Bio


Dr. Neal holds a medical degree and a doctoral degree in Tumor Cell Biology from Northwestern University in Chicago, Illinois. Subsequently, he completed a fellowship in oncology, rotating through the Dana-Farber Cancer Institute and Massachusetts General Hospital in Boston, Massachusetts. He is currently an Assistant Professor in the Division of Oncology at the Stanford Cancer Institute at Stanford University in Palo Alto, California. Dr Neal’s primary clinical interest is in thoracic oncology. In addition to maintaining an active practice, he focuses on the design and conduct of clinical trials involving targeted therapies and immunotherapy for lung cancer and mesothelioma. He has published dozens of articles in the field of thoracic oncology, including in Lancet Oncology, Nature Medicine, and the Journal of Clinical Oncology. He is a member of the International Association of the Study of Lung Cancer (IALSC), is a study chair and thoracic core committee member within the ECOG-ACRIN cooperative group, and has presented at a number of American Society of Clinical Oncology (ASCO) annual meetings.

Clinical Focus


  • Cancer > Thoracic Oncology
  • Thoracic Oncology
  • Lung Cancer
  • Medical Oncology

Academic Appointments


Professional Education


  • Medical Education:Northwestern University Feinberg School of Medicine (2004) IL
  • Fellowship:Dana Farber Cancer Institute Hematology Oncology Fellowship (2010) MA
  • Residency:Beth Israel Deaconess Medical Center (2007) MA
  • Board Certification: Medical Oncology, American Board of Internal Medicine (2010)
  • Board Certification: Internal Medicine, American Board of Internal Medicine (2007)

Current Research and Scholarly Interests


Non-small cell lung cancer (NSCLC) has historically been treated with combination chemotherapy. Over the last few years, molecular testing of NSCLC has revealed the presence of driving oncogenic mutations in a subset of tumors of adenocarcinoma histology, including EGFR, KRAS, and ALK. While chemotherapy is still effective for these patients, targeted therapies appear to be more specific with fewer side effects. For example, erlotinib treatment of EGFR mutant tumors results in better response rates and progression-free survival times than chemotherapy, and the investigational drug crizotinib is targeted against tumors harboring ALK translocations. My clinical and research interest is to apply evolving technologies to the diagnosis, characterization, and individualized treatment of NSCLC.

Clinical Trials


  • Erlotinib Hydrochloride or Crizotinib and Chemoradiation Therapy in Treating Patients With Stage III Non-small Cell Lung Cancer 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.

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  • 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 research 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.

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  • Identification of Circulating Tumor Cells in the Peripheral Blood of Lung Cancer Patients 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.

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  • Molecular Analysis of Thoracic Malignancies 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.

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  • Phase 1/2 Study of X-396, an Oral ALK Inhibitor, in Patients With ALK-positive Non-Small Cell Lung Cancer 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.

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  • Phase II Etirinotecan Pegol in Refractory Brain Metastases & Advanced Lung Cancer / Metastatic Breast Cancer Recruiting

    This phase II trial studies how well pegylated irinotecan NKTR 102 works in treating patients with non-small cell lung cancer, small cell lung cancer, or breast cancer that has spread to the brain and does not respond to treatment. Pegylated irinotecan NKTR 102 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

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  • 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 subjects with advanced solid tumors followed by an expansion phase in patients with advanced solid tumors. An exploration cohort has been added to determine the safety using Q4W dosing.

    Stanford is currently not accepting patients for this trial. For more information, please contact Melanie San Pedro-Salcedo, 650-724-1388.

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  • 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.

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  • 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.

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  • 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.

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  • 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.

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  • 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 .

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  • A Study of MEHD7945A Versus Cetuximab in Patients With Recurrent/Metastatic Squamous Cell Carcinoma of The Head And Neck Not Recruiting

    This phase II, open-label, randomized study will evaluate the efficacy and safety of MEHD7945A versus cetuximab in patients with recurrent/metastatic squamous cell carcinoma of the head and neck who have progressed during or following platinum-based chemotherapy. Patients will be randomized to receive either MEHD7945A 1100 mg intravenously (iv) every 2 weeks or cetuximab 400 mg/m2 iv loading dose followed by 250 mg/m2 iv weekly. Patients treated with cetuximab (Arm B) may cross-over to MEHD7945A (Arm A) upon central confirmation of progressive disease and upon meeting eligibility criteria. Anticipated time on study treatment is until disease progression or intolerable toxicity occurs.

    Stanford is currently not accepting patients for this trial. For more information, please contact Ruth Lira, (650) 723 - 1367.

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  • 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.

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  • 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.

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  • 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.

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  • 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.

