage Classification for Thymic Epithelial Tumors
JOURNAL OF THORACIC IMAGING
2018; 33 (3): 176–83
Abstract
The eighth edition of the TNM classification of malignant tumors for the first time includes an official staging system for thymic epithelial tumors (TETs) recognized by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC). Staging is critical for the management of TETs, and determining stage accurately from imaging has the potential to improve clinical outcomes. We examine preoperative computed tomography (CT) characteristics of TETs associated with AJCC/UICC pathologic TNM stage.In this retrospective study, patients were included if they met all the following criteria: (1) diagnosis of TET, (2) had primary curative intent surgery performed at Stanford University, and (3) had available preoperative CT imaging for review. Tumor pathology was staged according to the eighth edition TNM classification. Fifteen CT scan features were examined from each patient case according to the International Thymic Malignancy Interest Group standard report terms in a blinded manner. A Lasso-regularized multivariate model was used to produce a weighted scoring system predictive of pathologic TNM stage.Examining the 54 patients included, the following CT characteristics were associated with higher pathologic TNM stage when using the following scoring system: elevated hemidiaphragm (score of 6), vascular endoluminal invasion (score of 6), pleural nodule (score of 2), lobulated contour (score of 2), and heterogeneous internal density (score of 1). Area under the receiver operating characteristic curve was 0.76.TETs with clearly invasive or metastatic features seen on CT are associated with having higher AJCC/UICC pathologic TNM stage, as expected. However, features of lobulated contour and heterogeneous internal density are also associated with higher stage disease. These findings need to be validated in an independent cohort.
View details for PubMedID 29219888
-
Circulating tumor DNA testing in advanced non-small cell lung cancer
LUNG CANCER
2018; 119: 42–47
View details for DOI 10.1016/j.lungcan.2018.02.019
View details for Web of Science ID 000431157800007
-
Circulating tumor DNA testing in advanced non-small cell lung cancer.
Lung cancer (Amsterdam, Netherlands)
2018; 119: 42–47
Abstract
Circulating tumor DNA (ctDNA) shed from cancer cells into the peripheral blood can be non-invasively collected and tested for the presence of tumor-specific mutations. Mutations identified in ctDNA can predict responses to targeted therapies and emerging evidence suggests that changes in ctDNA levels over time can be used to monitor response to therapy and detect disease recurrence. Given the emergence of targeted therapies in advanced non-small cell lung cancer (NSCLC), liquid biopsies utilizing ctDNA testing represent a powerful approach to genotype tumors and monitor for the development of resistance. Here, we review current and potential future clinical applications of ctDNA testing for patients with advanced NSCLC.
View details for PubMedID 29656751
-
A First-in-Human Phase I Study of Subcutaneous Outpatient Recombinant Human IL15 (rhIL15) in Adults with Advanced Solid Tumors
CLINICAL CANCER RESEARCH
2018; 24 (7): 1525–35
Abstract
Purpose: Preclinical data established IL15 as a homeostatic factor and powerful stimulator of NK and CD8+ T-cell function, the basis for clinical testing.Experimental Design: A first-in-human outpatient phase I dose escalation trial of subcutaneous (SC) rhIL15 was conducted in refractory solid tumor cancer patients. Therapy consisted of daily (Monday-Friday) subcutaneous injections of rhIL15 for two consecutive weeks (10 total doses/cycle). Clinical response was assessed by RECIST. Pharmacokinetics of rhIL15 and immune biomarkers were evaluated.Results: Nineteen patients were treated with rhIL15 at dose levels of 0.25, 0.5, 1, 2, and 3 mcg/kg/day. Fourteen patients completed ≥ 2 cycles of therapy that was well tolerated. One serious adverse event (SAE), grade 2 pancreatitis, required overnight hospitalization. Enrollment was halted after a patient receiving 3 mcg/kg/day developed a dose-limiting SAE of grade 3 cardiac chest pain associated with hypotension and increased troponin. No objective responses were observed; however, several patients had disease stabilization including a renal cell carcinoma patient who continued protocol treatment for 2 years. The treatment induced profound expansion of circulating NK cells, especially among the CD56bright subset. A proportional but less dramatic increase was found among circulating CD8+ T cells with maximal 3-fold expansion for the 2 and 3 mcg/kg patients.Conclusions: SC rhIL15 treatment was well tolerated, producing substantial increases in circulating NK and CD8+ T cells. This protocol establishes a safe outpatient SC rhIL15 regimen of 2 mcg/kg/day dosing amenable to self-injection and with potential as a combination immunotherapeutic agent. Clin Cancer Res; 24(7); 1525-35. ©2017 AACR.
View details for PubMedID 29203590
-
Population-based differences in the outcome and presentation of lung cancer patients based upon racial, histologic, and economic factors in all lung patients and those with metastatic disease
CANCER MEDICINE
2018; 7 (4): 1211–20
Abstract
To investigate the interrelation between economic, marital, and known histopathologic/therapeutic prognostic factors in presentation and survival of patients with lung cancer in nine different ethnic groups. A retrospective review of the SEER database was conducted through the years 2007-2012. Population differences were assessed via chi-square testing. Multivariable analyses (MVA) were used to detect overall survival (OS) differences in the total population (TP, N = 153,027) and for those patients presenting with Stage IV (N = 70,968). Compared to Whites, Blacks were more likely to present with younger age, male sex, lower income, no insurance, single/widowed partnership, less squamous cell carcinomas, and advanced stage; and experience less definitive surgery, lower OS, and lung cancer-specific (LCSS) survival. White Hispanics presented with younger age, higher income, lower rates of insurance, single/widowed partnership status, advanced stage, more adenocarcinomas, and lower rates of definitive surgery, but no difference in OS and LCSS than Whites. In the TP and Stage IV populations, MVAs revealed that OS was better or equivalent to Whites for all other ethnic groups and was positively associated with insurance, marriage, and higher income. Blacks presented with more advanced disease and were more likely to succumb to lung cancer, but when adjusted for prognostic factors, they had a better OS in the TP compared to Whites. Disparities in income, marital status, and insurance rather than race affect OS of patients with lung cancer. Because of their presentation with advanced disease, Black and Hispanics are likely to have increased benefit from lung cancer screening.
View details for PubMedID 29533006
-
Update on International Cooperative Groups Studies in Thoracic Malignancies: The Emergence of Immunotherapy.
Clinical lung cancer
2018
Abstract
Cancer cooperative groups have historically played a critical role in the advancement of non-small-cell lung cancer therapy. Representatives from cooperative groups worldwide convene at the International Lung Cancer Congress annually. The International Lung Cancer Congress had its 17th anniversary in the summer of 2016. The present review highlights the thoracic malignancy studies discussed by presenters. The included studies are merely a sample of the trials of thoracic malignancies ongoing globally.
View details for PubMedID 29653819
-
EGFR Genotyping of Matched Urine, Plasma , and Tumor Tissue in Patients With Non-Small-Cell Lung Cancer Treated With Rociletinib, an EGFR Tyrosine Kinase Inhibitor
JCO PRECISION ONCOLOGY
2018; 2: 1–13
Abstract
OBJECTIVECerebral cavernous malformations (CCMs) are frequently diagnosed vascular malformations of the brain. Although most CCMs are asymptomatic, some can be responsible for intracerebral hemorrhage or seizures. In selected cases, microsurgical resection is the preferred treatment option. Treatment with the unselective β-blocker propranolol has been presumed to stabilize and eventually lead to CCM size regression in a limited number of published case series; however, the underlying mechanism and evidence for this effect remain unclear. The aim of this study was to investigate the risk for CCM-related hemorrhage in patients on long-term β-blocker medication.METHODSA single-center database containing data on patients harboring CCMs was retrospectively interrogated for a time period of 35 years. The database included information about hemorrhage and antihypertensive medication. Descriptive and survival analyses were performed, focusing on the risk of hemorrhage at presentation and during follow-up (first or subsequent hemorrhage) in patients on long-term β-blocker medication versus those who were not. Follow-up was censored at the first occurrence of new hemorrhage, surgery, or the last clinical review. For purposes of this analysis, the β-blocker group was divided into the following main subgroups: any β-blocker, β1-selective β-blocker, and any unselective β-blocker.RESULTSOf 542 CCMs among 408 patients, 81 (14.9%) were under treatment with any β-blocker; 65 (12%) received β1-selective β-blocker, and 16 (3%) received any unselective β-blocker. One hundred thirty-six (25.1%) CCMs presented with hemorrhage at diagnosis. None of the β-blocker groups was associated with a lower risk of hemorrhage at the time of diagnosis in a univariate descriptive analysis (any β-blocker: p = 0.64, β1-selective: p = 0.93, any unselective β-blocker: p = 0.25). Four hundred ninety-six CCMs were followed up after diagnosis and included in the survival analysis, for a total of 1800 lesion-years. Follow-up hemorrhage occurred in 36 (7.3%) CCMs. Neither univariate descriptive nor univariate Cox proportional-hazards regression analysis showed a decreased risk for follow-up hemorrhage under treatment with β-blocker medication (any β-blocker: p = 0.70, HR 1.19, 95% CI 0.49-2.90; β1-selective: p = 0.78, HR 1.15, 95% CI 0.44-3.00; any unselective β-blocker: p = 0.76, HR 1.37, 95% CI 0.19-10.08). Multivariate Cox proportional-hazards regression analysis including brainstem location, hemorrhage at diagnosis, age, and any β-blocker treatment showed no reduced risk for follow-up hemorrhage under any β-blocker treatment (p = 0.53, HR 1.36, 95% CI 0.52-3.56).CONCLUSIONSIn this retrospective cohort study, β-blocker medication does not seem to be associated with a decreased risk of CCM-related hemorrhage at presentation or during follow-up.
View details for DOI 10.1200/PO.17.00116
View details for Web of Science ID 000462068300001
View details for PubMedID 29905510
-
Randomized phase 2 study of tivantinib plus erlotinib versus single-agent chemotherapy in previously treated KRAS mutant advanced non-small cell lung cancer
LUNG CANCER
2018; 117: 44–49
Abstract
KRAS mutations are identified in approximately 25% of non-small cell lung cancer (NSCLC) cases and are associated with resistance to currently available targeted therapies. The MET oncogene may be implicated in malignant progression of KRAS-mutant tumors. In a pre-specified subset analysis of KRAS mutant cancers in an earlier phase 2 study of erlotinib plus the oral MET inhibitor tivantinib, combination therapy was associated with substantial clinical benefit compared to erlotinib alone (progression-free survival [PFS] HR 0.18; P < 0.01). The current study was conducted to evaluate this combination further in KRAS mutant non-small cell lung cancer (NSCLC).Previously treated patients with advanced KRAS mutant NSCLC were randomized to receive either oral tivantinib (360 mg twice daily) plus erlotinib (150 mg daily) (ET) or single-agent chemotherapy (investigator's choice of pemetrexed, docetaxel, or gemcitabine) (C). The primary endpoint was PFS. At progression, crossover from C to ET was permitted.Ninety-six patients were randomly assigned to ET (n = 51) or to C (n = 45). Median PFS was 1.7 months (mos) for ET and 4.3 mos for C (HR 1.19; 95% CI, 0.71-1.97; P = 0.50). There was no difference in overall survival (HR 1.20; 95% CI, 0.76-1.88; P = 0.44). There were 4 partial responses in the C arm, and none in the ET arm. Overall, adverse events occurred more frequently in the C arm, with more cytopenias, nausea, fatigue, and alopecia. Dermatologic toxicities were more common in the ET arm.In previously treated patients with advanced KRAS mutant NSCLC, the combination of the MET inhibitor tivantinib and erlotinib is not superior to conventional single-agent chemotherapy.
View details for PubMedID 29496255
-
Paraneoplastic Syndromes and Thymic Malignancies: An Examination of the International Thymic Malignancy Interest Group Retrospective Database
JOURNAL OF THORACIC ONCOLOGY
2018; 13 (3): 436–46
Abstract
Thymic epithelial tumors (TETs) are associated with paraneoplastic/autoimmune (PN/AI) syndromes. Myasthenia gravis is the most common PN/AI syndrome associated with TETs.The International Thymic Malignancy Interest Group retrospective database was examined to determine (1) baseline and treatment characteristics associated with PN/AI syndromes and (2) the prognostic role of PN/AI syndromes for patients with TETs. The competing risks model was used to estimate cumulative incidence of recurrence (CIR) and the Kaplan-Meier method was used to calculate overall survival (OS). A Cox proportional hazards model was used for multivariate analysis.A total of 6670 patients with known PN/AI syndrome status from 1951 to 2012 were identified. PN/AI syndromes were associated with younger age, female sex, thymoma histologic type, earlier stage, and an increased rate of total thymectomy and complete resection status. There was a statistically significant lower CIR in the group with a PN/AI syndrome than in the group without a PN/AI syndrome (10-year CIR 17.3% versus 21.2%, respectively [p = 0.0003]). The OS was improved in the group with a PN/AI syndrome compared to the group without a PN/AI syndrome (median OS 21.6 years versus 17.0 years, respectively [hazard ratio = 0.63, 95% confidence interval: 0.54-0.74, p < 0.0001]). However, in the multivariate model for recurrence-free survival and OS, PN/AI syndrome was not an independent prognostic factor.Previously, there have been mixed data regarding the prognostic role of PN/AI syndromes for patients with TETs. Here, using the largest data set in the world for TETs, PN/AI syndromes were associated with favorable features (i.e., earlier stage and complete resection status) but were not an independent prognostic factor for patients with TETs.
View details for PubMedID 29191778
-
Improved EGFR mutation detection using combined exosomal RNA and circulating tumor DNA in NSCLC patient plasma
ANNALS OF ONCOLOGY
2018; 29 (3): 700–706
Abstract
A major limitation of circulating tumor DNA (ctDNA) for somatic mutation detection has been the low level of ctDNA found in a subset of cancer patients. We investigated whether using a combined isolation of exosomal RNA (exoRNA) and cell-free DNA (cfDNA) could improve blood-based liquid biopsy for EGFR mutation detection in non-small-cell lung cancer (NSCLC) patients.Matched pretreatment tumor and plasma were collected from 84 patients enrolled in TIGER-X (NCT01526928), a phase 1/2 study of rociletinib in mutant EGFR NSCLC patients. The combined isolated exoRNA and cfDNA (exoNA) was analyzed blinded for mutations using a targeted next-generation sequencing panel (EXO1000) and compared with existing data from the same samples using analysis of ctDNA by BEAMing.For exoNA, the sensitivity was 98% for detection of activating EGFR mutations and 90% for EGFR T790M. The corresponding sensitivities for ctDNA by BEAMing were 82% for activating mutations and 84% for T790M. In a subgroup of patients with intrathoracic metastatic disease (M0/M1a; n = 21), the sensitivity increased from 26% to 74% for activating mutations (P = 0.003) and from 19% to 31% for T790M (P = 0.5) when using exoNA for detection.Combining exoRNA and ctDNA increased the sensitivity for EGFR mutation detection in plasma, with the largest improvement seen in the subgroup of M0/M1a disease patients known to have low levels of ctDNA and poses challenges for mutation detection on ctDNA alone.NCT01526928.
View details for PubMedID 29216356
View details for PubMedCentralID PMC5889041
-
Current and Emergent Therapy Options for Advanced Squamous Cell Lung Cancer
JOURNAL OF THORACIC ONCOLOGY
2018; 13 (2): 165–83
Abstract
Squamous cell lung cancer (SqCLC) is a distinct histologic subtype of NSCLC that is challenging to treat because of specific clinicopathologic characteristics, which include older age, advanced disease at diagnosis, comorbid diseases, and the central location of tumors. These characteristics have a bearing on treatment outcomes in advanced SqCLC, resulting in a median survival approximately 30% shorter than for patients with other NSCLC subtypes. In the context of the specific features of SqCLC, we review challenges of treating SqCLC and the current guideline-recommended treatments for advanced (metastatic) SqCLC in different patient subpopulations. We also evaluate recently approved treatment options, including necitumumab, afatinib, nivolumab, pembrolizumab, and atezolizumab; discuss the survival benefits associated with each agent in the advanced SqCLC population; and propose a treatment algorithm incorporating these agents for this challenging-to-treat disease. Lastly, we review the preliminary clinical evidence for immunotherapy agents in development for advanced NSCLC.
View details for PubMedID 29175116
-
Progress in the Management of Early-Stage Non-Small Cell Lung Cancer in 2017.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2018; 13 (6): 767–78
Abstract
The landscape of care for early-stage non-small cell lung cancer continues to evolve. While some of the developments do not seem as dramatic as what has occurred in advanced disease in recent years, there is a continuous improvement in our ability to diagnose disease earlier and more accurately. We have an increased understanding of the diversity of early-stage disease and how to better tailor treatments to make them more tolerable without impacting efficacy. The International Association for the Study of Lung Cancer and the Journal of Thoracic Oncology publish this annual update to help readers keep pace with these important developments. Experts in the care of early-stage lung cancer patients have provided focused updates across multiple areas including screening, pathology, staging, surgical techniques and novel technologies, adjuvant therapy, radiotherapy, surveillance, disparities, and quality of life. The source for information includes large academic meetings, the published literature, or novel unpublished data from other international oncology assemblies.
View details for PubMedID 29654928
-
Treatment of Thymic Neoplasms by Drug Therapy
MODERN THORACIC ONCOLOGY, VOL 3: ESOPHAGUS, MEDIASTINUM, CHEST WALL, AND DIAPHRAGM
2018: 229-241
View details for Web of Science ID 000582590800030
-
Osimertinib for EGFR-Mutant Lung Cancer with Brain Metastases: Results from a Single-Center Retrospective Study.
The oncologist
2018
Abstract
Osimertinib is a third-generation tyrosine kinase inhibitor, initially approved for epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) with T790M acquired resistance, and now approved in the first-line setting. However, data supporting the use of osimertinib in untreated brain metastases are limited, although it has established central nervous system (CNS) activity. Our study compares the clinical outcomes of patients experiencing progressing brain metastases treated with cranial irradiation and osimertinib with those treated with osimertinib alone.Forty patients who were treated with osimertinib at the Stanford Cancer Center from November 2015 to December 2016 were identified by searching an electronic medical record database. Eleven patients had progressing brain metastases and did not receive radiation (group A), 9 patients had progressing brain metastases and received radiation when starting osimertinib (group B), and 20 patients had stable brain metastases at the time of initiating osimertinib (group C). Patient and disease characteristics, radiographic responses, and survival outcomes were evaluated retrospectively for the three groups.The CNS response rate was 32.3%. Median time to treatment failure (TTF), overall progression-free survival (PFS), and overall survival (OS) were 10.0 months (95% confidence interval [CI], 4.5-11.8), 8.8 months (95% CI, 6.2-12.1), and 16.2 months, respectively. Median TTF was 15.1 months for group A (95% CI, 1.7-28.5), 7.7 months for group B (95% CI, 0-15.5), and 10.7 months for group C (95% CI, 9.0-12.5). The median PFS was 8.8 months for group A (95% CI, 4.3-13.4), not reached for group B, and 8.4 months for group C (95% CI, 5.6-11.1). The median OS was not reached for group A and C, and was 16.2 months for group B. There was no apparent difference in TTF, PFS, or OS between the three groups.Receiving radiation prior to starting osimertinib for patients with progressing brain metastases did not prolong TTF, PFS, or OS in our series. To minimize the risks of radiation-related toxicity, delaying radiation could be considered for some patients with EGFR-mutant NSCLC with brain metastases who initially respond to osimertinib in the second-line setting.Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor recently approved for the first-line treatment of EGFR-mutant non-small cell lung cancer. Although it appears to have central nervous system (CNS) activity, most clinical trials have excluded patients with untreated, progressing brain metastases. This study included patients with stable and progressing CNS metastases treated with osimertinib and found no apparent differences in median time to treatment failure, time to progression, and overall survival in patients who received osimertinib alone compared with those who received osimertinib and radiosurgery. This may support a clinician's decision to defer radiation for selected patients with untreated brain metastases who are candidates for osimertinib therapy.