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  • 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.

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  • 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.

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  • 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.

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  • 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.

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  • Cisplatin and Etoposide With or Without Veliparib in Treating Patients With Extensive Stage Small Cell Lung Cancer or Metastatic Large Cell Neuroendocrine Non-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.

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  • 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.

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  • 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 MMB in combination with erlotinib. Escalation of 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 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.

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  • 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.

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  • 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.

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  • 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.

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  • 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.

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  • 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.

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  • 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.

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  • 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.

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  • 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.

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  • 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.

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  • 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.

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  • 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.

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  • 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.

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  • Study is Designed to Assess the Safety and Tolerability of AZD4547 at Increasing Doses in Patients With Advanced Tumours Not Recruiting

    This study is primarily designed to assess the safety and tolerability of AZD4547 at increasing doses in patients with advanced solid malignancies and for whom no standard medication options are available. It also assesses the blood levels and action of AZD4547 in the body over a period of time.

    Stanford is currently not accepting patients for this trial. For more information, please contact Prachi Nandoskar, 650-725-0438.

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  • 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.

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  • 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.

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  • Study of Two Doses of Pembrolizumab (MK-3475) Versus Docetaxel in Previously Treated Participants With Non-Small Cell Lung Cancer (MK-3475-010/KEYNOTE-010) Not Recruiting

    This study compared two doses of pembrolizumab (MK-3475) versus docetaxel in participants with non-small cell lung cancer (NSCLC) who had experienced disease progression after platinum-containing systemic therapy. Participants were assigned randomly to receive either pembrolizumab 2 mg/kg once every three weeks (Q3W), pembrolizumab 10 mg/kg Q3W or docetaxel 75 mg/m^2 Q3W. This study used an adaptive trial design so that the total number of participants randomized depended upon demonstration of sufficient objective responses at an interim analysis. Based on the positive outcome of the Overall Survival (OS) analysis, Protocol Amendment 12 (effective date: 09 Dec 2015) enabled eligible participants who were allocated to docetaxel and experienced disease progression, to be permitted to crossover to receive pembrolizumab 2 mg/kg Q3W as long as Inclusion/Exclusion criteria were met. These participants were participating in the Cross-Over Phase. The primary study hypotheses are that pembolizumab prolongs OS and Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by independent radiologists' review in previously-treated participants with NSCLC in the strongly positive programmed cell death ligand 1 (PD-L1) stratum compared to docetaxel and in participants whose tumors express PD-L1 compared to docetaxel.

    Stanford is currently not accepting patients for this trial. For more information, please contact Smriti Rai, 650-723-0270.

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  • 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.

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  • 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.

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  • 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.

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  • Weekly Docetaxel, Cisplatin, and Cetuximab (TPC) in Palliative Treatment of Patients With Squamous Cell Carcinoma of the Head and Neck (SCCHN) Not Recruiting

    Docetaxel and cetuximab are FDA approved for the treatment of squamous cell carcinoma of the head and neck. Cisplatin and carboplatin, while not FDA approved for Squamous Cell Carcinoma of the Head and Neck (SCCHN), have been used as standard of care in patients with SCCHN in combination with other drugs. This study will determine if weekly cisplatin and docetaxel, in combination with cetuximab, will be effective in palliative treatment of patients with squamous cell carcinoma of the head and neck. These drugs will be given intravenously weekly, repeated 3 of every 4 weeks until evidence of disease progression or unacceptable adverse events.

    Stanford is currently not accepting patients for this trial. For more information, please contact Risa Jiron, 650-736-1598.

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2017-18 Courses


All Publications


  • Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global, Multicenter RET Registry JOURNAL OF CLINICAL ONCOLOGY Gautschi, O., Milia, J., Filleron, T., Wolf, J., Carbone, D. P., Owen, D., Camidge, R., Narayanan, V., Doebele, R. C., Besse, B., Remon-Masip, J., Janne, P. A., Awad, M. M., Peled, N., Byoung, C., Karp, D. D., van den Heuvel, M., Wakelee, H. A., Neal, J. W., Mok, T. S., Yang, J. C., Ou, S. I., Pall, G., Froesch, P., Zalcman, G., Gandara, D. R., Riess, J., Velcheti, V., Zeidler, K., Diebold, J., Frueh, M., Michels, S., Monnet, I., Popat, S., Rosell, R., Karachaliou, N., Rothschild, S. I., Shih, J., Warth, A., Muley, T., Cabillic, F., Mazieres, J., Drilon, A. 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 Web of Science ID 000400335500005

    View details for PubMedID 28447912

  • 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 Wang, S. X., Zhang, B., Wakelee, H. A., Diehn, M., Kunder, C., Neal, J. W. 2017; 98 (1): 239-?