View details for PubMedID 30126856
-
Prognostic Value of Pretreatment FDG-PET Parameters in High-dose Image-guided Radiotherapy for Oligometastatic Non-Small-cell Lung Cancer.
Clinical lung cancer
2018
Abstract
Emerging data support aggressive local treatment of oligometastatic non-small-cell lung cancer (NSCLC) patients. We sought to determine whether the metabolic burden of disease found by fluorodeoxyglucose positron emission tomography at the time of high-dose radiotherapy (RT) for oligometastatic NSCLC can serve as a prognostic biomarker.We conducted a retrospective cohort study of 67 RT treatment courses in 55 patients with oligometastatic NSCLC who had undergone high-dose RT to all sites of active disease at our institution. The metabolic tumor volume, total lesion glycolysis (TLG), and maximum standardized uptake value of all lesions were measured on the pretreatment fluorodeoxyglucose positron emission tomography scans. Cox regression analysis was used to assess the influence of imaging and clinical factors on overall survival (OS).On univariate analysis, a greater metabolic tumor volume and TLG were predictive of shorter OS (hazard ratio of death, 2.42 and 2.14, respectively; P = .009 and P = .004, respectively). The effects remained significant on multivariate analysis. Neither the maximum standardized uptake value nor the number of lesions was significantly associated with OS. Patients within the highest quartile of TLG values (> 86.8 units) had a shorter median OS than those within the lower 3 quartiles (12.4 vs. 30.1 months; log-rank P = .014).The metabolic tumor burden was prognostic of OS and might help to better select oligometastatic NSCLC patients for locally ablative therapy.
View details for PubMedID 29759331
-
A pooled analysis of advanced nonsquamous non-small cell lung cancer patients with stable treated brain metastases in two phase II trials receiving bevacizumab and pemetrexed as second-line therapy
JOURNAL OF THORACIC DISEASE
2018; 10 (1): 219–27
Abstract
Brain metastases are a common complication of advanced non-small cell lung cancer (NSCLC). Patients with brain metastases were excluded from the registration trials of bevacizumab that showed a survival benefit with the use of angiogenesis inhibition.In this study, we pooled data from two separate trials designed to evaluate the risk of central nervous system (CNS) hemorrhage in patients with stable treated brain metastases to look specifically at both the safety and efficacy of bevacizumab and pemetrexed when used as second-line treatment in NSCLC patients with stable treated brain metastases.We report acceptable safety and promising efficacy from our analysis.Our study adds further evidence of safety of administering pemetrexed and bevacizumab to patients with stable brain metastases. There is increasing roles for systemic therapies to treat stable brain metastases for patients with advanced NSCLC.
View details for PubMedID 29600052
View details for PubMedCentralID PMC5863135
-
Anaplastic Lymphoma Kinase Testing: IHC vs. FISH vs. NGS
CURRENT TREATMENT OPTIONS IN ONCOLOGY
2017; 18 (12): 71
Abstract
Personalized targeted therapy has emerged as a promising strategy in lung cancer treatment, with current attention focused on elucidation and detection of oncogenic drivers responsible for tumor initiation and maintenance and development of drug resistance. In lung cancer, several oncogenic drivers have been reported, triggering the application of tyrosine kinase inhibitors (TKIs) to target these dysfunctional genes. The anaplastic lymphoma kinase (ALK) rearrangement is responsible for about 4-7% of all non-small cell lung cancers (NSCLCs) and perhaps as high as a third in specific patient populations such as younger, male, non-smokers with advanced stage, epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene (KRAS) wild type, and signet ring cell adenocarcinoma with abundant intracytoplasmic mucin. The selection of patients based on their ALK status is vital on account of the high response rates with the ALK-targeted agents in this subset of patients. Standardization and validation of ALK rearrangement detection methods is essential for accurate and reproducible results. There are currently three detection methods widely available in clinical practice, including fluorescent in situ hybridization (FISH), immunohistochemistry (IHC), and polymerase chain reaction (PCR)-based next generation sequencing (NGS) technology. However, the choice of diagnostic methodology for ALK rearrangement detection in clinical practice remains a matter of debate. With accumulating data enumerating the advantages and disadvantages of each of the three methods, combining more than one testing method for ALK fusion detection may be beneficial for patients. In this review, we will discuss the current methods used in ALK rearrangement detection with emphasis on their key advantages and disadvantages.
View details for PubMedID 29143897
-
Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial
LANCET ONCOLOGY
2017; 18 (12): 1610–23
Abstract
Adjuvant chemotherapy for resected early-stage non-small-cell lung cancer (NSCLC) provides a modest survival benefit. Bevacizumab, a monoclonal antibody directed against VEGF, improves outcomes when added to platinum-based chemotherapy in advanced-stage non-squamous NSCLC. We aimed to evaluate the addition of bevacizumab to adjuvant chemotherapy in early-stage resected NSCLC.We did an open-label, randomised, phase 3 trial of adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and who had completely resected stage IB (≥4 cm) to IIIA (defined by the American Joint Committee on Cancer 6th edition) NSCLC. We enrolled patients from across the US National Clinical Trials Network, including patients from the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) affiliates in Europe and from the Canadian Cancer Trials Group, within 6-12 weeks of surgery. The chemotherapy regimen for each patient was selected before randomisation and administered intravenously; it consisted of four 21-day cycles of cisplatin (75 mg/m2 on day 1 in all regimens) in combination with investigator's choice of vinorelbine (30 mg/m2 on days 1 and 8), docetaxel (75 mg/m2 on day 1), gemcitabine (1200 mg/m2 on days 1 and 8), or pemetrexed (500 mg/m2 on day 1). Patients in the bevacizumab group received bevacizumab 15 mg/kg intravenously every 21 days starting with cycle 1 of chemotherapy and continuing for 1 year. We randomly allocated patients (1:1) to group A (chemotherapy alone) or group B (chemotherapy plus bevacizumab), centrally, using permuted blocks sizes and stratified by chemotherapy regimen, stage of disease, histology, and sex. No one was masked to treatment assignment, except the Data Safety and Monitoring Committee. The primary endpoint was overall survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00324805.Between June 1, 2007, and Sept 20, 2013, 1501 patients were enrolled and randomly assigned to the two treatment groups: 749 to group A (chemotherapy alone) and 752 to group B (chemotherapy plus bevacizumab). 383 (26%) of 1458 patients (with complete staging information) had stage IB, 636 (44%) had stage II, and 439 (30%) had stage IIIA disease (stage of disease data were missing for 43 patients). Squamous cell histology was reported for 422 (28%) of 1501 patients. All four cisplatin-based chemotherapy regimens were used: 377 (25%) patients received vinorelbine, 343 (23%) received docetaxel, 283 (19%) received gemcitabine, and 497 (33%) received pemetrexed. At a median follow-up of 50·3 months (IQR 32·9-68·0), the estimated median overall survival in group A has not been reached, and in group B was 85·8 months (95% CI 74·9 to not reached); hazard ratio (group B vs group A) 0·99 (95% CI 0·82-1·19; p=0·90). Grade 3-5 toxicities of note (all attributions) that were reported more frequently in group B (the bevacizumab group) than in group A (chemotherapy alone) were overall worst grade (ie, all grade 3-5 toxicities; 496 [67%] of 738 in group A vs 610 [83%] of 735 in group B), hypertension (60 [8%] vs 219 [30%]), and neutropenia (241 [33%] vs 275 [37%]). The number of deaths on treatment did not differ between the groups (15 deaths in group A vs 19 in group B). Of these deaths, three in group A and ten in group B were considered at least possibly related to treatment.Addition of bevacizumab to adjuvant chemotherapy did not improve overall survival for patients with surgically resected early-stage NSCLC. Bevacizumab does not have a role in this setting and should not be considered as an adjuvant therapy for patients with resected early-stage NSCLC.National Cancer Institute of the National Institutes of Health.
View details for PubMedID 29129443
-
Survival and risk factors for progression after resection of the dominant tumor in multifocal, lepidic-type pulmonary adenocarcinoma
MOSBY-ELSEVIER. 2017: 2092-+
Abstract
It remains unclear whether a dominant lung adenocarcinoma that presents with multifocal ground glass opacities (GGOs) should be treated by local therapy. We sought to address survival in this setting and to identify risk factors for progression of unresected GGOs.Retrospective review of 70 patients who underwent resection of a pN0, lepidic adenocarcinoma, who harbored at least 1 additional GGO. Features associated with GGO progression were determined using logistic regression and survival was evaluated using the Kaplan-Meier method.Subjects harbored 1 to 7 GGOs beyond their dominant tumor (DT). Mean follow-up was 4.1 ± 2.8 years. At least 1 GGO progressed after DT resection in 21 patients (30%). In 11 patients (15.7%), this progression prompted resection (n = 5) or stereotactic radiotherapy (n = 6) at mean 2.8 ± 2.3 years. Several measures of the overall tumor burden were associated with GGO progression (all P values < .03) and with progression prompting intervention (all P values < .01). In logistic regression, greater DT size (odds ratio, 1.07; 95% confidence interval, 1.01-1.14) and an initial GGO > 1 cm (odds ratio, 4.98; 95% confidence interval, 1.15-21.28) were the only factors independently associated with GGO progression. Survival was not negatively influenced by GGO progression (100% with vs 80.7% without; P = .1) or by progression-prompting intervention (P = .4).At 4.1-year mean follow-up, 15.7% of patients with unresected GGOs after resection of a pN0 DT underwent subsequent intervention for a progressing GGO. Some features correlated with GGO growth, but neither growth, nor need for an intervention, negatively influenced survival. Thus, even those at highest risk for GGO progression should not be denied resection of a DT.
View details for PubMedID 28863952
-
Mid-radiotherapy PET/CT for prognostication and detection of early progression in patients with stage III non-small cell lung cancer
RADIOTHERAPY AND ONCOLOGY
2017; 125 (2): 338–43
Abstract
Pre- and mid-radiotherapy FDG-PET metrics have been proposed as biomarkers of recurrence and survival in patients treated for stage III non-small cell lung cancer. We evaluated these metrics in patients treated with definitive radiation therapy (RT). We also evaluated outcomes after progression on mid-radiotherapy PET/CT.Seventy-seven patients treated with RT with or without chemotherapy were included in this retrospective study. Primary tumor and involved nodes were delineated. PET metrics included metabolic tumor volume (MTV), total lesion glycolysis (TLG), and SUVmax. For mid-radiotherapy PET, both absolute value of these metrics and percentage decrease were analyzed. The influence of PET metrics on time to death, local recurrence, and regional/distant recurrence was assessed using Cox regression.91% of patients had concurrent chemotherapy. Median follow-up was 14months. None of the PET metrics were associated with overall survival. Several were positively associated with local recurrence: pre-radiotherapy MTV, and mid-radiotherapy MTV and TLG (p=0.03-0.05). Ratio of mid- to pre-treatment SUVmax was associated with regional/distant recurrence (p=0.02). 5/77 mid-radiotherapy scans showed early out-of-field progression. All of these patients died.Several PET metrics were associated with risk of recurrence. Progression on mid-radiotherapy PET/CT was a poor prognostic factor.
View details for PubMedID 28830717
-
Response to Ensartinib in TKI Naive ALK plus NSCLC Patients
ELSEVIER SCIENCE INC. 2017: S1826
View details for DOI 10.1016/j.jtho.2017.09.504
View details for Web of Science ID 000463860800400
-
Activity of Ensartinib after Second Generation Anaplastic Lymphoma Kinase (ALK) Tyrosine Kinase Inhibitors (TKI)
ELSEVIER SCIENCE INC. 2017: S1556
View details for DOI 10.1016/j.jtho.2017.09.020
View details for Web of Science ID 000461257300019
-
Oral Bisphosphonate Use and Lung Cancer Incidence among Postmenopausal Women
ELSEVIER SCIENCE INC. 2017: S1564–S1565
View details for DOI 10.1016/j.jtho.2017.09.040
View details for Web of Science ID 000461257300038
-
A Phase 1b Study of Erlotinib and Momelotinib for TKI-Naive EGFR-Mutated Metastatic Non-Small Cell Lung
ELSEVIER SCIENCE INC. 2017: S2142–S2143
View details for Web of Science ID 000463860801716
-
IMpower010: A Phase III Study of Atezolizumab vs Best Supportive Care Following Adjuvant Chemotherapy in Completely Resected NSCLC
ELSEVIER SCIENCE INC. 2017: S2398–S2399
View details for DOI 10.1016/j.jtho.2017.11.017
View details for Web of Science ID 000463860802553
-
Tiger-3: A Phase 3 Randomized Study of Rociletinib Vs Chemotherapy in EGFR-mutated Non-small Cell Lung Cancer (NSCLC)
ELSEVIER SCIENCE INC. 2017: S2397
View details for DOI 10.1016/j.jtho.2017.11.013
View details for Web of Science ID 000463860802549
-
Clinical and Pathological Variables Influencing Noninvasive Detection of Early Stage Lung Cancer Using Circulating Tumor DNA
ELSEVIER SCIENCE INC. 2017: S1851
View details for DOI 10.1016/j.jtho.2017.09.560
View details for Web of Science ID 000463860800456
-
Characterization of Autoantibody Responses in Thymoma with Myasthenia Gravis by Single-Cell Sequencing of B-cells
ELSEVIER SCIENCE INC. 2017: S1866–S1867
View details for DOI 10.1016/j.jtho.2017.09.596
View details for Web of Science ID 000463860801028
-
First-Line Ensartinib (X396) versus Crizotinib in Advanced ALK-Rearranged NSCLC (eXalt3): A Randomized, Open-Label, Phase 3 Study
ELSEVIER SCIENCE INC. 2017: S2402
View details for DOI 10.1016/j.jtho.2017.11.025
View details for Web of Science ID 000463860802561
-
Liquid Biopsy
ELSEVIER SCIENCE INC. 2017: S1666–S1667
View details for DOI 10.1016/j.jtho.2017.09.197
View details for Web of Science ID 000463860800102
-
Comparison of Circulating Tumor DNA Analysis and Surveillance Imaging After Treatment for Localized Lung Cancer
ELSEVIER SCIENCE INC. 2017: S114
View details for DOI 10.1016/j.ijrobp.2017.06.269
View details for Web of Science ID 000411559107060
-
Outcomes of Moderately Hypofractionated Intensity-Modulated Thoracic Radiotherapy with Concurrent Chemotherapy for Treatment of Non-Small Cell Lung Cancer
ELSEVIER SCIENCE INC. 2017: E504
View details for DOI 10.1016/j.ijrobp.2017.06.1806
View details for Web of Science ID 000411559104073
-
Mid-radiation Therapy PET/CT for Prognostication and Detection of Early Progression in Patients With Stage III Non-small Cell Lung Cancer
ELSEVIER SCIENCE INC. 2017: E456
View details for DOI 10.1016/j.ijrobp.2017.06.1695
View details for Web of Science ID 000411559103253
-
Circulating Tumor DNA Quantitation for Early Response Assessment of Immune Checkpoint Inhibitors for Lung Cancer
ELSEVIER SCIENCE INC. 2017: S20–S21
View details for DOI 10.1016/j.ijrobp.2017.06.061
View details for Web of Science ID 000411559106127
-
Circulating Tumor DNA Analysis during Radiation Therapy for Localized Lung Cancer Predicts Treatment Outcome
ELSEVIER SCIENCE INC. 2017: S1–S2
View details for DOI 10.1016/j.ijrobp.2017.06.021
View details for Web of Science ID 000411559106087
-
Monitoring Neutropenia for Cancer Patients at the Point of Care.
Small methods
2017; 1 (9)
Abstract
Neutrophils have a critical role in regulating the immune system. The immune system is compromised during chemotherapy, increasing infection risks and imposing a need for regular monitoring of neutrophil counts. Although commercial hematology analyzers are currently used in clinical practice for neutrophil counts, they are only available in clinics and hospitals, use large blood volumes, and are not available at the point of care (POC). Additionally, phlebotomy and blood processing require trained personnel, where patients are often admitted to hospitals when the infections are at late stage due to lack of frequent monitoring. Here, a reliable method is presented that selectively captures and quantifies white blood cells (WBCs) and neutrophils from a finger prick volume of whole blood by integrating microfluidics with high-resolution imaging algorithms. The platform is compact, portable, and easy to use. It captures and quantifies WBCs and neutrophils with high efficiency (>95%) and specificity (>95%) with an overall 4.2% bias compared to standard testing. The results from a small cohort of patients (N = 11 healthy, N = 5 lung and kidney cancer) present a unique disposable cell counter, demonstrating the ability of this tool to monitor neutrophil and WBC counts within clinical or in resource-constrained environments.
View details for DOI 10.1002/smtd.201700193
View details for PubMedID 30740513
View details for PubMedCentralID PMC6364993
-
The Evolution of Frontline Therapy in ALK-Positive Advanced NSCLC: Which ALK TKI to Use Upfront?
AMERICAN JOURNAL OF HEMATOLOGY-ONCOLOGY
2017; 13 (9): 32–36
View details for Web of Science ID 000419469500007
-
Risk Stratification for Second Primary Lung Cancer
JOURNAL OF CLINICAL ONCOLOGY
2017; 35 (25): 2893-+
Abstract
Purpose This study estimated the 10-year risk of developing second primary lung cancer (SPLC) among survivors of initial primary lung cancer (IPLC) and evaluated the clinical utility of the risk prediction model for selecting eligibility criteria for screening. Methods SEER data were used to identify a population-based cohort of 20,032 participants diagnosed with IPLC between 1988 and 2003 and who survived ≥ 5 years after the initial diagnosis. We used a proportional subdistribution hazards model to estimate the 10-year risk of developing SPLC among survivors of lung cancer LC in the presence of competing risks. Considered predictors included age, sex, race, treatment, histology, stage, and extent of disease. We examined the risk-stratification ability of the prediction model and performed decision curve analysis to evaluate the clinical utility of the model by calculating its net benefit in varied risk thresholds for screening. Results Although the median 10-year risk of SPLC among survivors of LC was 8.36%, the estimated risk varied substantially (range, 0.56% to 14.3%) when stratified by age, histology, and extent of IPLC in the final prediction model. The stratification by deciles of estimated risk showed that the observed incidence of SPLC was significantly higher in the tenth-decile group (12.5%) versus the first-decile group (2.9%; P < 10-10). The decision curve analysis yielded a range of risk thresholds (1% to 11.5%) at which the clinical net benefit of the risk model was larger than those in hypothetical all-screening or no-screening scenarios. Conclusion The risk stratification approach in SPLC can be potentially useful for identifying survivors of LC to be screened by computed tomography. More comprehensive environmental and genetic data may help enhance the predictability and stratification ability of the risk model for SPLC.
View details for PubMedID 28644772
-
The J-ALEX trial-is frontline alectinib a new standard of care?
JOURNAL OF THORACIC DISEASE
2017; 9 (8): 2242–45
View details for PubMedID 28932515
View details for PubMedCentralID PMC5594119
-
Does Plasma-Based Molecular Testing Have a Role in the Routine Care of Lung Cancer?