    View details for DOI 10.1016/j.ijrobp.2017.01.170

    View details for PubMedID 28587017

  • Identification of a Novel Somatic Mutation Leading to Allele Dropout for EGFR L858R Genotyping in Non-Small Cell Lung Cancer. Molecular diagnosis & therapy Costa, H. A., Neal, J. W., Bustamante, C. D., Zehnder, J. L. 2017

    Abstract

    While PCR-based genotyping methods abound in molecular testing for lung cancer therapy, these approaches may not provide the robust sensitivity to detect accurate genotypes in a variable cancer genomic background.Here, we describe a study of a clinical tumor specimen containing a novel somatic single nucleotide variant that caused allele drop-out in EGFR L858R genotyping, resulting in a false-negative interpretation and impacting patient clinical management.We demonstrate that a subsequent unbiased next-generation sequencing approach correctly identified the driver mutation, and therefore may be more reliable for somatic variant detection.These findings magnify the potential pitfalls of PCR amplification-based approaches and stress the importance of unbiased and sensitive molecular testing strategies for therapeutic marker detection as molecular testing becomes the standard for determining clinical management of cancer patients.

    View details for DOI 10.1007/s40291-017-0275-y

    View details for PubMedID 28357677

  • Molecular profiling of single circulating tumor cells from lung cancer patients PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Park, S., Wong, D. J., Ooi, C. C., Kurtz, D. M., Vermesh, O., Aalipour, A., Suh, S., Pian, K. L., Chabon, J. J., Lee, S. H., Jamali, M., Say, C., Carter, J. N., Lee, L. P., Kuschner, W. G., Schwartz, E. J., Shrager, J. B., Neal, J. W., Wakelee, H. A., Diehn, M., Nair, V. S., Wang, S. X., Gambhir, S. S. 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 Web of Science ID 000391090800003

    View details for PubMedID 27956614

    View details for PubMedCentralID PMC5206556

  • 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 Neal, J. W., Dahlberg, S. E., Wakelee, H. A., Aisner, S. C., Bowden, M., Huang, Y., Carbone, D. P., Gerstner, G. J., Lerner, R. E., Rubin, J. L., Owonikoko, T. K., Stella, P. J., Steen, P. D., Khalid, A. A., Ramalingam, S. S. 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

  • Acute, Unilateral Breast Toxicity From Gemcitabine in the Setting of Thoracic Inlet Obstruction. Journal of oncology practice / American Society of Clinical Oncology Weiskopf, K., Creighton, D., Lew, T., Caswell, J. L., Ouyang, D., Shah, A. T., Hofmann, L. V., Neal, J. W., Telli, M. L. 2016; 12 (8): 763-764

    View details for DOI 10.1200/JOP.2016.014241

    View details for PubMedID 27511721

    View details for PubMedCentralID PMC5012631

  • Concordant and Discordant EGFR Mutations in Patients With Multifocal Adenocarcinomas: Implications for EGFR-Targeted Therapy. Clinical therapeutics Chuang, J. C., Shrager, J. B., Wakelee, H. A., Neal, J. W. 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

    View details for PubMedCentralID PMC4985173

  • Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients NATURE COMMUNICATIONS Chabon, J. J., Simmons, A. D., Lovejoy, A. F., Esfahani, M. S., Newman, A. M., Haringsma, H. J., Kurtz, D. M., Stehr, H., Scherer, F., Karlovich, C. A., Harding, T. C., Durkin, K. A., Otterson, G. A., Purcell, W. T., Camidge, D. R., Goldman, J. W., Sequist, L. V., Piotrowska, Z., Wakelee, H. A., Neal, J. W., Alizadeh, A. A., Diehn, M. 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 Web of Science ID 000378007200001

    View details for PubMedID 27283993

    View details for PubMedCentralID PMC4906406

  • Integrated digital error suppression for improved detection of circulating tumor DNA NATURE BIOTECHNOLOGY Newman, A. M., Lovejoy, A. F., Klass, D. M., Kurtz, D. M., Chabon, J. J., Scherer, F., Stehr, H., Liu, C. L., Bratman, S. V., Say, C., Zhou, L., Carter, J. N., West, R. B., Sledge, G. W., Shrager, J. B., Loo, B. W., Neal, J. W., Wakelee, H. A., Diehn, M., Alizadeh, A. A. 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 Web of Science ID 000375735000036