CLINICAL ADVANCES IN HEMATOLOGY & ONCOLOGY
2017; 15 (8): 599–601
View details for PubMedID 28949946
-
Calcium plus vitamin D supplementation and lung cancer incidence among postmenopausal women in the Women's Health Initiative
LUNG CANCER
2017; 110: 42–47
Abstract
Magnesium and calcium are antagonistic in many physiologic processes. However, few studies have investigated the associations of supplemental calcium with lung cancer risk taking this antagonism into account. We evaluated the effect of calcium and vitamin D supplementation on lung cancer incidence and explored whether the ratio of baseline calcium to magnesium (Ca:Mg) intake modifies the association in the Women's Health Initiative (WHI) calcium plus vitamin D supplementation (CaD) trial.The intervention phase of the WHI CaD was a double-blinded, randomized, placebo-controlled trial in 36,382 postmenopausal women aged 50-79 years, recruited at 40U.S. centers. Post-intervention follow-up continued among 29,862 (86%) of the surviving participants. Risk of lung cancer in association with CaD supplementation was evaluated using proportional hazard regression models.After 11 years' cumulative follow-up, there were 207 lung cancers (incidence 0.11% per year) in the supplement arm and 241 (0.12%) in the placebo arm (hazard ratio (HR) for the intervention, 0.91; 95% confidence interval (CI), 0.71-1.17). Subgroup analyses suggested that the HR for lung cancer varied by baseline Ca:Mg intake ratio among women who were current smokers at enrollment (p=0.04 for interaction).Over the entire follow-up period, calcium and vitamin D supplementation did not reduce lung cancer incidence among postmenopausal women. In exploratory analyses, an interaction was found for the baseline Ca:Mg intake ratio on lung cancer among current smokers at the trial entry. This findings need to be further studied for the role of calcium with magnesium in lung carcinogenesis in current smokers.
View details for PubMedID 28676217
-
Circulating Tumor DNA Detects Residual Disease and Anticipates Tumor Progression Earlier Than CT Imaging
ELSEVIER SCIENCE INC. 2017: E4
View details for DOI 10.1016/j.ijrobp.2017.02.048
View details for Web of Science ID 000403079100013
-
Heather Wakelee on the role of checkpoint inhibitors in advanced lung cancer
ONCOLOGY-NEW YORK
2017; 31 (6): 440-+
View details for Web of Science ID 000403633000001
View details for PubMedID 28620899
-
A population-based comparative effectiveness study of chemoradiation regimens and sequences in stage III non-small cell lung cancer
LUNG CANCER
2017; 108: 173–82
Abstract
In patients receiving concurrent chemoradiation for locally advanced non-small cell lung cancer (NSCLC), consolidation chemotherapy is frequently given even though several randomized trials have failed to show a benefit. We explored the potential benefits of consolidation chemotherapy using a population-based comparative effectiveness approach.Surveillance, Epidemiology, and End Results-Medicare was used to identify patients with Stage III NSCLC aged ≥65 and diagnosed 2002-2009. We selected patients who received concurrent chemoradiotherapy and determined whether they were (concurrent-consolidation) or were not (concurrent-alone) treated with consolidation chemotherapy. Outcomes were overall and cancer specific survival using a conditional landmark analysis approach.1688 patients treated with concurrent-alone or concurrent-consolidation were identified with a median follow up of 29 months. Choice of chemotherapy agents did not correlate with outcome. For concurrent-consolidation versus concurrent-alone, the median overall survival was 21 months versus 18 months, respectively (log-rank p=0.008) and the median cancer specific survival was 23 months versus 19 months, respectively (log-rank p=0.03). On multivariate analysis, concurrent-consolidation remained associated with improved overall survival (HR 0.85, p=0.04), and there was a trend for improved cancer specific survival (HR 0.87, p=0.12). Inverse probability of treatment weighting using propensity scores demonstrated similar findings. Importantly, the benefit of concurrent-consolidation held only for patients treated with carboplatin-taxane but not with cisplatin-etoposide.Survival outcomes were similar among the five most commonly employed platinum-based doublets. We found that patients receiving cisplatin during radiation do not appear to benefit from additional chemotherapy. However, for patients receiving carboplatin, consolidation chemotherapy was associated with improved overall and cancer specific survival.
View details for PubMedID 28625632
-
Lung cancer incidence trends in California by race/ethnicity, histology, sex, and neighborhood socioeconomic status: An analysis spanning 28 years
LUNG CANCER
2017; 108: 140–49
Abstract
Lung cancer incidence trends by histology, sex, race/ethnicity, and neighborhood socioeconomic status (nSES) have not been previously reported. We conducted a population-based study of lung cancer incidence over three peri-censal periods: 1988-1992, 1998-2002, and 2008-2012.We abstracted lung cancer cases from the California Cancer Registry and used US Census and American Community Survey data to develop multidimensional nSES indices for each census period. We calculated nSES tertile-specific incidence rates and rate ratios for each peri-censal period and used incidence rate ratios (IRR) to assess changes in rates from 1988 to 1992 to 1998-2002 and 2008-2012.There were a total of 231,205 lung cancer cases. Males: Among males, incidence rates of lung cancer decreased over time, all race/ethnicities, and all nSES tertiles, with larger declines among males in higher nSES areas. Rates either declined or were stable for adenocarcinoma, with larger declines for other histologic subtypes. Females: Among females, declines in incidence rates of lung cancer were more pronounced for females in higher nSES areas, but diverged more so than for males, with variations by histology and race/ethnicity. Incidence rates of adenocarcinoma increased over time among all females, with greater increase among females in low nSES areas.Our findings demonstrate differences in incidence trends over three decades by histology, gender, race/ethnicity, and nSES. While incidence rates consistently declined over time for males, there were greater declines in incidence for high nSES populations. In contrast, among females, there was evidence of increases in lung cancer incidence among low SES API females, and for adenocarcinoma.
View details for PubMedID 28625626
-
Scientific Advances in Thoracic Oncology 2016.
Journal of thoracic oncology
2017
Abstract
Lung cancer care is rapidly changing with advances in genomic testing, the development of next-generation targeted kinase inhibitors, and the continued broad study of immunotherapy in new settings and potential combinations. The IASLC and the Journal of Thoracic Oncology publish this annual update to help readers keep pace with these important developments. Experts in thoracic cancer and care provide focused updates across multiple areas including prevention and early detection, molecular diagnostics, pathology and staging, surgery, adjuvant therapy, radiotherapy, molecular targeted therapy, and immunotherapy for non-small cell lung cancer, small cell lung cancer, and mesothelioma. Quality and value of care and perspectives on the future of lung cancer research and treatment have also been included in this concise review.
View details for DOI 10.1016/j.jtho.2017.05.019
View details for PubMedID 28579481
-
The morbidity and mortality conference (MMC) concept applied to contemporary oncology practice: Retrospective findings on management of 233 patients (pts) who died of ovarian cancer (OC), colorectal cancer (CRC) and wild-type (no identified targetable mutation) nonsquamous non-small cell lung cancer (WTLC)
AMER SOC CLINICAL ONCOLOGY. 2017
View details for DOI 10.1200/JCO.2017.35.15_suppl.e18195
View details for Web of Science ID 000411931707084
-
Risk factors associated with brain metastases in ECOG-ACRIN E1505, a phase III randomized trial of adjuvant chemotherapy with or without bevacizumab for patients with completely resected stage IB (>/=4 cm) - IIIA non-small cell lung cancer (NSCLC).
AMER SOC CLINICAL ONCOLOGY. 2017
View details for DOI 10.1200/JCO.2017.35.15_suppl.8539
View details for Web of Science ID 000411932201117
-
A phase III trial to compare atezolizumab (atezo) vs best supportive care (BSC) following adjuvant chemotherapy in patients (pts) with completely resected NSCLC: IMpower010.
AMER SOC CLINICAL ONCOLOGY. 2017
View details for DOI 10.1200/JCO.2017.35.15_suppl.TPS8576
View details for Web of Science ID 000411932201153
-
-Mutant Non-Small Cell Lung Cancer: From Molecular Profiling to Rationally Designed Therapy.
oncologist
2017
Abstract
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths globally. However, the identification of oncogenic driver alterations involved in the initiation and maintenance of NSCLC, such as epidermal growth factor receptor mutations and anaplastic lymphoma kinase translocation, has led to the development of novel therapies that directly target mutant proteins and associated signaling pathways, resulting in improved clinical outcomes. As sequencing techniques have improved, the molecular heterogeneity of NSCLC has become apparent, leading to the identification of a number of potentially actionable oncogenic driver mutations. Of these, one of the most promising therapeutic targets is B-Raf proto-oncogene, serine/threonine kinase (BRAF). Mutations in BRAF, observed in 2%-4% of NSCLCs, typically lead to constitutive activation of the protein and, as a consequence, lead to activation of the mitogen-activated protein kinase signaling pathway. Direct inhibition of mutant BRAF and/or the downstream mitogen-activated protein kinase kinase (MEK) has led to prolonged survival in patients with BRAF-mutant metastatic melanoma. This comprehensive review will discuss the clinical characteristics and prognostic implications of BRAF-mutant NSCLC, the clinical development of BRAF and MEK inhibitors from melanoma to NSCLC, and practical considerations for clinicians involving BRAF mutation screening and the choice of targeted therapy. The Oncologist 2017;22:1-11 IMPLICATIONS FOR PRACTICE: Personalized medicine has begun to provide substantial benefit to patients with oncogene-driven non-small cell lung cancer (NSCLC). However, treatment options for patients with oncogenic driver mutations lacking targeted treatment strategies remain limited. Direct inhibition of mutant B-Raf proto-oncogene, serine/threonine kinase (BRAF) and/or downstream mitogen-activated protein kinase kinase has the potential to change the course of the disease for patients with BRAF-mutant NSCLC, as it has in BRAF-mutant melanoma. Optimization of screening strategies for rare mutations and the choice of appropriate agents on an individual basis will be key to providing timely and successful intervention.
View details for DOI 10.1634/theoncologist.2016-0458
View details for PubMedID 28487464
-
-Mutant Non-Small Cell Lung Cancer: From Molecular Profiling to Rationally Designed Therapy.
oncologist
2017
Abstract
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths globally. However, the identification of oncogenic driver alterations involved in the initiation and maintenance of NSCLC, such as epidermal growth factor receptor mutations and anaplastic lymphoma kinase translocation, has led to the development of novel therapies that directly target mutant proteins and associated signaling pathways, resulting in improved clinical outcomes. As sequencing techniques have improved, the molecular heterogeneity of NSCLC has become apparent, leading to the identification of a number of potentially actionable oncogenic driver mutations. Of these, one of the most promising therapeutic targets is B-Raf proto-oncogene, serine/threonine kinase (BRAF). Mutations in BRAF, observed in 2%-4% of NSCLCs, typically lead to constitutive activation of the protein and, as a consequence, lead to activation of the mitogen-activated protein kinase signaling pathway. Direct inhibition of mutant BRAF and/or the downstream mitogen-activated protein kinase kinase (MEK) has led to prolonged survival in patients with BRAF-mutant metastatic melanoma. This comprehensive review will discuss the clinical characteristics and prognostic implications of BRAF-mutant NSCLC, the clinical development of BRAF and MEK inhibitors from melanoma to NSCLC, and practical considerations for clinicians involving BRAF mutation screening and the choice of targeted therapy. The Oncologist 2017;22:1-11 IMPLICATIONS FOR PRACTICE: Personalized medicine has begun to provide substantial benefit to patients with oncogene-driven non-small cell lung cancer (NSCLC). However, treatment options for patients with oncogenic driver mutations lacking targeted treatment strategies remain limited. Direct inhibition of mutant B-Raf proto-oncogene, serine/threonine kinase (BRAF) and/or downstream mitogen-activated protein kinase kinase has the potential to change the course of the disease for patients with BRAF-mutant NSCLC, as it has in BRAF-mutant melanoma. Optimization of screening strategies for rare mutations and the choice of appropriate agents on an individual basis will be key to providing timely and successful intervention.
View details for DOI 10.1634/theoncologist.2016-0458
View details for PubMedID 28487464
-
Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global, Multicenter RET Registry
JOURNAL OF CLINICAL ONCOLOGY
2017; 35 (13): 1403-?
Abstract
Purpose In addition to prospective trials for non-small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response to targeted therapies. Here, we present the results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. Methods A global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement. Molecular profiling was performed locally by reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization, or next-generation sequencing. Anonymized data-clinical, pathologic, and molecular features-were collected centrally and analyzed by an independent statistician. Best response to RET tyrosine kinase inhibition administered outside of a clinical trial was determined by RECIST v1.1. Results By April 2016, 165 patients with RET-rearranged NSCLC from 29 centers across Europe, Asia, and the United States were accrued. Median age was 61 years (range, 29 to 89 years). The majority of patients were never smokers (63%) with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent rearrangement was KIF5B-RET (72%). Of those patients, 53 received one or more RET tyrosine kinase inhibitors in sequence: cabozantinib (21 patients), vandetanib (11 patients), sunitinib (10 patients), sorafenib (two patients), alectinib (two patients), lenvatinib (two patients), nintedanib (two patients), ponatinib (two patients), and regorafenib (one patient). The rate of any complete or partial response to cabozantinib, vandetanib, and sunitinib was 37%, 18%, and 22%, respectively. Further responses were observed with lenvantinib and nintedanib. Median progression-free survival was 2.3 months (95% CI, 1.6 to 5.0 months), and median overall survival was 6.8 months (95% CI, 3.9 to 14.3 months). Conclusion Available multikinase inhibitors had limited activity in patients with RET-rearranged NSCLC in this retrospective study. Further investigation of the biology of RET-rearranged lung cancers and identification of new targeted therapeutics will be required to improve outcomes for these patients.
View details for DOI 10.1200/JCO.2016.70.9352
View details for PubMedID 28447912
-
METLung: a disappointing result in a challenging patient population
TRANSLATIONAL CANCER RESEARCH
2017; 6: S489–S493
View details for DOI 10.21037/tcr.2017.04.02
View details for Web of Science ID 000404110200011
-
A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer
CANCER CHEMOTHERAPY AND PHARMACOLOGY
2017; 79 (5): 923-932
Abstract
Cabozantinib is a multi-kinase inhibitor that targets MET, AXL, and VEGFR2, and may synergize with EGFR inhibition in NSCLC. Cabozantinib was assessed alone or in combination with erlotinib in patients with progressive NSCLC and EGFR mutations who had previously received erlotinib.This was a phase Ib/II study (NCT00596648). The primary objectives of phase I were to assess the safety, pharmacokinetics, and pharmacodynamics and to determine maximum tolerated dose (MTD) of cabozantinib plus erlotinib in patients who failed prior erlotinib treatment. In phase II, patients with prior response or stable disease with erlotinib who progressed were randomized to single-agent cabozantinib 100 mg qd vs cabozantinib 100 mg qd and erlotinib 50 mg qd (phase I MTD), with a primary objective of estimating objective response rate (ORR).Sixty-four patients were treated in phase I. Doses of 100 mg cabozantinib plus 50 mg erlotinib, or 40 mg cabozantinib plus 150 mg erlotinib were determined to be MTDs. Diarrhea was the most frequent dose-limiting toxicity and the most frequent AE (87.5% of patients). The ORR for phase I was 8.2% (90% CI 3.3-16.5). In phase II, one patient in the cabozantinib arm (N = 15) experienced a partial response, for an ORR of 6.7% (90% CI 0.3-27.9), with no responses for cabozantinib plus erlotinib (N = 13). There was no evidence that co-administration of cabozantinib markedly altered erlotinib pharmacokinetics or vice versa.Despite responses with cabozantinib/erlotinib in phase I, there were no responses in the combination arm of phase II in patients with acquired resistance to erlotinib. Cabozantinib did not appear to re-sensitize these patients to erlotinib.
View details for DOI 10.1007/s00280-017-3283-z
View details for Web of Science ID 000400070400009
View details for PubMedID 28352985
-
Case Series of MET Exon 14 Skipping Mutation-positive Non-Small Cell Lung Cancers and Response to Crizotinib.
International journal of radiation oncology, biology, physics
2017; 98 (1): 239-?
View details for DOI 10.1016/j.ijrobp.2017.01.170
View details for PubMedID 28587017
-
CNS activity of ensartinib in ALK1 non-small cell lung cancer (NSCLC) patients (pts)
OXFORD UNIV PRESS. 2017
View details for Web of Science ID 000405512800076
-
The morbidity and mortality conference (MMC) concept applied to contemporary oncology practice: Retrospective findings on management of 233 patients (pts) who died of ovarian cancer (OC), colorectal cancer (CRC), and wild-type (no identified targetable mutation) nonsquamous non-small cell lung cancer (WTLC)
AMER SOC CLINICAL ONCOLOGY. 2017
View details for Web of Science ID 000443301600240
-
Elusive Target of Angiogenesis in Small-Cell Lung Cancer.
Journal of clinical oncology
2017: JCO2016716084-?
View details for DOI 10.1200/JCO.2016.71.6084
View details for PubMedID 28165898
-
ERBB2-Mutated Metastatic Non-Small Cell Lung Cancer: Response and Resistance to Targeted Therapies.
Journal of thoracic oncology
2017
Abstract
Erb-b2 receptor tyrosine kinase 2 gene (ERBB2) (also called HER2) has long been recognized as an oncogenic driver in some breast and gastroesophageal cancers in which amplification of this gene confers sensitivity to treatment with Erb-b2 receptor tyrosine kinase 2 (ERBB2)-directed agents. More recently, somatic mutations in ERBB2 have been reported in 1% to 2% of patients with lung adenocarcinoma. Previous case series have suggested clinical tumor responses using anti-ERBB2 small molecules and antibody therapies.Here we report the outcomes of nine patients with metastatic lung adenocarcinoma with ERBB2 mutations being treated with ERBB2-targeted therapies.Four of the nine patients had response to targeted therapies, with durations of response ranging from 3 to 10 months. We identified a de novo phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation and ERBB2 copy number gain as potential resistance mechanisms.We showed patients with ERBB2-mutated lung adenocarcinoma can respond to targeted therapies, and we identified potential resistance mechanisms upon progression to targeted therapies.
View details for DOI 10.1016/j.jtho.2017.01.023
View details for PubMedID 28167203
-
Neoadjuvant and Adjuvant Therapy for Non-Small Cell Lung Cancer
HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA
2017; 31 (1): 31-?
Abstract
The use of 4 cycles of cisplatin-based adjuvant chemotherapy is now the standard of care for patients with resected stage II and IIIA non-small cell lung cancer. Neoadjuvant chemotherapy lacks the same level of data as adjuvant treatment, but meta-analyses of this approach support its use. Selection of patients who are most likely to benefit from chemotherapy remain elusive. Ongoing adjuvant trials are exploring biomarkers, molecularly targeted agents, postoperative radiation therapy, and immunotherapy.
View details for DOI 10.1016/j.hoc.2016.08.011
View details for PubMedID 27912832
-
Determinants of Complete Resection of Thymoma by Minimally Invasive and Open Thymectomy: Analysis of an International Registry
JOURNAL OF THORACIC ONCOLOGY
2017; 12 (1): 129-136
Abstract
Minimally invasive thymectomy (MIT) is a surgical approach to thymectomy that has more favorable short-term outcomes for myasthenia gravis than open thymectomy (OT). The oncologic outcomes of MIT performed for thymoma have not been rigorously evaluated. We analyzed determinants of complete (R0) resection among patients undergoing MIT and OT in a large international database.The retrospective database of the International Thymic Malignancy Interest Group was queried. Chi-square and Wilcoxon rank sum tests, multivariate logistic regression models, and propensity matching were performed.A total of 2514 patients underwent thymectomy for thymoma between 1997 and 2012; 2053 of them (82%) underwent OT and 461 (18%) underwent MIT, with the use of MIT increasing significantly in recent years. The rate of R0 resection among patients undergoing OT was 86%, and among those undergoing MIT it was 94% (p < 0.0001). In propensity-matched MIT and OT groups (n = 266 in each group); however, the rate of R0 resection did not differ significantly (96% in both the MIT and OT groups, p = 0.7). Multivariate analyses were performed to identify determinants of R0 resection. Factors independently associated with R0 resection were geographical region, later time period, less advanced Masaoka stage, total thymectomy, and the absence of radiotherapy. Surgical approach, whether minimally invasive or open, was not associated with completeness of resection.The use of MIT for resection of thymoma has been increasing substantially over time, and MIT can achieve rates of R0 resection for thymoma similar to those achieved with OT.
View details for DOI 10.1016/j.jtho.2016.08.131
View details for Web of Science ID 000391518500015
-
Chart Review Versus an Automated Bioinformatic Approach to Assess Real-World Crizotinib Effectiveness in Anaplastic Lymphoma Kinase–Positive Non–Small-Cell Lung Cancer
JCO: Clinical Cancer Informatics
2017
View details for DOI 10.1200/CCI.16.00055
-
The CD47 Macrophage Checkpoint as a New Immunotherapy Target
ELSEVIER SCIENCE INC. 2017: S108–S109
View details for Web of Science ID 000413055800089
-
IMpower010: Phase III Study of Atezolizumab vs BSC after Adjuvant Chemotherapy in Patients with Completely Resected NSCLC
ELSEVIER SCIENCE INC. 2017: S1305
View details for Web of Science ID 000413055803094
-
Global RET Registry (GLORY): Activity of RET-Directed Targeted Therapies in RET-Rearranged Lung Cancers
ELSEVIER SCIENCE INC. 2017: S435–S436
View details for Web of Science ID 000413055801012
-
Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling.
Cancer discovery
2017
Abstract
Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here we apply Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I-III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first post-treatment blood sample, indicating reliable identification of MRD. Post-treatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in lung cancer patients can be accurately detected using CAPP-Seq and may allow personalized adjuvant treatment while disease burden is lowest.
View details for PubMedID 28899864
-
Monitoring Neutropenia for Cancer Patients at the Point of Care
Small Methods
2017
View details for DOI 10.1002/smtd.201700193
-
Clinical Activity of Osimertinib in EGFR Mutation Positive Non-Small Cell Lung Cancer (NSCLC) Patients (Pts) Previously Treated with Rociletinib
ELSEVIER SCIENCE INC. 2017: S1263
View details for Web of Science ID 000413055803032
-
Smoking Behavior in Patients with Early Stage Non-Small Cell Lung Cancer: A Report from ECOG-ACRIN 1505 Trial
ELSEVIER SCIENCE INC. 2017: S256
View details for Web of Science ID 000413055800233
-
Perspectives of Targeted Therapies and Immunotherapy in Completely Resected NSCLC
ELSEVIER SCIENCE INC. 2017: S45–S46
View details for Web of Science ID 000413055800037
-
Circulating Tumor DNA Detects Minimal Residual Disease and Predicts Outcome in Localized Lung Cancer
ELSEVIER SCIENCE INC. 2017: S445
View details for Web of Science ID 000413055801024
-
A Highly Sensitive Next-Generation Sequencing Platform for Detection of NSCLC EGFR T790M Mutation in Urine and Plasma
ELSEVIER SCIENCE INC. 2017: S384–S385
View details for Web of Science ID 000413055800415
-
A Phase lb Study of Erlotinib and Momelotinib for EGFR TKI Naive EGFR Mutated Metastatic Non-Small Cell Lung Cancer
ELSEVIER SCIENCE INC. 2017: S1070–S1071
View details for Web of Science ID 000413055802312
-
A Phase II Study of Etirinotecan Pegol (NKTR-102) in Patients with Refractory Brain Metastases and Advanced Lung Cancer
ELSEVIER SCIENCE INC. 2017: S940
View details for Web of Science ID 000413055802110
-
Response and Plasma Genotyping from Phase I/II Trial of Ensartinib (X-396) in Patients (Pts) with ALK plus NSCLC
ELSEVIER SCIENCE INC. 2017: S1159
View details for Web of Science ID 000413055802442
-
Vorinostat and Concurrent Stereotactic Radiosurgery for Non-Small Cell Lung Cancer Brain Metastases: A Phase 1 Dose Escalation Trial.
International journal of radiation oncology, biology, physics
2017; 99 (1): 16–21
Abstract
To determine the maximum tolerated dose (MTD) of vorinostat, a histone deacetylase inhibitor, given concurrently with stereotactic radiosurgery (SRS) to treat non-small cell lung cancer (NSCLC) brain metastases. Secondary objectives were to determine toxicity, local failure, distant intracranial failure, and overall survival rates.In this multicenter study, patients with 1 to 4 NSCLC brain metastases, each ≤2 cm, were enrolled in a phase 1, 3 + 3 dose escalation trial. Vorinostat dose levels were 200, 300, and 400 mg orally once daily for 14 days. Single-fraction SRS was delivered on day 3. A dose-limiting toxicity (DLT) was defined as any Common Terminology Criteria for Adverse Events version 3.0 grade 3 to 5 acute nonhematologic adverse event related to vorinostat or SRS occurring within 30 days.From 2009 to 2014, 17 patients were enrolled and 12 patients completed study treatment. Because no DLTs were observed, the MTD was established as 400 mg. Acute adverse events were reported by 10 patients (59%). Five patients discontinued vorinostat early and withdrew from the study. The most common reasons for withdrawal were dyspnea (n=2), nausea (n=1), and fatigue (n=2). With a median follow-up of 12 months (range, 1-64 months), Kaplan-Meier overall survival was 13 months. There were no local failures. One patient (8%) at the 400-mg dose level with a 2.0-cm metastasis developed histologically confirmed grade 4 radiation necrosis 2 months after SRS.The MTD of vorinostat with concurrent SRS was established as 400 mg. Although no DLTs were observed, 5 patients withdrew before completing the treatment course, a result that emphasizes the need for supportive care during vorinostat administration. There were no local failures. A larger, randomized trial may evaluate both the tolerability and potential local control benefit of vorinostat concurrent with SRS for brain metastases.
View details for PubMedID 28816142
-
Efficacy and Safety of Onartuzumab in Combination With First-Line Bevacizumab- or Pemetrexed-Based Chemotherapy Regimens in Advanced Non-Squamous Non Small-Cell Lung Cancer
CLINICAL LUNG CANCER
2017; 18 (1): 50-59
Abstract
Onartuzumab is a monovalent monoclonal antibody that binds with the extracellular domain of the MET receptor. Given the role of MET in non-small-cell lung cancer (NSCLC), we investigated whether onartuzumab added to first-line chemotherapy efficacy in non-squamous NSCLC.Patients with untreated stage IIIB/IV non-squamous NSCLC, stratified by MET diagnostic status, were randomized to receive onartuzumab (15 mg/kg intravenously every 3 weeks) or placebo in combination with either paclitaxel/platinum/bevacizumab (bevacizumab cohort), or in combination with platinum/pemetrexed (pemetrexed cohort) with maintenance bevacizumab or pemetrexed and onartuzumab/placebo as appropriate. Co-primary endpoints of this phase II study were progression-free survival (PFS) in all patients and in MET+ patients (2+/3+), defined by the Ventana immunohistochemistry assay; secondary endpoints included overall survival (OS), objective response rate (ORR), safety, and pharmacokinetics.Efficacy data were available for 139 and 120 patients in the bevacizumab and pemetrexed cohorts, respectively. No benefit was seen in the PFS endpoint in the intent-to treat population of either cohort, but was numerically worse in the onartuzumab arm of the MET+ subgroup of the bevacizumab cohort. The onartuzumab and placebo arms had similar ORR and OS results in both cohorts. A higher incidence of some adverse events was observed with onartuzumab versus placebo, including peripheral edema (30% vs. 3%, bevacizumab cohort; 48% vs. 14%, pemetrexed cohort) and venous thromboembolic events (bevacizumab cohort only, 15% vs. 6%).Onartuzumab does not appear to provide any additional clinical benefit when given in combination with current first-line standard-of-care chemotherapy for non-squamous NSCLC.
View details for DOI 10.1016/j.cllc.2016.09.013
View details for PubMedID 27856142
-
Reply to Comment on 'Statin use and all-cancer survival: prospective results from the Women's Health Initiative'.
British journal of cancer
2017; 116 (3)
View details for DOI 10.1038/bjc.2016.396
View details for PubMedID 27923034
-
Overview of Thoracic Oncology Trials in Cooperative Groups Around the Globe.
Clinical lung cancer
2017; 18 (1): 5-12
Abstract
Survival rates of patients with either early and advanced stage non-small-cell lung cancer (NSCLC) have improved with newer systemic therapy and radiation techniques, including combination regimens, targeted therapies, and immunotherapies. The cancer cooperative groups have historically played a critical role in the advancement of NSCLC therapy. Annually, representatives from cooperative groups worldwide convene at the International Lung Cancer Congress (ILCC). In summer 2015, the ILCC reached its 16th anniversary. This article highlights the NSCLC studies presented by participating groups in 2015.
View details for DOI 10.1016/j.cllc.2016.06.007
View details for PubMedID 27473736
-
Molecular profiling of single circulating tumor cells from lung cancer patients
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2016; 113 (52): E8379-E8386
Abstract
Circulating tumor cells (CTCs) are established cancer biomarkers for the "liquid biopsy" of tumors. Molecular analysis of single CTCs, which recapitulate primary and metastatic tumor biology, remains challenging because current platforms have limited throughput, are expensive, and are not easily translatable to the clinic. Here, we report a massively parallel, multigene-profiling nanoplatform to compartmentalize and analyze hundreds of single CTCs. After high-efficiency magnetic collection of CTC from blood, a single-cell nanowell array performs CTC mutation profiling using modular gene panels. Using this approach, we demonstrated multigene expression profiling of individual CTCs from non-small-cell lung cancer (NSCLC) patients with remarkable sensitivity. Thus, we report a high-throughput, multiplexed strategy for single-cell mutation profiling of individual lung cancer CTCs toward minimally invasive cancer therapy prediction and disease monitoring.
View details for DOI 10.1073/pnas.1608461113
View details for PubMedID 27956614
-
Protective Effects of Statins in Cancer: Should They Be Prescribed for High-Risk Patients?
Current atherosclerosis reports
2016; 18 (12): 72-?
Abstract
Statins are one of the most widely prescribed drug classes in the USA. This review aims to summarize recent research on the relationship between statin use and cancer outcomes, in the context of clinical guidelines for statin use in patients with cancer or who are at high risk for cancer.A growing body of research has investigated the relationship between statins and cancer with mixed results. Cancer incidence has been more extensively studied than cancer survival, though results are inconsistent as some large meta-analyses have not found an association, while other studies have reported improved cancer outcomes with the use of statins. Additionally, two large studies reported increased all-cancer survival with statin use. Studies on specific cancer types in relation to cancer use have also been mixed, though the most promising results appear to be found in gastrointestinal cancers. Few studies have reported an increased risk of cancer incidence or decreased survival with statin use, though this type of association has been more commonly reported for cutaneous cancers. The overall literature on statins in relation to cancer incidence and survival is mixed, and additional research is warranted before any changes in clinical guidelines can be recommended. Future research areas include randomized controlled trials, studies on specific cancer types in relation to statin use, studies on populations without clinical indication for statins, elucidation of underlying biological mechanisms, and investigation of different statin types. However, studies seem to suggest that statins may be protective and are not likely to be harmful in the setting of cancer, suggesting that cancer patients who already take statins should not have this medication discontinued.
View details for PubMedID 27796821
-
IMpower010: A Phase III trial investigating atezolizumab (atezo) vs best supportive care (BSC) after adjuvant chemotherapy (chemo) in patients (pts) with completely resected NSCLC
OXFORD UNIV PRESS. 2016
View details for Web of Science ID 000393980600427
-
Physical activity and sedentary behavior in relation to lung cancer incidence and mortality in older women: The Women's Health Initiative.
International journal of cancer
2016; 139 (10): 2178-2192
Abstract
Physical activity has been associated with lower lung cancer incidence and mortality in several populations. We investigated these relationships in the Women's Health Initiative Observational Study (WHI-OS) and Clinical Trial (WHI-CT) prospective cohort of postmenopausal women. The WHI study enrolled 161,808 women aged 50-79 years between 1993-1998 at 40 U.S. clinical centers; 129,401 were eligible for these analyses. Cox proportional hazards models were used to assess the association of baseline physical activity levels [metabolic equivalent (MET)-minutes/week: none <100 (reference), low 100-<500, medium 500-<1200, high 1200+] and sedentary behavior with total lung cancer incidence and mortality. Over 11.8 mean follow-up years, 2,148 incident lung cancer cases and 1,365 lung cancer deaths were identified. Compared to no activity, higher physical activity levels at study entry were associated with lower lung cancer incidence [p=0.009; hazard ratios (95% confidence intervals) for each physical activity category: low, HR: 0.86 (0.76-0.96); medium, HR: 0.82 (0.73-0.93); and high, HR: 0.90 (0.79-1.03)], and mortality [p<0.0001; low, HR: 0.80 (0.69-0.92); medium, HR: 0.68 (0.59-0.80); and high, HR: 0.78 (0.66-0.93)]. Body mass index (BMI) modified the association with lung cancer incidence (p=0.01), with a stronger association in women with BMI<30 kg/m(2) . Significant associations with sedentary behavior were not observed. In analyses by lung cancer subtype, higher total physical activity levels were associated with lower lung cancer mortality for both overall NSCLC and adenocarcinoma. In conclusion, physical activity may be protective for lung cancer incidence and mortality in postmenopausal women, particularly in non-obese women. This article is protected by copyright. All rights reserved.
View details for DOI 10.1002/ijc.30281
View details for PubMedID 27439221
-
Corrigendum: Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients.
Nature communications
2016; 7: 13513-?
View details for DOI 10.1038/ncomms13513
View details for PubMedID 27841271
View details for PubMedCentralID PMC5114547
-
Adding to the targeted therapy toolbox: BRAF and MEK inhibition in the treatment of BRAF V600E metastatic non-small cell lung cancer
TRANSLATIONAL CANCER RESEARCH
2016; 5: S1233-S1240
View details for DOI 10.21037/tcr.2016.11.50
View details for Web of Science ID 000393328100052
-
MINI01.02: Response and Plasma Genotyping from Phase I/II Trial of Ensartinib (X-396) in Patients (pts) with ALK+ NSCLC: Topic: Medical Oncology.
Journal of thoracic oncology
2016; 11 (11S): S256-S257
View details for DOI 10.1016/j.jtho.2016.09.017
View details for PubMedID 27969449
-
PS01.22: Novel 3-Dimensional Preclinical Models: Topic: Medical Oncology.
Journal of thoracic oncology
2016; 11 (11S): S282-?
View details for DOI 10.1016/j.jtho.2016.09.057
View details for PubMedID 27969489
-
PS01.55: IMpower010: Phase III Study of Atezolizumab vs BSC After Adjuvant Chemotherapy in Patients with Completely Resected NSCLC: Topic: Medical Oncology.
Journal of thoracic oncology
2016; 11 (11S): S304-?
View details for DOI 10.1016/j.jtho.2016.09.090
View details for PubMedID 27969522
-
PS01.04: A Phase II Study of Etirinotecan Pegol (NKTR-102) in Patients with Refractory Brain Metastases and Advanced Lung Cancer: Topic: Medical Oncology.
Journal of thoracic oncology
2016; 11 (11S): S271-S272
View details for DOI 10.1016/j.jtho.2016.09.040
View details for PubMedID 27969472
-
PS01.67: Case Series of MET Exon 14 Skipping Mutation-Positive Non-Small Cell Lung Cancers and Response to Crizotinib: Topic: Medical Oncology.
Journal of thoracic oncology
2016; 11 (11S): S312-S313
View details for DOI 10.1016/j.jtho.2016.09.102
View details for PubMedID 27969534
-
PS01.77: Risk-Stratification for Second Primary Lung Cancer: Topic: Medical Oncology.
Journal of thoracic oncology
2016; 11 (11S): S319-S320
View details for DOI 10.1016/j.jtho.2016.09.112
View details for PubMedID 27969544
-
PS01.66: Biomarker Stratification of Outcomes of Third-Generation EGFR TKI Therapy in Patients with Previously-Treated Advanced NSCLC: Topic: Medical Oncology.
Journal of thoracic oncology
2016; 11 (11S): S311-S312
View details for DOI 10.1016/j.jtho.2016.09.101
View details for PubMedID 27969533
-
ORAL01.04: Phase II Trial of Atezolizumab for Patients with PD-L1-Selected Advanced NSCLC (BIRCH): Updated Efficacy and Exploratory Biomarker Results: Topic: Medical Oncology.
Journal of thoracic oncology
2016; 11 (11S): S251-S252
View details for DOI 10.1016/j.jtho.2016.09.009
View details for PubMedID 27969443
-
The Burden of Cancer in Asian Americans: A Report of National Mortality Trends by Asian Ethnicity
CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION
2016; 25 (10): 1371-1382
Abstract
Asian Americans (AA) are the fastest growing U.S. population, and when properly distinguished by their ethnic origins, exhibit substantial heterogeneity in socioeconomic status, health behaviors, and health outcomes. Cancer is the second leading cause of death in the United States, yet trends and current patterns in the mortality burden of cancer among AA ethnic groups have not been documented.We report age-adjusted rates, standardized mortality ratios, and modeled trends in cancer-related mortality in the following AA ethnicities: Asian Indians, Chinese, Filipinos, Japanese, Koreans, and Vietnamese, from 2003 to 2011, with non-Hispanic whites (NHW) as the reference population.For most cancer sites, AAs had lower cancer mortality than NHWs; however, mortality patterns were heterogeneous across AA ethnicities. Stomach and liver cancer mortality was very high, particularly among Chinese, Koreans, and Vietnamese, for whom these two cancer types combined accounted for 15% to 25% of cancer deaths, but less than 5% of cancer deaths in NHWs. In AA women, lung cancer was a leading cause of death, but (unlike males and NHW females) rates did not decline over the study period.Ethnicity-specific analyses are critical to understanding the national burden of cancer among the heterogeneous AA population.Our findings highlight the need for disaggregated reporting of cancer statistics in AAs and warrant consideration of tailored screening programs for liver and gastric cancers. Cancer Epidemiol Biomarkers Prev; 25(10); 1371-82. ©2016 AACR.