    View details for PubMedID 27018799

    View details for PubMedCentralID PMC4907374

  • Long-Term Survival of a Patient With Non-Small-Cell Lung Cancer Harboring a V600E Mutation in the BRAF Oncogene. Clinical lung cancer Myall, N. J., Neal, J. W., Cho-Phan, C. D., Zhou, L. Y., Stehr, H., Zhou, L., Diehn, M., Wakelee, H. A. 2016; 17 (2): e17-21

    View details for DOI 10.1016/j.cllc.2015.12.001

    View details for PubMedID 26776917

  • Pruritus as a Paraneoplastic Symptom of Thymoma JOURNAL OF THORACIC ONCOLOGY Padda, S. K., Shrager, J. B., Riess, J. W., Pagtama, J. Y., Tisch, A. J., Kwong, B. Y., Liang, Y., Schwartz, E. J., Loo, B. W., Neal, J. W., Hardy, R., Wakelee, H. A. 2015; 10 (11): E110-E112

    View details for DOI 10.1097/JTO.0000000000000623

    View details for Web of Science ID 000363312300001

    View details for PubMedID 26536199

  • Rapid Onset of Retinal Toxicity From High-Dose Hydroxychloroquine Given for Cancer Therapy. American journal of ophthalmology Leung, L. B., Neal, J. W., Wakelee, H. A., Sequist, L. V., Marmor, M. F. 2015; 160 (4): 799-805 e1

    View details for DOI 10.1016/j.ajo.2015.07.012

    View details for PubMedID 26189086

  • Adjuvant therapy for EGFR mutant and ALK positive NSCLC: Current data and future prospects. Lung cancer Chuang, J. C., Neal, J. W., Niu, X., Wakelee, H. A. 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

  • Management of Dermatologic Complications of Lung Cancer Therapies. Current treatment options in oncology Pugliese, S. B., Neal, J. W., Kwong, B. Y. 2015; 16 (10): 368-?

    View details for DOI 10.1007/s11864-015-0368-y

    View details for PubMedID 26338208

  • Crizotinib as first line therapy for advanced ALK-positive non-small cell lung cancers. Translational lung cancer research Chuang, J. C., Neal, J. W. 2015; 4 (5): 639-641

    View details for DOI 10.3978/j.issn.2218-6751.2015.03.06

    View details for PubMedID 26629437

    View details for PubMedCentralID PMC4630528

  • Dovitinib and erlotinib in patients with metastatic non-small cell lung cancer: A drug-drug interaction LUNG CANCER Das, M., Padda, S. K., Frymoyer, A., Zhou, L., Riess, J. W., Neal, J. W., Wakelee, H. A. 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 Liang, Y., Wakelee, H. A., Neal, J. W. 2015; 16 (5): 366-373
  • Heterogeneity Underlies the Emergence of EGFRT790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor. Cancer discovery Piotrowska, Z., Niederst, M. J., Karlovich, C. A., Wakelee, H. A., Neal, J. W., Mino-Kenudson, M., Fulton, L., Hata, A. N., Lockerman, E. L., Kalsy, A., Digumarthy, S., Muzikansky, A., Raponi, M., Garcia, A. R., Mulvey, H. E., Parks, M. K., DiCecca, R. H., Dias-Santagata, D., Iafrate, A. J., Shaw, A. T., Allen, A. R., Engelman, J. A., Sequist, L. V. 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

    View details for PubMedCentralID PMC4497836

  • Diffuse High Intensity PD-L1 Staining in Thymic Epithelial Tumors. Journal of thoracic oncology Padda, S. K., Riess, J. W., Schwartz, E. J., Tian, L., Kohrt, H. E., Neal, J. W., West, R. B., Wakelee, H. A. 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

  • Developing biomarker-specific end points in lung cancer clinical trials NATURE REVIEWS CLINICAL ONCOLOGY Neal, J. W., Gainor, J. F., Shaw, A. T. 2015; 12 (3): 135-146

    Abstract

    In cancer-drug development, a number of different end points have been used to establish efficacy and support regulatory approval, such as overall survival, progression-free survival (PFS), and radiographic response rate. However, these traditional end points have important limitations. For example, in lung cancer clinical trials, evaluating overall survival end points is a protracted process and these end points are most reliable when crossover to the investigational therapy is not permitted. Furthermore, although radiographic surrogate end points, such as PFS and response rate, generally correlate with clinical benefit in the setting of cytotoxic chemotherapy and molecular targeted therapies, novel immunotherapies might have atypical response kinetics, which confounds radiographic interpretation. In this Review, we discuss the need to develop alternative or surrogate end points for lung cancer clinical trials, and focus on several new biomarkers that could serve as surrogate end points, including functional imaging biomarkers, circulating factors (tumour proteins, DNA, and cells), and pharmacodynamic tumour markers. By enabling the size, duration, and complexity of cancer trials to be reduced, biomarker end points hold the promise to accelerate drug development and improve patient outcomes.

    View details for DOI 10.1038/nrclinonc.2014.222

    View details for Web of Science ID 000350673000006

    View details for PubMedID 25533947

  • Improved tumor vascularization after anti-VEGF therapy with carboplatin and nab-paclitaxel associates with survival in lung cancer. Proceedings of the National Academy of Sciences of the United States of America Heist, R. S., Duda, D. G., Sahani, D. V., Ancukiewicz, M., Fidias, P., Sequist, L. V., Temel, J. S., Shaw, A. T., Pennell, N. A., Neal, J. W., Gandhi, L., Lynch, T. J., Engelman, J. A., Jain, R. K. 2015; 112 (5): 1547-1552

    Abstract

    Addition of anti-VEGF antibody therapy to standard chemotherapies has improved survival and is an accepted standard of care for advanced non-small cell lung cancer (NSCLC). However, the mechanisms by which anti-VEGF therapy increases survival remain unclear. We evaluated dynamic CT-based vascular parameters and plasma cytokines after bevacizumab alone and after bevacizumab plus chemotherapy with carboplatin and nab-paclitaxel in advanced NSCLC patients to explore potential biomarkers of treatment response and resistance to this regimen. Thirty-six patients were enrolled in this study. The primary end point was 6-mo progression-free survival rate, which was 74% (95% CI: 57, 97). This regimen has a promising overall response rate of 36% and median time to progression of 8.5 (6.0, 38.7) mo and overall survival of 12.2 (9.6, 44.1) mo. We found that anti-VEGF therapy led to a sustained increase in plasma PlGF, a potential pharmacodynamic marker. We also found that higher levels of soluble VEGFR1 measured before starting bevacizumab with chemotherapy were associated with worse survival, supporting its potential role as biomarker of treatment resistance. Our imaging biomarker studies indicate that bevacizumab-based treatment-while reducing blood flow, volume, and permeability in the overall population-may be associated with improved survival in patients with improved tumor vasculature and blood perfusion after treatment. This hypothesis-generating study supports the notion that excessively decreasing vascular permeability and pruning/rarefaction after bevacizumab therapy may negatively impact the outcome of combination therapy in NSCLC patients. This hypothesis warrants further dose-titration studies of bevacizumab to examine the dose effect on tumor vasculature and treatment efficacy.

    View details for DOI 10.1073/pnas.1424024112

    View details for PubMedID 25605928

    View details for PubMedCentralID PMC4321320

  • GLI1, CTNNB1 and NOTCH1 protein expression in a thymic epithelial malignancy tissue microarray. Anticancer research Riess, J. W., West, R., Dean, M., Klimowicz, A. C., Neal, J. W., Hoang, C., Wakelee, H. A. 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 Riess, J. W., West, R., Dean, M., Klimowicz, A. C., Neal, J. W., Hoang, C., Wakelee, H. A. 2015; 35 (2): 669-676

    View details for PubMedID 25667444

  • Pemetrexed in patients with thymic malignancies previously treated with chemotherapy. Lung cancer Liang, Y., Padda, S. K., Riess, J. W., West, R. B., Neal, J. W., Wakelee, H. A. 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 meaningful duration, and supports previous reports of pemetrexed efficacy in these rare diseases.

    View details for DOI 10.1016/j.lungcan.2014.11.006

    View details for PubMedID 25443273

  • Decade in review-targeted therapy: successes, toxicities and challenges in solid tumours. Nature reviews. Clinical oncology Neal, J. W., Sledge, G. W. 2014; 11 (11): 627-628

    View details for DOI 10.1038/nrclinonc.2014.171

    View details for PubMedID 25286974

  • Review of the current targeted therapies for non-small-cell lung cancer. World journal of clinical oncology Nguyen, K. H., Neal, J. W., Wakelee, H. 2014; 5 (4): 576-587

    Abstract

    The last decade has witnessed the development of oncogene-directed targeted therapies that have significantly changed the treatment of non-small-cell lung cancer (NSCLC). In this paper we review the data demonstrating efficacy of gefitinib, erlotinib, and afatinib, which target the epidermal growth factor receptor (EGFR), and crizotinib which targets anaplastic lymphoma kinase (ALK). We discuss the challenge of acquired resistance to these small-molecular tyrosine kinase inhibitors and review promising agents which may overcome resistance, including the EGFR T790M-targeted agents CO-1686 and AZD9291, and the ALK-targeted agents ceritinib (LDK378), AP26113, alectinib (CH/RO5424802), and others. Emerging therapies directed against other driver oncogenes in NSCLC including ROS1, HER2, and BRAF are covered as well. The identification of specific molecular targets in a significant fraction of NSCLC has led to the personalized deployment of many effective targeted therapies, with more to come.