View details for DOI 10.1158/1055-9965.EPI-16-0167
View details for PubMedID 27694108
-
Phase I/II Trial of X-396, A Novel ALK Inhibitor, in Patients With ALK plus NSCLC
ELSEVIER SCIENCE INC. 2016: S209–S210
View details for Web of Science ID 000427345100060
-
Phase I/II Trial of X-396, a Novel ALK Inhibitor, in Patients With ALK plus NSCLC
ELSEVIER SCIENCE INC. 2016: S176–S177
View details for Web of Science ID 000427345100013
-
CAPP-Seq Circulating Tumor DNA Analysis for Early Detection of Tumor Progression After Definitive Radiation Therapy for Lung Cancer
ELSEVIER SCIENCE INC. 2016: S41–S42
View details for DOI 10.1016/j.ijrobp.2016.06.112
View details for Web of Science ID 000387655804429
-
Phase I/II trial of X-396 in patients (pts) with ALK plus non-small cell lung cancer (NSCLC): Correlation with plasma and tissue genotyping and response to therapy (tx)
OXFORD UNIV PRESS. 2016
View details for Web of Science ID 000393913000302
-
Rociletinib-associated cataracts in EGFR-mutant NSCLC
OXFORD UNIV PRESS. 2016
View details for DOI 10.1093/annonc/mdw383.39
View details for Web of Science ID 000393913000331
-
A Highly Sensitive and Quantitative Test Platform for Detection of NSCLC EGFR Mutations in Urine and Plasma.
Journal of thoracic oncology
2016; 11 (10): 1690-1700
Abstract
In approximately 60% of patients with NSCLC who are receiving EGFR tyrosine kinase inhibitors, resistance develops through the acquisition of EGFR T790M mutation. We aimed to demonstrate that a highly sensitive and quantitative next-generation sequencing analysis of EGFR mutations from urine and plasma specimens is feasible.Short footprint mutation enrichment next-generation sequencing assays were used to interrogate EGFR activating mutations and the T790M resistance mutation in urine or plasma specimens from patients enrolled in TIGER-X (NCT01526928), a phase 1/2 clinical study of rociletinib in previously treated patients with EGFR mutant-positive advanced NSCLC.Of 63 patients, 60 had evaluable tissue specimens. When the tissue result was used as a reference, the sensitivity of EGFR mutation detection in urine was 72% (34 of 47 specimens) for T790M, 75% (12 of 16) for L858R, and 67% (28 of 42) for exon 19 deletions. With specimens that met a recommended volume of 90 to 100 mL, the sensitivity was 93% (13 of 14 specimens) for T790M, 80% (four of five) for L858R, and 83% (10 of 12) for exon 19 deletions. A comparable sensitivity of EGFR mutation detection was observed in plasma: 93% (38 of 41 specimens) for T790M, 100% (17 of 17) for L858R, and 87% (34 of 39) for exon 19 deletions. Together, urine and plasma testing identified 12 additional T790M-positive cases that were either undetectable or inadequate by tissue test. In nine patients monitored while receiving treatment with rociletinib, a rapid decrease in urine T790M levels was observed by day 21.DNA derived from NSCLC tumors can be detected with high sensitivity in urine and plasma, enabling diagnostic detection and monitoring of therapeutic response from these noninvasive "liquid biopsy" samples.
View details for DOI 10.1016/j.jtho.2016.05.035
View details for PubMedID 27468937
-
Clinicopathologic Features of Advanced Squamous NSCLC.
Journal of thoracic oncology
2016; 11 (9): 1411-1422
Abstract
Lung cancer remains the leading cause of cancer-related death worldwide. NSCLC accounts for more than 85% of all lung cancers, and the prognosis for advanced-stage disease is typically poor. In recent years, the importance of histologic subtypes of NSCLC has been recognized, and the distinction between squamous and other NSCLC histologic subtypes is now critical to patient management. Squamous cell lung cancer (sqCLC) represents approximately 25% to 30% of NSCLC. The prognosis for patients with advanced NSCLC is poorer for those with sqCLC than for those with adenocarcinoma. This is partly due to a number of clinical characteristics that distinguish sqCLC from other NSCLC histologic subtypes, such as smoking history, comorbid diseases, age, and molecular profile. Together, these factors make sqCLC an especially challenging disease to manage. Herein, we review some of the key clinicopathologic features of sqCLC. Understanding these features to optimally address many of the unique therapeutic challenges of this disease is likely to be central to ultimately improving outcomes for patients with squamous NSCLC.
View details for DOI 10.1016/j.jtho.2016.05.024
View details for PubMedID 27296106
-
Incremental Innovation and Progress in Advanced Squamous Cell Lung Cancer: Current Status and Future Impact of Treatment.
Journal of thoracic oncology
2016
Abstract
Squamous cell lung cancer (sqCLC) is an aggressive form of cancer that poses many therapeutic challenges. Patients tend to be older, present at a later stage, and have a high incidence of comorbidities, which can compromise treatment delivery and exacerbate toxicity. In addition, certain agents routinely available for nonsquamous cell histologic subtypes, such as bevacizumab and pemetrexed, are contraindicated or lack efficacy in sqCLC. Therapeutic progress has been much slower for advanced sqCLC, with median survival times of approximately 9 to 11 months in most studies. Herein, we discuss the current therapeutic landscape for patients with sqCLC versus with nonsquamous NSCLC. Current evidence indicates that new targeted treatments, notably monoclonal antibodies such as ramucirumab and necitumumab, and immunotherapies such as nivolumab and pembrolizumab can provide survival prolongation, although the benefits are still relatively modest. These incremental improvements, all realized since 2012, in aggregate, will very likely have a clinically meaningful impact for patients with sqCLC. We also discuss recent genomic studies of sqCLC that have identified potentially actionable molecular targets, as well as the relevant targeted agents in clinical development. Finally, we discuss the magnitude of survival benefit and the risk-to-benefit ratio that would prove clinically meaningful in this underserved patient population with unmet needs.
View details for DOI 10.1016/j.jtho.2016.08.138
View details for PubMedID 27575423
-
Determinants of Complete Resection of Thymoma by Minimally Invasive and Open Thymectomy: Analysis of an International Registry.
Journal of thoracic oncology
2016
Abstract
Minimally invasive thymectomy (MIT) is a surgical approach to thymectomy that has more favorable short-term outcomes for myasthenia gravis than open thymectomy (OT). The oncologic outcomes of MIT performed for thymoma have not been rigorously evaluated. We analyzed determinants of complete (R0) resection among patients undergoing MIT and OT in a large international database.The retrospective database of the International Thymic Malignancy Interest Group was queried. Chi-square and Wilcoxon rank sum tests, multivariate logistic regression models, and propensity matching were performed.A total of 2514 patients underwent thymectomy for thymoma between 1997 and 2012; 2053 of them (82%) underwent OT and 461 (18%) underwent MIT, with the use of MIT increasing significantly in recent years. The rate of R0 resection among patients undergoing OT was 86%, and among those undergoing MIT it was 94% (p < 0.0001). In propensity-matched MIT and OT groups (n = 266 in each group); however, the rate of R0 resection did not differ significantly (96% in both the MIT and OT groups, p = 0.7). Multivariate analyses were performed to identify determinants of R0 resection. Factors independently associated with R0 resection were geographical region, later time period, less advanced Masaoka stage, total thymectomy, and the absence of radiotherapy. Surgical approach, whether minimally invasive or open, was not associated with completeness of resection.The use of MIT for resection of thymoma has been increasing substantially over time, and MIT can achieve rates of R0 resection for thymoma similar to those achieved with OT.
View details for DOI 10.1016/j.jtho.2016.08.131
View details for PubMedID 27566187
-
Multicenter Phase II Study of Whole-Body and Intracranial Activity With Ceritinib in Patients With ALK-Rearranged Non-Small-Cell Lung Cancer Previously Treated With Chemotherapy and Crizotinib: Results From ASCEND-2.
Journal of clinical oncology
2016; 34 (24): 2866-2873
Abstract
Phase I data (ASCEND-1) showed ceritinib efficacy in patients with ALK-rearranged non-small-cell lung cancer (NSCLC), regardless of brain metastases status and with or without prior therapy with an inhibitor of the ALK protein. Data are presented from a phase II trial (ASCEND-2) in which ceritinib efficacy and safety were evaluated in patients who had ALK-rearranged NSCLC previously treated with at least one platinum-based chemotherapy and who had experienced progression during crizotinib treatment as their last prior therapy.Patients with advanced ALK-rearranged NSCLC, including those with asymptomatic or neurologically stable baseline brain metastases, received oral ceritinib 750 mg/d. Whole-body and intracranial responses were investigator assessed (according to RECIST version 1.1). Patient-reported outcomes were evaluated with the Lung Cancer Symptom Scale and European Organisation for Research and Treatment of Cancer surveys (the core-30 and the 13-item lung cancer-specific quality-of-life questionnaires).All 140 patients enrolled had received two or more previous treatment regimens, and all patients had received crizotinib. The median duration of exposure and the follow-up time with ceritinib were 8.8 months (range, 0.1 to 19.4 months) and 11.3 months (range, 0.1 to 18.9 months), respectively. Investigator-assessed overall response rate was 38.6% (95% CI, 30.5% to 47.2%). Secondary end points, all investigator assessed, included disease control rate (77.1%; 95% CI, 69.3% to 83.8%), time to response (median, 1.8 months; range, 1.6 to 5.6 months), duration of response (median, 9.7 months; 95% CI, 7.1 to 11.1 months), and progression-free survival (median, 5.7 months; 95% CI, 5.4 to 7.6 months). Of 100 patients with baseline brain metastases, 20 had active target lesions at baseline; investigator-assessed intracranial overall response rate was 45.0% (95% CI, 23.1% to 68.5%). The most common adverse events (majority, grade 1 or 2) for all treated patients were nausea (81.4%), diarrhea (80.0%), and vomiting (62.9%). Patient-reported outcomes showed a trend toward improved symptom burden. The global quality-of-life score was maintained during treatment.Consistent with its activity in ASCEND-1, ceritinib treatment provided clinically meaningful and durable responses with manageable tolerability in chemotherapy- and crizotinib-pretreated patients, including those with brain metastases.
View details for DOI 10.1200/JCO.2015.65.5936
View details for PubMedID 27432917
-
Pretreatment biopsy for thymic epithelial tumors-does histology subtype matter for treatment strategy?
Journal of thoracic disease
2016; 8 (8): 1895-1900
View details for DOI 10.21037/jtd.2016.06.77
View details for PubMedID 27618984
-
Concordant and Discordant EGFR Mutations in Patients With Multifocal Adenocarcinomas: Implications for EGFR-Targeted Therapy.
Clinical therapeutics
2016; 38 (7): 1567-1576
Abstract
Adenocarcinoma remains the most common subtype of lung cancer in the United States. Most patients present with tumors that are invasive and often metastatic, but in some patients, multiple precursor in situ or minimally invasive adenocarcinoma tumors develop that can be synchronous and metachronous. These precursor lesions harbor the same spectrum of genetic mutations found in purely invasive adenocarcinomas, such as EGFR, KRAS, and p53 mutations. It is less clear, however, whether separate lesions in patients who present with multifocal disease share common underlying genetic driver mutations.Here we review the relevant literature on molecular driver alterations in adenocarcinoma precursor lesions. We then report 4 patients with multifocal EGFR mutant adenocarcinomas in whom we performed molecular testing on 2 separate lesions.In 2 of these patients, the mutations are concordant, and in 2 patients, the mutations are discordant. A review of the literature demonstrates increasing evidence that lesions with discordant mutations may confer a more favorable prognosis because they are unlikely to represent metastases.Our findings suggest that the emergence of the dominant EGFR driver alteration is often independent between lesions in patients with multifocal adenocarcinomas, and thus the same targeted therapy may not be effective for all lesions. However, genetic testing of multiple lesions can help to distinguish separate primary tumors from metastatic disease.
View details for DOI 10.1016/j.clinthera.2016.06.005
View details for PubMedID 27368115
-
Statin use and all-cancer survival: prospective results from the Women's Health Initiative
BRITISH JOURNAL OF CANCER
2016; 115 (1): 129-135
Abstract
This study aims to investigate the association between statin use and all-cancer survival in a prospective cohort of postmenopausal women, using data from the Women's Health Initiative Observational Study (WHI-OS) and Clinical Trial (WHI-CT).The WHI study enrolled women aged 50-79 years from 1993 to 1998 at 40 US clinical centres. Among 146 326 participants with median 14.6 follow-up years, 23 067 incident cancers and 3152 cancer deaths were observed. Multivariable-adjusted Cox proportional hazards models were used to investigate the relationship between statin use and cancer survival.Compared with never-users, current statin use was associated with significantly lower risk of cancer death (hazard ratio (HR), 0.78; 95% confidence interval (CI), 0.71-0.86, P<0.001) and all-cause mortality (HR, 0.80; 95% CI, 0.74-0.88). Use of other lipid-lowering medications was also associated with increased cancer survival (P-interaction (int)=0.57). The lower risk of cancer death was not dependent on statin potency (P-int=0.22), lipophilicity/hydrophilicity (P-int=0.43), type (P-int=0.34) or duration (P-int=0.33). However, past statin users were not at lower risk of cancer death compared with never-users (HR, 1.06; 95% CI, 0.85-1.33); in addition, statin use was not associated with a reduction of overall cancer incidence despite its effect on survival (HR, 0.96; 95% CI, 0.92-1.001).In a cohort of postmenopausal women, regular use of statins or other lipid-lowering medications was associated with decreased cancer death, regardless of the type, duration, or potency of statin medications used.British Journal of Cancer advance online publication, 9 June 2016; doi:10.1038/bjc.2016.149 www.bjcancer.com.
View details for DOI 10.1038/bjc.2016.149
View details for PubMedID 27280630
-
Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients
NATURE COMMUNICATIONS
2016; 7
Abstract
Circulating tumour DNA (ctDNA) analysis facilitates studies of tumour heterogeneity. Here we employ CAPP-Seq ctDNA analysis to study resistance mechanisms in 43 non-small cell lung cancer (NSCLC) patients treated with the third-generation epidermal growth factor receptor (EGFR) inhibitor rociletinib. We observe multiple resistance mechanisms in 46% of patients after treatment with first-line inhibitors, indicating frequent intra-patient heterogeneity. Rociletinib resistance recurrently involves MET, EGFR, PIK3CA, ERRB2, KRAS and RB1. We describe a novel EGFR L798I mutation and find that EGFR C797S, which arises in ∼33% of patients after osimertinib treatment, occurs in <3% after rociletinib. Increased MET copy number is the most frequent rociletinib resistance mechanism in this cohort and patients with multiple pre-existing mechanisms (T790M and MET) experience inferior responses. Similarly, rociletinib-resistant xenografts develop MET amplification that can be overcome with the MET inhibitor crizotinib. These results underscore the importance of tumour heterogeneity in NSCLC and the utility of ctDNA-based resistance mechanism assessment.
View details for DOI 10.1038/ncomms11815
View details for PubMedID 27283993
-
Comprehensive Genomic Profiling Identifies a Subset of Crizotinib-Responsive ALK-Rearranged Non-Small Cell Lung Cancer Not Detected by Fluorescence In Situ Hybridization
ONCOLOGIST
2016; 21 (6): 762-770
Abstract
For patients with non-small cell lung cancer (NSCLC) to benefit from ALK inhibitors, sensitive and specific detection of ALK genomic rearrangements is needed. ALK break-apart fluorescence in situ hybridization (FISH) is the U.S. Food and Drug Administration approved and standard-of-care diagnostic assay, but identification of ALK rearrangements by other methods reported in NSCLC cases that tested negative for ALK rearrangements by FISH suggests a significant false-negative rate. We report here a large series of NSCLC cases assayed by hybrid-capture-based comprehensive genomic profiling (CGP) in the course of clinical care.Hybrid-capture-based CGP using next-generation sequencing was performed in the course of clinical care of 1,070 patients with advanced lung cancer. Each tumor sample was evaluated for all classes of genomic alterations, including base-pair substitutions, insertions/deletions, copy number alterations and rearrangements, as well as fusions/rearrangements.A total of 47 patients (4.4%) were found to harbor ALK rearrangements, of whom 41 had an EML4-ALK fusion, and 6 had other fusion partners, including 3 previously unreported rearrangement events: EIF2AK-ALK, PPM1B-ALK, and PRKAR1A-ALK. Of 41 patients harboring ALK rearrangements, 31 had prior FISH testing results available. Of these, 20 were ALK FISH positive, and 11 (35%) were ALK FISH negative. Of the latter 11 patients, 9 received crizotinib based on the CGP results, and 7 achieved a response with median duration of 17 months.Comprehensive genomic profiling detected canonical ALK rearrangements and ALK rearrangements with noncanonical fusion partners in a subset of patients with NSCLC with previously negative ALK FISH results. In this series, such patients had durable responses to ALK inhibitors, comparable to historical response rates for ALK FISH-positive cases.Comprehensive genomic profiling (CGP) that includes hybrid capture and specific baiting of intron 19 of ALK is a highly sensitive, alternative method for identification of drug-sensitive ALK fusions in patients with non-small cell lung cancer (NSCLC) who had previously tested negative using standard ALK fluorescence in situ hybridization (FISH) diagnostic assays. Given the proven benefit of treatment with crizotinib and second-generation ALK inhibitors in patients with ALK fusions, CGP should be considered in patients with NSCLC, including those who have tested negative for other alterations, including negative results using ALK FISH testing.
View details for DOI 10.1634/theoncologist.2015-0497
View details for PubMedID 27245569
-
Plasma genotyping of patients enrolled on the expansion phase VII trial of X-396 in patients (pts) with ALK plus non-small cell lung cancer (NSCLC).
AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.9056
View details for Web of Science ID 000404711506202
-
E1505: Adjuvant chemotherapy +/- bevacizumab for early stage NSCLC-Outcomes based on chemotherapy subsets.
AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.8507
View details for Web of Science ID 000404711505239
-
TIGER-3: A phase 3 multinational open-label randomized study of rociletinib vs investigator-choice chemotherapy in patients (pts) with epidermal growth factor receptor mutant-positive (EGFRm) non-small cell lung cancer (NSCLC) progressing on prior EGFR tyrosine kinase inhibitor (TKI) therapy and doublet chemotherapy.
AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.TPS9106
View details for Web of Science ID 000404711506252
-
Integrated digital error suppression for noninvasive detection of circulating tumor DNA in NSCLC.
AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.e20500
View details for Web of Science ID 000404711506257
-
Epidermal growth factor receptor (EGFR) genotyping of matched urine, plasma and tumor tissue from non-small cell lung cancer (NSCLC) patients (pts) treated with rociletinib.
AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.9001
View details for Web of Science ID 000404711506149
-
Safety and clinical activity of durvalumab (MEDI4736), an anti-PD-L1 antibody, in treatment-naive patients with advanced non small-cell lung cancer.
AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.9029
View details for Web of Science ID 000404711506177
-
Inter- and intra-patient heterogeneity of resistance mechanisms to the mutant EGFR selective inhibitor rociletinib.
AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.9000
View details for Web of Science ID 000404711506148
-
A first-in-human, first-in-class phase I trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers
AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.3019
View details for Web of Science ID 000404665404058
-
Updated results from TIGER-X, a phase open label study of rociletinib in patients (pts) with advanced, recurrent T790M-positive non-small cell lung cancer (NSCLC).
AMER SOC CLINICAL ONCOLOGY. 2016
View details for DOI 10.1200/JCO.2016.34.15_suppl.9045
View details for Web of Science ID 000404711506193
-
Assessment of EGFR Mutation Status in Matched Plasma and Tumor Tissue of NSCLC Patients from a Phase I Study of Rociletinib (CO-1686)
CLINICAL CANCER RESEARCH
2016; 22 (10): 2386-2395
Abstract
The evaluation of plasma testing for the EGFR resistance mutation T790M in NSCLC patients has not been broadly explored. We investigated the detection of EGFR activating and T790M mutations in matched tumor tissue and plasma, mostly from patients with acquired resistance to first-generation EGFR inhibitors.Samples were obtained from two studies, an observational study and a phase I trial of rociletinib, a mutant-selective inhibitor of EGFR that targets both activating mutations and T790M. Plasma testing was performed with the cobas EGFR plasma test and BEAMing.The positive percent agreement (PPA) between cobas plasma and tumor results was 73% (55/75) for activating mutations and 64% (21/33) for T790M. The PPA between BEAMing plasma and tumor results was 82% (49/60) for activating mutations and 73% (33/45) for T790M. Presence of extrathoracic (M1b) versus intrathoracic (M1a/M0) disease was found to be strongly associated with ability to identify EGFR mutations in plasma (P < 0.001). Rociletinib objective response rates (ORR) were 52% [95% confidence interval (CI), 31 - 74%] for cobas tumor T790M-positive and 44% (95% CI, 25 - 63%) for BEAMing plasma T790M-positive patients. A drop in plasma-mutant EGFR levels to ≤10 molecules/mL was seen by day 21 of treatment in 7 of 8 patients with documented partial response.These findings suggest the cobas and BEAMing plasma tests can be useful tools for noninvasive assessment and monitoring of the T790M resistance mutation in NSCLC, and could complement tumor testing by identifying T790M mutations missed because of tumor heterogeneity or biopsy inadequacy. Clin Cancer Res; 22(10); 2386-95. ©2016 AACR.
View details for DOI 10.1158/1078-0432.CCR-15-1260
View details for PubMedID 26747242
-
Scientific Advances in Lung Cancer 2015
JOURNAL OF THORACIC ONCOLOGY
2016; 11 (5): 613-638
Abstract
Lung cancer continues to be a major global health problem; the disease is diagnosed in more than 1.6 million new patients each year. However, significant progress is underway in both the prevention and treatment of lung cancer. Lung cancer therapy has now emerged as a "role model" for precision cancer medicine, with several important therapeutic breakthroughs occurring during 2015. These advances have occurred primarily in the immunotherapy field and in treatments directed against tumors harboring specific oncogenic drivers. Our knowledge about molecular mechanisms for oncogene-driven tumors and about resistance to targeted therapies has increased quickly over the past year. As a result, several regulatory approvals of new agents that significantly improve survival and quality of life for patients with lung cancer who have advanced disease have occurred. The International Association for the Study of Lung Cancer has gathered experts in different areas of lung cancer research and management to summarize the most significant scientific advancements related to prevention and therapy of lung cancer during the past year.
View details for DOI 10.1016/j.jtho.2016.03.012
View details for PubMedID 27013409
-
Association of non-melanoma skin cancer with second non-cutaneous malignancy in the Women's Health Initiative
ELSEVIER SCIENCE INC. 2016: S36
View details for DOI 10.1016/j.jid.2016.02.232
View details for Web of Science ID 000380028800204
-
Immunohistochemical analysis of lichenoid reactions in patients treated with anti-PD-L1 and anti-PD-1 therapy.
Journal of cutaneous pathology
2016; 43 (4): 339-346
Abstract
Recent advances in the immunotherapeutic treatment of cancer have led to the development of multiple new directed therapies including monoclonal antibodies that block the immune checkpoint T-cell receptor programmed death 1 (PD-1) and the PD-1 ligand, programmed death ligand 1 (PD-L1). Various immune-related toxicities have been associated with these drugs including, most commonly, skin rashes.Five cases of lichenoid dermatitis, including one case of lichenoid mucositis and one case of lichen sclerosus, associated with anti-PD-L1 and anti-PD1 therapy were compared with three biopsies of non-drug-related lichen planus (LP) and three lichen planus-like keratoses (LPLK) used as controls.Histopathologic and immunophenotypic analysis of these lichenoid lesions demonstrated significantly greater histiocytic infiltrates than observed in control lichenoid reactions (p = 0.0134). We also observed increased spongiosis and epidermal necrosis. No significant differences were seen in expression of CD3, CD4:CD8, CD20, PD-1, CD25, Foxp3, CXCL13 and PD-L1 expression.These findings expand the literature of immune-related toxicities of PD-L1 and PD-1 blockade to include lichenoid dermatitis and lichenoid mucositis. Of note, these cutaneous side effects were amenable to topical treatment, without the need for medication dose reduction or discontinuation.
View details for DOI 10.1111/cup.12666
View details for PubMedID 26762844
-
Long-Term Survival of a Patient With Non-Small-Cell Lung Cancer Harboring a V600E Mutation in the BRAF Oncogene.
Clinical lung cancer
2016; 17 (2): e17-21
View details for DOI 10.1016/j.cllc.2015.12.001
View details for PubMedID 26776917
-
Lung Cancer Survival Among Chinese Americans, 2000 to 2010.
Journal of global oncology
2016; 2 (1): 30–38
Abstract
PURPOSE: Despite being the leading cause of cancer death, no prior studies have characterized survival patterns among Chinese Americans diagnosed with lung cancer. This study was conducted to identify factors associated with survival after lung cancer in a contemporary cohort of Chinese patients with lung cancer.METHODS: The study design is a prospective descriptive analysis of population-based California Cancer Registry data. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) for overall mortality. Participants were Chinese American residents diagnosed with first primary invasive lung cancer from 2000 to 2010 (2,216 men and 1,616 women).RESULTS: Among Chinese men, decreased mortality was associated with care at a National Cancer Institute cancer center (HR, 0.85; 95% CI, 0.73 to 0.99) and adenocarcinoma versus small-cell carcinoma (HR, 0.78; 95% CI, 0.65 to 0.92). Women had better survival compared with men (HR, 0.82; 95% CI, 0.75 to 0.89), with mortality associated with never married versus currently married status (HR, 1.36; 95% CI, 1.11 to 1.66), lower versus higher neighborhood socioeconomic status (HR, 1.38; 95% CI, 1.10 to 1.72 comparing lowest to highest quintile), care at a cancer center (HR, 0.80; 95% CI, 0.67 to 0.96), and squamous cell relative to small-cell carcinoma (HR, 1.60; 95% CI, 1.04 to 2.48).CONCLUSION: Focusing on factors associated with marital status, community socioeconomic status, and characteristics unique to National Cancer Institute-designated cancer centers may help to identify potential strategies for improving the length of survival for Chinese Americans.
View details for DOI 10.1200/JGO.2015.000539
View details for PubMedID 28717680
-
Phase I/II trial of X-396, a novel anaplastic lymphoma kinase (ALK) inhibitor, in patients with ALK plus non-small cell lung cancer (NSCLC)
ELSEVIER SCIENCE INC. 2016: S36–S37
View details for Web of Science ID 000427344900061
-
Differences in Active and Passive Smoking Exposures and Lung Cancer Incidence Between Veterans and Non-Veterans in the Women's Health Initiative
GERONTOLOGIST
2016; 56: S102-S111
Abstract
Women Veterans may have higher rates of both active and passive tobacco exposure than their civilian counterparts, thereby increasing their risk for lung cancer.To compare differences in active and passive smoking exposure and lung cancer incidence among women Veterans and non-Veterans using prospective data from the Women's Health Initiative (WHI).We used data from the WHI, which collected longitudinal demographic, clinical, and laboratory data on 161,808 postmenopausal women. We employed linear and multinomial regression and generalized linear models to compare active and passive smoking exposure between Veterans and non-Veterans and Cox proportional hazards models to estimate differences in lung cancer incidence rates.After adjustment, Veterans had 2.54 additional pack years of smoking compared with non-Veterans (95% confidence interval [CI] 1.68, 3.40). Veterans also had a 1% increase in risk of any passive smoking exposure (95% CI 1.00, 1.02) and a 9% increase in risk of any workplace exposure (95% CI 1.07, 1.11) compared with non-Veterans. After adjustment for age and smoking exposures, Veterans did not have a higher risk of lung cancer compared with non-Veterans (relative risk = 1.06 95% CI 0.86, 1.30).Women Veterans had higher rates of tobacco use and exposure to passive smoking, which were associated with a higher risk for lung cancer compared with non-Veterans. Clinicians who care for Veterans need to be aware that older women Veterans have more exposures to risk factors for lung cancer.
View details for DOI 10.1093/geront/gnv664
View details for PubMedID 26768384
-
Resistance to Therapy.
Cancer treatment and research
2016; 170: 183-202
Abstract
Identification of driver mutations in adenocarcinoma of the lung has revolutionized the treatment of this disease. It is now standard of care to look for activating mutations in epidermal growth factor receptor (EGFR), and translocations in anaplastic lymphoma kinase (ALK) or ROS1 in all newly diagnosed adenocarcinoma of the lung, and in many patients with squamous cell carcinoma as well. Recognition of multiple other lung cancer driver mutations has also expanded treatment options. Targeted treatments of these mutations lead to rapid and prolonged responses, but resistance inevitably develops. Until recently, traditional chemotherapy was the only alternative at that time, but better understanding of resistance mechanisms has lead to additional therapeutic options. These mechanisms of resistance and treatments are the focus of this chapter. Understanding of mechanisms of chemotherapy resistance is touched upon, along with a brief discussion of immune checkpoint inhibitors.
View details for DOI 10.1007/978-3-319-40389-2_9
View details for PubMedID 27535395
-
Lung Cancer in Never Smokers
LUNG CANCER AND PERSONALIZED MEDICINE: CURRENT KNOWLEDGE AND THERAPIES
2016; 893: 43-57
View details for DOI 10.1007/978-3-319-24223-1_3
View details for Web of Science ID 000754428200004
-
Efficacy of Rociletinib (CO-1686) in Centrally Confirmed T790M-positive and T790M-negative Non-small Cell Lung Cancer (NSCLC) Patients (Pts)
KARGER. 2016: 121
View details for Web of Science ID 000371353700392
-
Association of non-melanoma skin cancer with second non-cutaneous malignancy in the Women's Health Initiative.
The British journal of dermatology
2016
Abstract
Non-melanoma skin cancer (NMSC), the most prevalent cancer in the US,(1) has been associated with increased risk of non-cutaneous malignancies, including breast cancer, lung cancer, and lymphoma. (2-7) In the Women's Health Initiative (WHI) Observational Study (OS), women with NMSC history at baseline were more likely to report history of another cancer (Odds ratio [OR] = 2.3, 95% CI = 2.18 -2.44.(6) Subsequently, Nurses Health Study (NHS) prospective analyses found increased risk of developing breast cancer, lung cancer, and melanoma in women with NMSC.(7) We sought to replicate these prospective findings in the large WHI cohort, for which important potential confounders, e.g. smoking and body mass index, and rich phenotypic data are available. This article is protected by copyright. All rights reserved.
View details for PubMedID 27229371
-
Estrogen Plus Progestin and Lung Cancer: Follow-up of the Women's Health Initiative Randomized Trial
CLINICAL LUNG CANCER
2016; 17 (1): 10-?
Abstract
In the Women's Health Initiative (WHI) estrogen plus progestin trial, after 5.6 years' intervention and 8 years' median follow-up, more women died from lung cancer in the hormone therapy group (hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.16-2.52; P = .01). Now after 14 years' median follow-up, we reexamined combined hormone therapy effects on lung cancer mortality.In the WHI placebo-controlled trial, 16,608 postmenopausal women aged 50 to 79 years and with an intact uterus were randomly assigned to once-daily 0.625 mg conjugated equine estrogen plus 2.5 mg medroxyprogesterone acetate (n = 8506) or placebo (n = 8102). Incidence and mortality rates for lung cancer were assessed from multivariant proportional hazard models.After 14 years' cumulative follow-up, there were 219 lung cancers (0.19% per year) in the estrogen plus progestin group and 184 (0.17%) in the placebo group (HR, 1.12; 95% CI, 0.92-1.37; P = .24). While there were more deaths from lung cancer with combined hormone therapy (153 [0.13%] vs. 132 [0.12%], respectively), the difference was not statistically significant (HR, 1.09; 95% CI, 0.87-1.38; P = .45). The statistically significant increase in deaths from lung cancer observed during intervention in women assigned to estrogen plus progestin was attenuated after discontinuation of study pills (linear trend over time, P = .042).The increased risk of death from lung cancer observed during estrogen plus progestin use was attenuated after discontinuation of combined hormone therapy.
View details for DOI 10.1016/j.cllc.2015.09.004
View details for Web of Science ID 000367538900002
-
Survival among Never-Smokers with Lung Cancer in the Cancer Care Outcomes Research and Surveillance Study.
Annals of the American Thoracic Society
2016; 13 (1): 58-66
Abstract
Differences in patient characteristics and outcomes have been observed among current, former, and never-smokers with lung cancer, but most prior studies included few never-smokers and were not prospective.We used data from a large, prospective study of lung cancer care and outcomes in the United States to compare characteristics of never-smokers and smokers with lung cancer and to examine survival among the never-smokers.Smoking status at diagnosis was determined by self-report and survival was determined from medical records and cancer registries, with follow-up through June 2010 or later. Cox regression was used to examine the association between smoking and survival, and to identify predictors of survival among never-smokers.Among 3,410 patients with lung cancer diagnosed between September 1, 2003 and October 14, 2005 who completed a baseline patient survey, there were 274 never-smokers (8%), 1,612 former smokers (47%), 1,496 current smokers or smokers who quit recently (44%), and 28 with missing information about smoking status (<1%). Never-smokers appeared more likely than former and current/recent smokers to be female and of Asian or Hispanic race/ethnicity, and to have adenocarcinoma histology, fewer comorbidities, private insurance, and higher income and education. Compared with never-smokers, the adjusted hazard of death from any cause was 29% higher among former smokers (hazard ratio, 1.29; 95% confidence interval, 1.08-1.55), and 39% higher among current/recent smokers (hazard ratio, 1.39; 95% confidence interval, 1.16-1.67). Factors predicting worse overall survival among never-smokers included Hispanic ethnicity, severe comorbidity, undifferentiated histology, and regional or distant stage. Never-smoking Hispanics appeared more likely to have regional or advanced disease at diagnosis and less likely to undergo surgical resection, although these differences were not statistically significant.Never-smokers with lung cancer are more likely than ever-smokers to be female, Asian or Hispanic, and more advantaged socioeconomically, suggesting possible etiologic differences in lung cancer by smoking status. Among never-smokers, Hispanics with lung cancer had worse survival than non-Hispanic whites.
View details for DOI 10.1513/AnnalsATS.201504-241OC
View details for PubMedID 26730864
-
Lung Cancer in Never Smokers.
Advances in experimental medicine and biology
2016; 893: 43-57
Abstract
Lung cancer is predominantly associated with cigarette smoking; however, a substantial minority of patients with the disease have never smoked. In the US it is estimated there are 17,000-26,000 annual deaths from lung cancer in never smokers, which as a separate entity would be the seventh leading cause of cancer mortality. Controversy surrounds the question of whether or not the incidence of lung cancer in never-smokers is increasing, with more data to support this observation in Asia. There are several factors associated with an increased risk of developing lung cancer in never smokers including second hand smoke, indoor air pollution, occupational exposures, and genetic susceptibility among others. Adenocarcinoma is the most common histology of lung cancer in never smokers and in comparison to lung cancer in smokers appears less complex with a higher likelihood to have targetable driver mutations.
View details for DOI 10.1007/978-3-319-24223-1_3
View details for PubMedID 26667338
-
Rociletinib, a third generation EGFR tyrosine kinase inhibitor: current data and future directions
EXPERT OPINION ON PHARMACOTHERAPY
2016; 17 (7): 989-993
Abstract
Major advances have been made since the discovery of driver mutations and their targeted therapies, especially in the treatment of patients with epidermal growth factor receptor (EGFR) mutations. Despite their initial efficacy in the majority of the patients with such driver mutations, all targeted therapies are limited by the eventual development of resistance mechanisms.EGFR T790M mutation is a common resistance mechanism after treatment with first or second generation EGFR tyrosine kinase inhibitors (TKI). Rociletinib is one of the third generation EGFR TKIs with activity against T790M and activating EGFR mutations while sparing the wild-type EGFR. In this review, we discuss the current understanding and available data on rociletinib, including the side effects associated with the medication. We will also review the BEAMing plasma test to detect T790M mutation without the need for repeat biopsy. Lastly, we review the potential resistance mechanisms after progression on rociletinib, and future directions.It is important to note that there are other 3(rd) generation EGFR TKIs with activity against T790M already approved by the US FDA (osimertinib) and many others in development. Future research will focus on figuring out which patients can benefit the most from a particular medication with minimal side effects, and further resistance mechanisms after rociletinib.
View details for DOI 10.1517/14656566.2016.1162786
View details for PubMedID 26950414
-
Monotherapy Administration of Sorafenib in Patients With Non-Small Cell Lung Cancer (MISSION) Trial A Phase III, Multicenter, Placebo-Controlled Trial of Sorafenib in Patients with Relapsed or Refractory Predominantly Nonsquamous Non-Small-Cell Lung Cancer after 2 or 3 Previous Treatment Regimens
JOURNAL OF THORACIC ONCOLOGY
2015; 10 (12): 1745-1753
Abstract
Sorafenib monotherapy has shown benefits in phase II trials as third-/fourth-line treatment in patients with non-small-cell lung cancer (NSCLC).The phase III, multinational, double-blind, placebo-controlled Monotherapy admInistration of Sorafenib in patientS wIth nOn-small-cell luNg cancer (MISSION) trial randomized patients with advanced relapsed/refractory NSCLC, following two or three prior treatment regimens, to sorafenib 400 mg twice a day (n = 350) or matching placebo (n = 353) plus best supportive care. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS) and time to progression. Epidermal growth factor receptor and KRAS mutation status was analyzed in archival tumor and/or circulating tumor DNA from blood samples obtained during screening.Median OS was similar in the sorafenib and placebo groups (8.2 versus 8.3 mo; hazard ratio [HR], 0.99; 95% confidence interval [CI], 0.84-1.17; p = 0.47). Median PFS (2.8 versus 1.4 mo; HR, 0.61; 95% CI, 0.51-0.72; p < 0.0001), and time to progression (2.9 versus 1.4 mo; HR, 0.54; 95% CI, 0.45-0.65; p < 0.0001) were significantly greater with sorafenib than with placebo. Among the 89 patients with epidermal growth factor receptor mutations, OS (13.9 versus 6.5 mo; HR, 0.48; 95% CI, 0.30-0.76; p = 0.002) and PFS (2.7 versus 1.4 mo; HR, 0.27; 95% CI, 0.16-0.46; p < 0.001) were significantly higher with sorafenib than placebo. PFS was significantly longer with sorafenib than placebo in patients with either wild-type or mutated KRAS, but OS was similar. Common drug-related adverse events were rash/desquamation, diarrhea, and fatigue, consistent with the safety profile of sorafenib.Third-/fourth-line sorafenib therapy did not significantly increase OS in patients with relapsed/refractory NSCLC, despite significantly increasing PFS.