    View details for DOI 10.5306/wjco.v5.i4.576

    View details for PubMedID 25302162

    View details for PubMedCentralID PMC4129523

  • An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nature medicine Newman, A. M., Bratman, S. V., To, J., Wynne, J. F., Eclov, N. C., Modlin, L. A., Liu, C. L., Neal, J. W., Wakelee, H. A., Merritt, R. E., Shrager, J. B., Loo, B. W., Alizadeh, A. A., Diehn, M. 2014; 20 (5): 548-554

    Abstract

    Circulating tumor DNA (ctDNA) is a promising biomarker for noninvasive assessment of cancer burden, but existing ctDNA detection methods have insufficient sensitivity or patient coverage for broad clinical applicability. Here we introduce cancer personalized profiling by deep sequencing (CAPP-Seq), an economical and ultrasensitive method for quantifying ctDNA. We implemented CAPP-Seq for non-small-cell lung cancer (NSCLC) with a design covering multiple classes of somatic alterations that identified mutations in >95% of tumors. We detected ctDNA in 100% of patients with stage II-IV NSCLC and in 50% of patients with stage I, with 96% specificity for mutant allele fractions down to ∼0.02%. Levels of ctDNA were highly correlated with tumor volume and distinguished between residual disease and treatment-related imaging changes, and measurement of ctDNA levels allowed for earlier response assessment than radiographic approaches. Finally, we evaluated biopsy-free tumor screening and genotyping with CAPP-Seq. We envision that CAPP-Seq could be routinely applied clinically to detect and monitor diverse malignancies, thus facilitating personalized cancer therapy.

    View details for DOI 10.1038/nm.3519

    View details for PubMedID 24705333

  • An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage NATURE MEDICINE Newman, A. M., Bratman, S. V., To, J., Wynne, J. F., Eclov, N. C., Modlin, L. A., Liu, C. L., Neal, J. W., Wakelee, H. A., Merritt, R. E., Shrager, J. B., Loo, B. W., Alizadeh, A. A., Diehn, M. 2014; 20 (5): 552-558

    View details for DOI 10.1038/nm.3519

    View details for Web of Science ID 000335710700028

  • Prolonged survival of patients with non-small-cell lung cancer with leptomeningeal carcinomatosis in the modern treatment era. Clinical lung cancer Riess, J. W., Nagpal, S., Iv, M., Zeineh, M., Gubens, M. A., Ramchandran, K., Neal, J. W., Wakelee, H. A. 2014; 15 (3): 202-206

    Abstract

    Leptomeningeal carcinomatosis (LM) is a severe complication of non-small-cell lung cancer (NSCLC) historically associated with poor prognosis. New chemotherapeutic and targeted treatments could potentially affect the natural history of LM.Patients with a pathologic diagnosis of NSCLC with LM treated at Stanford between 2003 and 2011 were identified via institutional databases and medical records. LM was defined by cerebrospinal fluid (CSF) that was positive for malignant cells or by LM enhancement on magnetic resonance imaging with gadolinium contrast. Retrospective, landmark analyses were performed to estimate survival. Statistical analyses were performed using SAS Enterprise Guide, version 4.3.LM was identified in 30 patients. All cases were adenocarcinoma; 60% of patients had a known or suspected driver mutation. The mean age was 58 years. Of the 30 patients, 67% were women; 70% were nonsmokers; 27% initially presented with LM; 84% received systemic treatment at or after development of LM; and 53% of these patients received modern systemic therapy for their LM, defined as a regimen containing pemetrexed, bevacizumab, or a tyrosine kinase inhibitor. Mean overall survival after LM diagnosis was 6 months (95% CI, 3-12). Patients who received modern systemic therapy for LM had decreased hazard of death (hazard ratio [HR], 0.24; P = .007).In this retrospective, single-institution analysis, median survival with LM was higher compared with historical experience. Patients who received modern systemic therapy for their LM had particularly good outcomes. These data provide evidence for improving survival outcomes in the modern treatment era for this difficult-to-treat complication.

    View details for DOI 10.1016/j.cllc.2013.12.009

    View details for PubMedID 24524822

  • Immune correlates of talactoferrin alfa in biopsied tumor of relapsed/refractory metastatic non-small cell lung cancer patients. Immunopharmacology and immunotoxicology Riess, J. W., Bhattacharya, N., Blenman, K. R., Neal, J. W., Hwang, G., Pultar, P., San-Pedro Salcedo, M., Engleman, E., Lee, P. P., Malik, R., Wakelee, H. A. 2014; 36 (2): 182-186

    Abstract

    Talactoferrin alfa (TLF) is a unique recombinant form of human lactoferrin. The hypothesized mechanism of action involves TLF binding to the intestinal endothelium inducing dendritic cell maturation and cytokine release leading to infiltration of tumor with monocytes and T-lymphocytes and inhibition of tumor growth.Based on promising phase II trial results, this correlative study was undertaken to examine immune mechanism of action of TLF in metastatic non-small cell lung cancer (NSCLC) patients.Talactoferrin was administered orally at 1.5 g bid weeks 1-12 with 2 weeks off on a 14-week cycle. Enrolled patients had a pathologic diagnosis of NSCLC previously treated with at least two lines of systemic treatment. Patients had core biopsy of tumor before initiation of talactoferrin and at week 7 on TLF. Flow cytometry and quantitative immunohistochemistry for immune correlates were performed on the biopsied specimens.Four patients with metastatic NSCLC were enrolled. The trial was halted pre-maturely in light of negative phase III trial results. For the two patients who had repeat on-treatment tumor biopsies, a consistent increase in monocytes as a percentage of total immune cells was observed. Otherwise, no clear trend of increase or decrease was observed in any other immune cell parameters compared to matched patient pre-treatment biopsies.Repeat biopsies for immune correlates by flow cytometry and quantitative immunohistochemistry in NSCLC patients are feasible. In the few patients sampled before trial closure, increased monocytes as a total percentage of the immune cell population within tumor was observed in response to TLF.

    View details for DOI 10.3109/08923973.2013.864671

    View details for PubMedID 24494587

  • Template for reporting results of biomarker testing of specimens from patients with non-small cell carcinoma of the lung. Archives of pathology & laboratory medicine Cagle, P. T., Sholl, L. M., Lindeman, N. I., Alsabeh, R., Divaris, D. X., Foulis, P., Lee, G., Neal, J. W., Nowak, J. A., Yu, P. P. 2014; 138 (2): 171-174

    View details for DOI 10.5858/arpa.2013-0232-CP

    View details for PubMedID 23808401

  • Isolation and mutational analysis of circulating tumor cells from lung cancer patients with magnetic sifters and biochips LAB ON A CHIP Earhart, C. M., Hughes, C. E., Gaster, R. S., Ooi, C. C., Wilson, R. J., Zhou, L. Y., Humke, E. W., Xu, L., Wong, D. J., Willingham, S. B., Schwartz, E. J., Weissman, I. L., Jeffrey, S. S., Neal, J. W., Rohatgi, R., Wakeleebe, H. A., Wang, S. X. 2014; 14 (1): 78-88

    View details for DOI 10.1039/c3lc50580d

    View details for Web of Science ID 000327669000008

  • Isolation and mutational analysis of circulating tumor cells from lung cancer patients with magnetic sifters and biochips. Lab on a chip Earhart, C. M., Hughes, C. E., Gaster, R. S., Ooi, C. C., Wilson, R. J., Zhou, L. Y., Humke, E. W., Xu, L., Wong, D. J., Willingham, S. B., Schwartz, E. J., Weissman, I. L., Jeffrey, S. S., Neal, J. W., Rohatgi, R., Wakelee, H. A., Wang, S. X. 2013; 14 (1): 78-88

    Abstract

    Detection and characterization of circulating tumor cells (CTCs) may reveal insights into the diagnosis and treatment of malignant disease. Technologies for isolating CTCs developed thus far suffer from one or more limitations, such as low throughput, inability to release captured cells, and reliance on expensive instrumentation for enrichment or subsequent characterization. We report a continuing development of a magnetic separation device, the magnetic sifter, which is a miniature microfluidic chip with a dense array of magnetic pores. It offers high efficiency capture of tumor cells, labeled with magnetic nanoparticles, from whole blood with high throughput and efficient release of captured cells. For subsequent characterization of CTCs, an assay, using a protein chip with giant magnetoresistive nanosensors, has been implemented for mutational analysis of CTCs enriched with the magnetic sifter. The use of these magnetic technologies, which are separate devices, may lead the way to routine preparation and characterization of "liquid biopsies" from cancer patients.