View details for DOI 10.1097/JTO.0000000000000693
View details for Web of Science ID 000365575100015
-
Monotherapy Administration of Sorafenib in Patients With Non-Small Cell Lung Cancer (MISSION) Trial: A Phase III, Multicenter, Placebo-Controlled Trial of Sorafenib in Patients with Relapsed or Refractory Predominantly Nonsquamous Non-Small-Cell Lung Cancer after 2 or 3 Previous Treatment Regimens.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
2015; 10 (12): 1745-53
Abstract
Sorafenib monotherapy has shown benefits in phase II trials as third-/fourth-line treatment in patients with non-small-cell lung cancer (NSCLC).The phase III, multinational, double-blind, placebo-controlled Monotherapy admInistration of Sorafenib in patientS wIth nOn-small-cell luNg cancer (MISSION) trial randomized patients with advanced relapsed/refractory NSCLC, following two or three prior treatment regimens, to sorafenib 400 mg twice a day (n = 350) or matching placebo (n = 353) plus best supportive care. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS) and time to progression. Epidermal growth factor receptor and KRAS mutation status was analyzed in archival tumor and/or circulating tumor DNA from blood samples obtained during screening.Median OS was similar in the sorafenib and placebo groups (8.2 versus 8.3 mo; hazard ratio [HR], 0.99; 95% confidence interval [CI], 0.84-1.17; p = 0.47). Median PFS (2.8 versus 1.4 mo; HR, 0.61; 95% CI, 0.51-0.72; p < 0.0001), and time to progression (2.9 versus 1.4 mo; HR, 0.54; 95% CI, 0.45-0.65; p < 0.0001) were significantly greater with sorafenib than with placebo. Among the 89 patients with epidermal growth factor receptor mutations, OS (13.9 versus 6.5 mo; HR, 0.48; 95% CI, 0.30-0.76; p = 0.002) and PFS (2.7 versus 1.4 mo; HR, 0.27; 95% CI, 0.16-0.46; p < 0.001) were significantly higher with sorafenib than placebo. PFS was significantly longer with sorafenib than placebo in patients with either wild-type or mutated KRAS, but OS was similar. Common drug-related adverse events were rash/desquamation, diarrhea, and fatigue, consistent with the safety profile of sorafenib.Third-/fourth-line sorafenib therapy did not significantly increase OS in patients with relapsed/refractory NSCLC, despite significantly increasing PFS.
View details for DOI 10.1097/JTO.0000000000000693
View details for PubMedID 26743856
-
MISSION Trial - A phase III, multi-center, placebo-controlled trial of sorafenib in patients with relapsed or refractory predominantly non-squamous NSCLC after 2 or 3 previous treatment regimens.
Journal of thoracic oncology
2015: -?
Abstract
Sorafenib monotherapy has shown benefits in phase II trials as third-/fourth-line treatment in patients with non-small-cell lung cancer (NSCLC).The phase III, multinational, double-blind, placebo-controlled MISSION trial randomized patients with advanced relapsed/refractory NSCLC, following 2 or 3 prior treatment regimens, to sorafenib 400 mg bid (n=353) or matching placebo (n=353) plus best supportive care. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and time-to-progression (TTP). EGFR and KRAS mutation status was analyzed in archival tumor and/or circulating tumor DNA from blood samples obtained during screening.Median OS was similar in the sorafenib and placebo groups (8.2 versus 8.3 months; hazard ratio [HR] 0.99; 95% confidence interval [CI] 0.84-1.17, p=0.47). Median PFS (2.8 versus 1.4 mo; HR 0.61; 95% CI 0.51-0.72, p<0.0001) and TTP (2.9 versus 1.4 months; HR 0.54; 95% CI 0.45-0.65, p<0.0001) were significantly greater with sorafenib than with placebo. Among the 89 patients with EGFR mutations, OS (13.9 versus 6.5 months; HR 0.48; 95% CI 0.30-0.76, p=0.002) and PFS (2.7 versus 1.4 months; HR 0.27; 95% CI 0.16-0.46, p<0.001) were significantly higher with sorafenib than placebo. PFS was significantly longer with sorafenib than placebo in patients with either wild-type or mutated KRAS, but OS was similar. Common drug-related adverse events were rash/desquamation, diarrhea and fatigue, consistent with the safety profile of sorafenib.Third-/fourth-line sorafenib therapy did not significantly increase OS in patients with relapsed/refractory NSCLC, despite significantly increasing PFS.
View details for PubMedID 26551592
-
Pruritus as a Paraneoplastic Symptom of Thymoma
JOURNAL OF THORACIC ONCOLOGY
2015; 10 (11): E110-E112
View details for DOI 10.1097/JTO.0000000000000623
View details for PubMedID 26536199
-
Vorinostat and Concurrent Stereotactic Radiosurgery for Non-Small Cell Lung Cancer Brain Metastases: A Phase 1 Dose-Escalation Trial
ELSEVIER SCIENCE INC. 2015: S178
View details for DOI 10.1016/j.ijrobp.2015.07.425
View details for Web of Science ID 000373215302104
-
Adjuvant therapy for EGFR mutant and ALK positive NSCLC: Current data and future prospects.
Lung cancer
2015; 90 (1): 1-7
Abstract
Tyrosine kinase inhibitors (TKIs) against targetable mutations such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are highly effective in treating advanced stage lung cancers harboring such mutations. Questions remain, however, about whether these agents can improve cure rates for early stage lung cancers in the adjuvant setting. Here, we examine the current data and ongoing trials addressing this issue.
View details for DOI 10.1016/j.lungcan.2015.07.016
View details for PubMedID 26275476
-
Rapid Onset of Retinal Toxicity From High-Dose Hydroxychloroquine Given for Cancer Therapy.
American journal of ophthalmology
2015; 160 (4): 799-805 e1
View details for DOI 10.1016/j.ajo.2015.07.012
View details for PubMedID 26189086
-
Rapid Onset of Retinal Toxicity From High-Dose Hydroxychloroquine Given for Cancer Therapy.
American journal of ophthalmology
2015; 160 (4): 799-805 e1
Abstract
To report rapid onset of retinal toxicity in a series of patients followed on high-dose (1000 mg daily) hydroxychloroquine during an oncologic clinical trial studying hydroxychloroquine with erlotinib for non-small cell lung cancer.Retrospective observational case series.Ophthalmic surveillance was performed on patients in a multicenter clinical trial testing high-dose (1000 mg daily) hydroxychloroquine for advanced non-small cell lung cancer. The US Food & Drug Administration-recommended screening protocol included only visual acuity testing, dilated fundus examination, Amsler grid testing, and color vision testing. In patients seen at Stanford, additional sensitive screening procedures were added at the discretion of the retinal physician: high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence (FAF) imaging, Humphrey visual field (HVF) testing, and multifocal electroretinography (mfERG).Out of the 7 patients having exposure of at least 6 months, 2 developed retinal toxicity (at 11 and 17 months of exposure). Damage was identified by OCT imaging, mfERG testing, and, in 1 case, visual field testing. Fundus autofluorescence imaging remained normal. Neither patient had symptomatic visual acuity loss.These cases show that high doses of hydroxychloroquine can initiate the development of retinal toxicity within 1-2 years. Although synergy with erlotinib is theoretically possible, there are no prior reports of erlotinib-associated retinal toxicity despite over a decade of use in oncology. These results also suggest that sensitive retinal screening tests should be added to ongoing and future clinical trials involving high-dose hydroxychloroquine to improve safety monitoring and preservation of vision.
View details for DOI 10.1016/j.ajo.2015.07.012
View details for PubMedID 26189086
-
Dovitinib and erlotinib in patients with metastatic non-small cell lung cancer: A drug-drug interaction
LUNG CANCER
2015; 89 (3): 280-286
Abstract
Erlotinib is a FDA approved small molecule inhibitor of epidermal growth factor receptor and dovitinib is a novel small molecule inhibitor of fibroblast growth factor and vascular endothelial growth factor receptor. This phase 1 trial was conducted to characterize the safety and determine the maximum tolerated dose of erlotinib plus dovitinib in patients with previously treated metastatic non-small cell lung cancer.Escalating dose cohorts of daily erlotinib and dovitinib dosed 5 days on/2 days off, starting after a 2-week lead-in of erlotinib alone, were planned. A potential pharmacokinetic interaction was hypothesized as dovitinib induces CYP1A1/1A2. Only cohort 1 (150mg erlotinib+300mg dovitinib) and cohort -1 (150mg erlotinib+200mg dovitinib) enrolled. Plasma concentrations of erlotinib were measured pre- and post-dovitinib exposure.Two of three patients in cohort 1 had a DLT (grade 3 transaminitis and grade 3 syncope). Two of 6 patients in cohort -1 had a DLT (grade 3 pulmonary embolism and grade 3 fatigue); thus, the study was terminated. Erlotinib exposure (average Cmax 2308±698ng/ml and AUC 0-24 41,030±15,577 ng×h/ml) approximated previous reports in the six patients with pharmacokinetic analysis. However, erlotinib Cmax and AUC0-24 decreased significantly by 93% (p=0.02) and 97% (p<0.01), respectively, during dovitinib co-administration.This small study demonstrated considerable toxicity and a significant pharmacokinetic interaction with a marked decrease in erlotinib exposure in the presence of dovitinib, likely mediated through CYP1A1/1A2 induction. Given the toxicity and the pharmacokinetic interaction, further investigation with this drug combination will not be pursued.
View details for DOI 10.1016/j.lungcan.2015.06.011
View details for Web of Science ID 000360513200010
-
Relationship of Driver Oncogenes to Long-Term Pemetrexed Response in Non--Small-Cell Lung Cancer.
Clinical lung cancer
2015; 16 (5): 366-73
Abstract
Pemetrexed is approved in the treatment of advanced stage nonsquamous non-small-cell lung cancer (NSCLC). The length of response is variable, and we thus sought to identify which clinicopathologic characteristics are associated with long-term disease control with pemetrexed.Patients with metastatic NSCLC received pemetrexed (with or without bevacizumab) for 12 months or longer, either as maintenance treatment after first-line platinum-based chemotherapy or as subsequent treatment. Clinical and pathologic characteristics were collected.Of a total of 196 patients who received pemetrexed starting in 2007, 25 patients were identified who received pemetrexed for over 1 year. Of these, 15 patients received pemetrexed with or without bevacizumab as maintenance treatment and 10 patients received pemetrexed as subsequent treatment. Fifteen (60%) of 25 patients had an oncogenic driver mutation as follows: 5 (20%) had ROS1 gene rearrangements, 4 (16%) had ALK gene rearrangements, 3 (12%) had KRAS mutations, 2 (8%) had epidermal growth factor receptor (EGFR) mutations, and 1 (4%) had an NRAS mutation. The median overall survival was 42.2 months (95% confidence interval, 37.4-61.3) and median progression-free survival was 22.1 months (95% confidence interval, 15.1-29.1). Patients with an oncogenic driver mutation had significantly better progression-free survival (P = .006) and overall survival (P = .001).Among patients with NSCLC who received pemetrexed for an extended time, those with ALK and ROS1 gene rearrangements were proportionally overrepresented compared with that anticipated in a general nonsquamous NSCLC population, and patients with oncogenic driver mutations had improved outcomes.
View details for DOI 10.1016/j.cllc.2014.12.009
View details for PubMedID 25665893
View details for PubMedCentralID PMC4490141
-
Dovitinib and erlotinib in patients with metastatic non-small cell lung cancer: A drug-drug interaction.
Lung cancer (Amsterdam, Netherlands)
2015; 89 (3): 280-6
Abstract
Erlotinib is a FDA approved small molecule inhibitor of epidermal growth factor receptor and dovitinib is a novel small molecule inhibitor of fibroblast growth factor and vascular endothelial growth factor receptor. This phase 1 trial was conducted to characterize the safety and determine the maximum tolerated dose of erlotinib plus dovitinib in patients with previously treated metastatic non-small cell lung cancer.Escalating dose cohorts of daily erlotinib and dovitinib dosed 5 days on/2 days off, starting after a 2-week lead-in of erlotinib alone, were planned. A potential pharmacokinetic interaction was hypothesized as dovitinib induces CYP1A1/1A2. Only cohort 1 (150mg erlotinib+300mg dovitinib) and cohort -1 (150mg erlotinib+200mg dovitinib) enrolled. Plasma concentrations of erlotinib were measured pre- and post-dovitinib exposure.Two of three patients in cohort 1 had a DLT (grade 3 transaminitis and grade 3 syncope). Two of 6 patients in cohort -1 had a DLT (grade 3 pulmonary embolism and grade 3 fatigue); thus, the study was terminated. Erlotinib exposure (average Cmax 2308±698ng/ml and AUC 0-24 41,030±15,577 ng×h/ml) approximated previous reports in the six patients with pharmacokinetic analysis. However, erlotinib Cmax and AUC0-24 decreased significantly by 93% (p=0.02) and 97% (p<0.01), respectively, during dovitinib co-administration.This small study demonstrated considerable toxicity and a significant pharmacokinetic interaction with a marked decrease in erlotinib exposure in the presence of dovitinib, likely mediated through CYP1A1/1A2 induction. Given the toxicity and the pharmacokinetic interaction, further investigation with this drug combination will not be pursued.
View details for DOI 10.1016/j.lungcan.2015.06.011
View details for PubMedID 26149476
-
Randomized Phase III Trial of Adjuvant Chemotherapy with or without Bevacizumab in Resected Non-Small Cell Lung Cancer (NSCLC): Results of E1505
ELSEVIER SCIENCE INC. 2015: S796
View details for Web of Science ID 000370365103677
-
Rociletinib treatment and outcomes in non-small cell lung cancer (NSCLC) patients with negative central testing for T790M
ELSEVIER SCI LTD. 2015: S636
View details for DOI 10.1016/S0959-8049(16)31745-2
View details for Web of Science ID 000361887403062
-
Rociletinib in NSCLC Patients with Negative Central Testing for T790M in TIGER-X
ELSEVIER SCIENCE INC. 2015: S271–S272
View details for Web of Science ID 000370365101030
-
Activity of rociletinib in EGFR mutant NSCLC patients with a history of CNS involvement
ELSEVIER SCI LTD. 2015: S598
View details for DOI 10.1016/S0959-8049(16)31654-9
View details for Web of Science ID 000361887402546
-
Dose Optimization of Rociletinib for EGFR Mutated NSCLC
ELSEVIER SCIENCE INC. 2015: S318–S319
View details for Web of Science ID 000370365101174
-
Activity of Rociletinib in EGFR Mutant NSCLC Patients with a History of CNS Involvement
ELSEVIER SCIENCE INC. 2015: S319
View details for Web of Science ID 000370365101175
-
Efficacy of rociletinib (co-1686) in EGFR-mutant non-small cell lung cancer (NSCLC) patients (pts) assessed with a plasma EGFR test
ELSEVIER SCI LTD. 2015: S628
View details for DOI 10.1016/S0959-8049(16)31729-4
View details for Web of Science ID 000361887403046
-
Ceritinib in ALK plus NSCLC Metastatic to Brain and/or Leptomeninges: The ASCEND-7 Study
ELSEVIER SCIENCE INC. 2015: S550–S551
View details for Web of Science ID 000370365102484
-
Dose optimization of rociletinib for EGFR mutated NSCLC: Benefit/risk analysis from the TIGER-X trial
ELSEVIER SCI LTD. 2015: S637
View details for DOI 10.1016/S0959-8049(16)31746-4
View details for Web of Science ID 000361887403063
-
Symptoms and QOL with Ceritinib in ALK plus NSCLC Patients with/without Brain Metastases
ELSEVIER SCIENCE INC. 2015: S379
View details for Web of Science ID 000370365101353
-
TIGER-3: A Phase 3 Open-Label, Randomized Study of Rociletinib vs Chemotherapy in NSCLC
ELSEVIER SCIENCE INC. 2015: S430
View details for Web of Science ID 000370365102086
-
Lung Cancer Incidence by Histology, Gender, Race/Ethnicity and Socioeconomic Status
ELSEVIER SCIENCE INC. 2015: S460–S461
View details for Web of Science ID 000370365102182
-
An Update on Clinical Trials: Is Tumor Angiogenesis Still a Viable Target in Advanced NSCLC?
ELSEVIER SCIENCE INC. 2015: S94–S95
View details for Web of Science ID 000370365100061
-
A Randomized Phase 2 Trial of Cabozantinib, Erlotinib or the Combination as 2nd or 3rd Line Therapy in EGFR Wild-Type NSCLC: ECOG-ACRIN E1512
ELSEVIER SCIENCE INC. 2015: S373
View details for Web of Science ID 000370365101334
-
Phase II Trial of Single Agent Amrubicin in Patients with Previously Treated Advanced Thymic Malignancies
ELSEVIER SCIENCE INC. 2015: S195
View details for Web of Science ID 000370365100271
-
VeriStrat (R) and Epidermal Growth Factor Receptor Mutation Status in a Phase 1b/2 Study of Cabozantinib plus /- Erlotinib in Non-Small Cell Lung Cancer
ELSEVIER SCIENCE INC. 2015: S291
View details for Web of Science ID 000370365101080
-
Case Series of HER2 Mutated Metastatic Lung Adenocarcinoma and Response to HER2 Targeted Therapies
ELSEVIER SCIENCE INC. 2015: S549
View details for Web of Science ID 000370365102479
-
Computed Tomography (CT) Characteristics Associated with the Proposed IASLC/ITMIG TNM Pathologic Staging System for Thymoma
ELSEVIER SCIENCE INC. 2015: S196
View details for Web of Science ID 000370365100273
-
Overcoming Resistance Without the Risk of Reaction: Use of Afatinib and Panitumumab in Two Cases of Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer With T790M Mutations
CLINICAL LUNG CANCER
2015; 16 (5): E97-E99
View details for DOI 10.1016/j.cllc.2015.02.005
View details for PubMedID 25842367
-
Relationship of Driver Oncogenes to Long-Term Pemetrexed Response in Non-Small-Cell Lung Cancer
CLINICAL LUNG CANCER
2015; 16 (5): 366-373
Abstract
Pemetrexed is approved in the treatment of advanced stage nonsquamous non-small-cell lung cancer (NSCLC). The length of response is variable, and we thus sought to identify which clinicopathologic characteristics are associated with long-term disease control with pemetrexed.Patients with metastatic NSCLC received pemetrexed (with or without bevacizumab) for 12 months or longer, either as maintenance treatment after first-line platinum-based chemotherapy or as subsequent treatment. Clinical and pathologic characteristics were collected.Of a total of 196 patients who received pemetrexed starting in 2007, 25 patients were identified who received pemetrexed for over 1 year. Of these, 15 patients received pemetrexed with or without bevacizumab as maintenance treatment and 10 patients received pemetrexed as subsequent treatment. Fifteen (60%) of 25 patients had an oncogenic driver mutation as follows: 5 (20%) had ROS1 gene rearrangements, 4 (16%) had ALK gene rearrangements, 3 (12%) had KRAS mutations, 2 (8%) had epidermal growth factor receptor (EGFR) mutations, and 1 (4%) had an NRAS mutation. The median overall survival was 42.2 months (95% confidence interval, 37.4-61.3) and median progression-free survival was 22.1 months (95% confidence interval, 15.1-29.1). Patients with an oncogenic driver mutation had significantly better progression-free survival (P = .006) and overall survival (P = .001).Among patients with NSCLC who received pemetrexed for an extended time, those with ALK and ROS1 gene rearrangements were proportionally overrepresented compared with that anticipated in a general nonsquamous NSCLC population, and patients with oncogenic driver mutations had improved outcomes.
View details for DOI 10.1016/j.cllc.2014.12.009
View details for Web of Science ID 000360182100017
View details for PubMedCentralID PMC4490141
-
Incidence Trends of Lung Cancer by Immigration Status among Chinese Americans
CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION
2015; 24 (8): 1157-1164
Abstract
Lung cancer is the leading cause of cancer-related death among Chinese Americans. A detailed examination of incidence trends by immigration status and histology may inform the etiology of lung cancer in this growing population.California Cancer Registry data were enhanced with data on patient nativity. Lung cancer incidence rates for Chinese males and females were computed for the years 1990-2010, and rates by immigration status and histology were computed for 1990-2004. Trends were assessed with annual percentage change (APC) statistics (two-sided P values) based on linear regression.A total of 8,167 lung cancers were diagnosed among California Chinese from 1990 to 2010. Overall incidence increased nonstatistically among U.S.-born males (APC, 2.1; 95% CI, -4.9 to 9.7), but decreased significantly among foreign-born (APC, -1.7; 95% CI, -2.9 to -0.6). Statistically significant decreasing trends were observed for non-small cell lung cancer (NSCLC), specifically the squamous cell and large cell carcinoma subtypes among foreign-born males. Among females, incidence decreased nonsignificantly among U.S.-born (APC, -2.8; 95% CI, -9.1 to 4.0) but was stable among foreign-born (APC, -0.4; 95% CI, -1.7 to 1.0). A statistically significant decreasing trend was observed for squamous cell among foreign-born females.These data provide critical evidence base to inform screening, research, and public health priorities in this growing population.Given the low smoking prevalence among Chinese Americans, especially females, and few known lung cancer risk factors in U.S. never-smoker populations, additional research of etiologic genetic or biologic factors may elucidate knowledge regarding lung cancer diagnosed in never smokers. Cancer Epidemiol Biomarkers Prev; 24(8); 1157-64. ©2015 AACR.
View details for DOI 10.1158/1055-9965.EPI-15-0123
View details for Web of Science ID 000359320500002
View details for PubMedID 25990553
-
COPD and risk of lung cancer in post-menopausal women: findings from the Women's Health Initiative
AMER ASSOC CANCER RESEARCH. 2015
View details for DOI 10.1158/1538-7445.AM2015-835
View details for Web of Science ID 000371578501288
-
Pretreatment and serial plasma assessments of EGFR mutations in NSCLC patients treated with rociletinib (CO-1686)
AMER ASSOC CANCER RESEARCH. 2015
View details for DOI 10.1158/1538-7445.AM2015-927
View details for Web of Science ID 000371578501378
-
Treatment, overall survival, and costs in patients with ALK-positive non-small-cell lung cancer after crizotinib monotherapy
CURRENT MEDICAL RESEARCH AND OPINION
2015; 31 (8): 1587-1597
Abstract
Limited post-crizotinib treatment options for ALK-positive non-small cell lung cancer (NSCLC) might lead to poor survival and high economic burden.To evaluate real-world treatment patterns, overall survival (OS), and costs following crizotinib discontinuation.This study used chart review and claims data. First, 27 participating US oncologists reviewed medical records of ALK-positive NSCLC patients who discontinued crizotinib monotherapy and reported patient demographic and clinical information, including post-crizotinib treatment and mortality. OS was estimated using Kaplan-Meier analyses. Second, three large administrative US claims databases were pooled. NSCLC patients were selected if they discontinued crizotinib monotherapy. Post-crizotinib costs were analyzed separately for patients who did or did not discontinue antineoplastic treatment after crizotinib monotherapy. All data were collected prior to ceritinib approval for this patient population.A total of 119 ALK-positive NSCLC patients discontinued crizotinib monotherapy. Upon discontinuation, 42% had no additional antineoplastic treatment and 13% received radiation therapy only. The median OS post-crizotinib was 61 days; patients with brain metastases had shorter OS than those who did not (44 vs. 69 days, P = 0.018), and patients without further antineoplastic treatment had shorter OS than those who did (17 vs. 180 days, P < 0.001). From claims data, 305 ALK-positive NSCLC patients discontinued crizotinib monotherapy. After discontinuation, 72% had no additional antineoplastic treatment. Among patients who continued antineoplastic treatment, monthly healthcare costs averaged $22,160, driven by pharmacy ($9202), inpatient ($6419), and outpatient radiotherapy ($2888) and imaging ($1179) costs. Among patients who discontinued any antineoplastic treatment, monthly healthcare costs averaged $3423, mostly driven by inpatient costs ($2074).After crizotinib monotherapy, most patients either received radiotherapy only or discontinued antineoplastic treatment altogether. OS after discontinuing crizotinib was poor and shorter among those with brain metastases than without, and among those without subsequent antineoplastic treatment than with. Patients who continued antineoplastic treatment incurred substantial healthcare costs.
View details for DOI 10.1185/03007995.2015.1057115
View details for Web of Science ID 000361264300016
View details for PubMedID 26029864
-
Hormone Use, Reproductive History, and Risk of Lung Cancer The Women's Health Initiative Studies
JOURNAL OF THORACIC ONCOLOGY
2015; 10 (7): 1004-1013
Abstract
Results from the Women's Health Initiative clinical trials demonstrated no increase in the risk of lung cancer in postmenopausal women treated with hormone therapy (HT). We conducted a joint analysis of the Women's Health Initiative observational study data and clinical trials data to further explore the association between estrogen and estrogen-related reproductive factors and lung cancer risk.Reproductive history, oral contraceptive use, and postmenopausal HT were evaluated in 160,855 women with known HT exposures. Follow-up for lung cancer was through September 17, 2012; 2467 incident lung cancer cases were ascertained, with median follow-up of 14 years.For all lung cancers, women with previous use of estrogen plus progestin of less than 5 years (hazard ratio = 0.84; 95% confidence interval = 0.71-0.99) were at reduced risk. A limited number of reproductive factors demonstrated associations with risk. There was a trend toward decreased risk with increasing age at menopause (ptrend = 0.04) and a trend toward increased risk with increasing number of live births (ptrend = 0.03). Reduced risk of non-small-cell lung cancer was associated with age 20-29 years at first live birth. Risk estimates varied with smoking history, years of HT use and previous bilateral oophorectomy.Indirect measures of estrogen exposure to lung tissue, as used in this study, provide only weak evidence for an association between reproductive history or HT use and risk of lung cancer. More detailed mechanistic studies and evaluation of risk factors in conjunction with estrogen receptor expression in the lung should continue as a role for estrogen cannot be ruled out and may hold potential for prevention and treatment strategies.
View details for DOI 10.1097/JTO.0000000000000558
View details for PubMedID 25852020
-
Heterogeneity Underlies the Emergence of EGFRT790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor.
Cancer discovery
2015; 5 (7): 713-722
Abstract
Rociletinib is a third-generation EGFR inhibitor active in lung cancers with T790M, the gatekeeper mutation underlying most first-generation EGFR drug resistance. We biopsied patients at rociletinib progression to explore resistance mechanisms. Among 12 patients with T790M-positive cancers at rociletinib initiation, six had T790-wild-type rociletinib-resistant biopsies. Two T790-wild-type cancers underwent small cell lung cancer transformation; three T790M-positive cancers acquired EGFR amplification. We documented T790-wild-type and T790M-positive clones coexisting within a single pre-rociletinib biopsy. The pretreatment fraction of T790M-positive cells affected response to rociletinib. Longitudinal circulating tumor DNA (ctDNA) analysis revealed an increase in plasma EGFR-activating mutation, and T790M heralded rociletinib resistance in some patients, whereas in others the activating mutation increased but T790M remained suppressed. Together, these findings demonstrate the role of tumor heterogeneity when therapies targeting a singular resistance mechanism are used. To further improve outcomes, combination regimens that also target T790-wild-type clones are required.This report documents that half of T790M-positive EGFR-mutant lung cancers treated with rociletinib are T790-wild-type upon progression, suggesting that T790-wild-type clones can emerge as the dominant source of resistance. We show that tumor heterogeneity has important clinical implications and that plasma ctDNA analyses can sometimes predict emerging resistance mechanisms. Cancer Discov; 5(7); 713-22. ©2015 AACR.See related commentary by Ichihara and Lovly, p. 694.This article is highlighted in the In This Issue feature, p. 681.
View details for DOI 10.1158/2159-8290.CD-15-0399
View details for PubMedID 25934077
-
A phase II study of saracatinib (AZD0530), a Src inhibitor, administered orally daily to patients with advanced thymic malignancies
LUNG CANCER
2015; 89 (1): 57-60
Abstract
Thymic malignancies are rare, and options are limited for metastatic disease. Src plays a role in normal thymic epithelial maturation, and its inhibition with the oral compound saracatinib was postulated to be effective in controlling thymic malignancy.Patients with unresectable thymic malignancy were treated with saracatinib 175mg by mouth daily in 28 days cycles with radiographic evaluation at cycle 2 day 1 for safety, then cycle 3 day 1 and every 8 weeks thereafter. Response was evaluated by RECIST 1.0. A two-stage optimal design was used, powered to detect a true response rate of 20%.21 patients were enrolled at two institutions, 12 of them with thymoma, 9 with thymic carcinoma. Thymoma patients received a median of 4.5 cycles and thymic carcinoma patients a median of 1 cycle. There were no responses, so accrual was halted after the first stage per protocol. 9 patients had stable disease beyond the first assessment. Median time to progression was 5.7 months for thymoma patients and 3.6 months for thymic carcinoma patients. Saracatinib was well tolerated.Src inhibition by saracatinib did not produce any radiographic responses, though some patients did experience stable disease. Though negative, this study shows the feasibility of completing a trial in this rare disease, and of accruing reasonably significant numbers of thymic carcinoma patients. More clinical trials are required for this population (NCT00718809).
View details for DOI 10.1016/j.lungcan.2015.04.008
View details for PubMedID 26009269
-
ALK rearrangement testing and treatment patterns for patients with ALK-positive non-small cell lung cancer
CANCER EPIDEMIOLOGY
2015; 39 (3): 307-312
Abstract
Approximately 2-8% of non-small cell lung cancer (NSCLC) patients have rearrangements in the anaplastic lymphoma kinase gene (ALK). ALK-targeted therapy is available to patients with tumors known to be ALK+. This chart review study described characteristics of patients with ALK+ NSCLC, patterns of ALK testing and subsequent treatments, and oncologists' experience with ALK testing in the US.US oncologists provided information in September and October of 2013 on patients from their practice diagnosed with ALK+ locally advanced or metastatic NSCLC, including the timing of ALK testing and treatment received after testing. Participating oncologists were also surveyed about their experience with ALK testing.27 oncologists provided data on 273 ALK+ NSCLC patients. Patients' median age was 67 years upon NSCLC diagnosis. Smoking history varied, with 33% nonsmokers, 33% light smokers, and 33% heavy smokers. Patients were racially diverse: 59% White, 18% Black, 13% Asian, and 10% other. Upon diagnosis of advanced/metastatic NSCLC, patients who were either not tested (19%) or initially tested negative/inconclusive (1%) all received first-line chemotherapy; the other 219 patients (80%) tested positive, with 133 (61%) receiving an ALK inhibitor and 78 (29%) receiving chemotherapy as first-line treatment. Many oncologists stated being more likely to test for ALK rearrangements among Asians, nonsmokers, and light smokers.In this sample, ALK+ NSCLC patients were racially diverse with mixed smoking history. One in five patients were not tested before first-line therapy. Oncologists reported being more likely to consider ALK testing for patients with particular smoking and race characteristics.
View details for DOI 10.1016/j.canep.2015.04.005
View details for PubMedID 25914136
-
Cabozantinib (C), erlotinib (E) or the combination (E plus C) as second-or third-line therapy in patients with EGFR wild-type (wt) non-small cell lung cancer (NSCLC): A randomized phase 2 trial of the ECOG-ACRIN Cancer Research Group (E1512).
AMER SOC CLINICAL ONCOLOGY. 2015
View details for Web of Science ID 000358036901716
-
Recreational activity and sedentary behavior in relation to lung cancer incidence and mortality in the Women's Health Initiative
AMER SOC CLINICAL ONCOLOGY. 2015
View details for Web of Science ID 000358036900386
-
Efficacy of rociletinib (CO-1686) in plasma-genotyped T790M-positive non-small cell lung cancer (NSCLC) patients (pts).
AMER SOC CLINICAL ONCOLOGY. 2015
View details for Web of Science ID 000358036901714
-
ASCEND-2: A single-arm, open-label, multicenter phase II study of ceritinib in adult patients (pts) with ALK-rearranged (ALK plus ) non-small cell lung cancer (NSCLC) previously treated with chemotherapy and crizotinib (CRZ).
AMER SOC CLINICAL ONCOLOGY. 2015
View details for Web of Science ID 000358036901771
-
TIGER-3: A phase 3, open-label, randomized study of rociletinib vs cytotoxic chemotherapy in patients (pts) with mutant EGFR non-small cell lung cancer (NSCLC) progressing on prior EGFR TKI therapy and doublet chemotherapy.
AMER SOC CLINICAL ONCOLOGY. 2015
View details for Web of Science ID 000358036904858
-
Statin use and all-cancer mortality: Prospective results from the Women's Health Initiative
AMER SOC CLINICAL ONCOLOGY. 2015
View details for Web of Science ID 000358036900373
-
Phase II trial of single agent amrubicin (A) in patients (pts) with previously treated advanced thymic malignancies (TM).
AMER SOC CLINICAL ONCOLOGY. 2015
View details for Web of Science ID 000358036901710
-
Rociletinib in EGFR-Mutated Non-Small-Cell Lung Cancer
NEW ENGLAND JOURNAL OF MEDICINE
2015; 372 (18): 1700-1709
Abstract
Non-small-cell lung cancer (NSCLC) with a mutation in the gene encoding epidermal growth factor receptor (EGFR) is sensitive to approved EGFR inhibitors, but resistance develops, mediated by the T790M EGFR mutation in most cases. Rociletinib (CO-1686) is an EGFR inhibitor active in preclinical models of EGFR-mutated NSCLC with or without T790M.In this phase 1-2 study, we administered rociletinib to patients with EGFR-mutated NSCLC who had disease progression during previous treatment with an existing EGFR inhibitor. In the expansion (phase 2) part of the study, patients with T790M-positive disease received rociletinib at a dose of 500 mg twice daily, 625 mg twice daily, or 750 mg twice daily. Key objectives were assessment of safety, side-effect profile, pharmacokinetics, and preliminary antitumor activity of rociletinib. Tumor biopsies to identify T790M were performed during screening. Treatment was administered in continuous 21-day cycles.A total of 130 patients were enrolled. The first 57 patients to be enrolled received the free-base form of rociletinib (150 mg once daily to 900 mg twice daily). The remaining patients received the hydrogen bromide salt (HBr) form (500 mg twice daily to 1000 mg twice daily). A maximum tolerated dose (the highest dose associated with a rate of dose-limiting toxic effects of less than 33%) was not identified. The only common dose-limiting adverse event was hyperglycemia. In an efficacy analysis that included patients who received free-base rociletinib at a dose of 900 mg twice daily or the HBr form at any dose, the objective response rate among the 46 patients with T790M-positive disease who could be evaluated was 59% (95% confidence interval [CI], 45 to 73), and the rate among the 17 patients with T790M-negative disease who could be evaluated was 29% (95% CI, 8 to 51).Rociletinib was active in patients with EGFR-mutated NSCLC associated with the T790M resistance mutation. (Funded by Clovis Oncology; ClinicalTrials.gov number, NCT01526928.).
View details for DOI 10.1056/NEJMoa1413654
View details for PubMedID 25923550
-
GLI1, CTNNB1 and NOTCH1 protein expression in a thymic epithelial malignancy tissue microarray.
Anticancer research
2015; 35 (2): 669-676
Abstract
Thymic epithelial tumors (TET) are rare. Wingless and INT (WNT), NOTCH and sonic hedgehog pathway interactions between thymocytes and thymic stroma are important to thymus and T-cell development. We analyzed a thymoma tissue microarray (TMA) for glioma associated oncogene homolog 1 (GLI1), NOTCH1 and catenin (cadherin-associated protein, beta 1) (CTNNB1) expression as surrogate markers of sonic hedgehog, NOTCH and WNT pathway activity.GLI1, NOTCH1 and CTNNB1 expression were assayed in a tissue microarray of 68 TET and eight benign thymus by fluorescent immunohistochemistry (AQUA) as surrogates for activity of the sonic hedgehog, NOTCH and WNT pathways respectively.No difference in tumor GLI1 (mean 201 vs. 211, p=0.31), CTNNB1 (mean 222 vs. 306, p=0.66) or NOTCH1 expression (mean 317 vs. 325, p=0.82) was noted between thymic tumor and benign thymus.No evidence for preferential expression of GLI1, NOTCH1 or CTNNB1 was noted. High-throughput immunofluorescence using AQUA technology can help overcome limitations of small sample size and tissue heterogeneity when analyzing protein expression in thymic tumors.
View details for PubMedID 25667444
-
GLI1, CTNNB1 and NOTCH1 Protein Expression in a Thymic Epithelial Malignancy Tissue Microarray.
Anticancer research
2015; 35 (2): 669-676
Abstract
Thymic epithelial tumors (TET) are rare. Wingless and INT (WNT), NOTCH and sonic hedgehog pathway interactions between thymocytes and thymic stroma are important to thymus and T-cell development. We analyzed a thymoma tissue microarray (TMA) for glioma associated oncogene homolog 1 (GLI1), NOTCH1 and catenin (cadherin-associated protein, beta 1) (CTNNB1) expression as surrogate markers of sonic hedgehog, NOTCH and WNT pathway activity.GLI1, NOTCH1 and CTNNB1 expression were assayed in a tissue microarray of 68 TET and eight benign thymus by fluorescent immunohistochemistry (AQUA) as surrogates for activity of the sonic hedgehog, NOTCH and WNT pathways respectively.No difference in tumor GLI1 (mean 201 vs. 211, p=0.31), CTNNB1 (mean 222 vs. 306, p=0.66) or NOTCH1 expression (mean 317 vs. 325, p=0.82) was noted between thymic tumor and benign thymus.No evidence for preferential expression of GLI1, NOTCH1 or CTNNB1 was noted. High-throughput immunofluorescence using AQUA technology can help overcome limitations of small sample size and tissue heterogeneity when analyzing protein expression in thymic tumors.
View details for PubMedID 25667444
-
Pemetrexed in patients with thymic malignancies previously treated with chemotherapy.
Lung cancer
2015; 87 (1): 34-38
Abstract
Thymic malignancies are rare, with limited published trials of chemotherapy activity. We performed a retrospective analysis of pemetrexed activity in patients with thymic malignancies.Patients with unresectable histologically confirmed invasive, recurrent, or metastatic thymoma or thymic carcinoma seen at the Stanford Cancer Center between January 2005 and November 2013 were identified, and those who were treated with pemetrexed in the second-line setting and beyond were included in this analysis.A total of 81 thymic malignancy patients were identified, of whom 16 received pemetrexed alone (N=14) or in combination (N=2). There were 10 patients (62.5%) with thymic carcinoma and 6 patients (37.5%) with thymoma. Among the 6 patients with thymoma, best response was 1 (17%) with a partial response (PR) and 5 (83%) with stable disease (SD). At a median follow-up of 21.2 months, the median PFS in the thymoma patients was 13.8 months (95% CI, 4.9-22.6 months) and the median OS was 20.1 months (95% CI, 16.4-23.9 months). Among the 10 patients with thymic carcinoma, best response to treatment was 1 (10%) PR, 5 (50%) SD, and 4 (40%) progressive disease (PD). At a median follow-up of 13.5 months, the median PFS in patients with thymic carcinoma was 6.5 months (95% CI, 0.2-12.8 months) and the median OS was 12.7 months (95% CI, 2.9-22.5 months).This small retrospective study demonstrates modest pemetrexed activity and disease stabilization in thymic malignancies with a clinically meaningfu