    View details for DOI 10.1039/c3lc50580d

    View details for PubMedID 23969419

  • Adjuvant molecularly targeted therapy-epidermal growth factor tyrosine kinase inhibition and beyond. Translational lung cancer research Neal, J. W., Sequist, L. V. 2013; 2 (5): 411-414

    View details for DOI 10.3978/j.issn.2218-6751.2013.10.06

    View details for PubMedID 25806260

    View details for PubMedCentralID PMC4367722

  • A Case Series of Lengthy Progression-Free Survival With Pemetrexed-Containing Therapy in Metastatic Non-Small-Cell Lung Cancer Patients Harboring ROS1 Gene Rearrangements. Clinical lung cancer Riess, J. W., Padda, S. K., Bangs, C. D., Das, M., Neal, J. W., Adrouny, A. R., Cherry, A., Wakelee, H. A. 2013; 14 (5): 592-595

    View details for DOI 10.1016/j.cllc.2013.04.008

    View details for PubMedID 23810364

  • A Patient With Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer With Development of Leptomeningeal Carcinomatosis While on Targeted Treatment With Crizotinib JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Riess, J. W., Nagpal, S., Neal, J. W., Wake, H. A. 2013; 11 (4): 389-394

    Abstract

    Leptomeningeal carcinomatosis (LM) is an infrequent yet morbid and often fatal complication of non-small cell lung cancer (NSCLC). Management of LM is multimodal, often involving systemic chemotherapy, radiotherapy, and a variety of symptom management maneuvers to address elevated intracranial pressure, pain, and mood changes that can accompany the disease. It is increasingly recognized that tumors with actionable mutations in NSCLC, including epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations, respond well to systemic therapy with tyrosine kinase inhibitors yet often progress in the central nervous system. More information is needed regarding the natural history and optimal management of LM in specific molecular subtypes of NSCLC. This case report summarizes the management of a patient with ALK-positive NSCLC who developed LM while on targeted treatment with crizotinib within the context of current NCCN Clinical Practice Guidelines in Oncology and recently published studies.

    View details for Web of Science ID 000317543800006

    View details for PubMedID 23584342

  • A Case Series of NSCLC Patients with Different Molecular Characteristics and Choroidal Metastases Improvement in Vision with Treatment Including Pemetrexed and Bevacizumab JOURNAL OF THORACIC ONCOLOGY Riess, J. W., Nagpal, S., Das, M., Neal, J. W., Kim, J. W., Wakelee, H. A. 2013; 8 (2): E17-E18

    View details for DOI 10.1097/JTO.0b013e31827690da

    View details for Web of Science ID 000316204900003

    View details for PubMedID 23328555

  • A case series of NSCLC patients with different molecular characteristics and choroidal metastases: improvement in vision with treatment including pemetrexed and bevacizumab. Journal of thoracic oncology Riess, J. W., Nagpal, S., Das, M., Neal, J. W., Kim, J. W., Wakelee, H. A. 2013; 8 (2): e17-8

    View details for DOI 10.1097/JTO.0b013e31827690da

    View details for PubMedID 23328555

  • Aflibercept in lung cancer EXPERT OPINION ON BIOLOGICAL THERAPY Neal, J. W., Wakelee, H. A. 2013; 13 (1): 115-120

    Abstract

    Angiogenesis, the recruitment and growth of blood vessels, is a process central to the growth of solid tumors. One of the key mediators of angiogenesis is the vascular endothelial growth factor (VEGF) family of ligands. An antibody to VEGF-A, bevacizumab, has demonstrated a survival benefit in conjunction with platinum-based doublet chemotherapy in non-small-cell lung cancer (NSCLC). Aflibercept (VEGF Trap) is a recombinant VEGF receptor-antibody protein fusion with higher affinity for VEGF-A than bevacizumab, plus affinity for VEGF-B and placental growth factor (PlGF). AREAS COVERED: This article reviews recent clinical trials investigating the role of aflibercept in the treatment of lung cancer, both published in the literature and those for which preliminary data have been presented at major scientific meetings. EXPERT OPINION: Aflibercept has proven Phase III efficacy in metastatic colorectal cancer, but in lung cancer, large clinical trials have not yielded positive results. There remains hope that identification of biomarkers of response will one day help select patients most likely to benefit from antiangiogenesis therapy.

    View details for DOI 10.1517/14712598.2013.745847

    View details for Web of Science ID 000312219700010

    View details for PubMedID 23199019

  • Targeting fibroblast growth factor receptor and discoidin domain receptor 2 in non-small-cell lung cancer. Journal of thoracic oncology Riess, J. W., Neal, J. W. 2012; 7 (16): S385-6

    View details for DOI 10.1097/JTO.0b013e31826df166

    View details for PubMedID 23160327

  • MET inhibitors in combination with other therapies in non-small cell lung cancer. Translational lung cancer research Padda, S., Neal, J. W., Wakelee, H. A. 2012; 1 (4): 238-253

    Abstract

    MET and its ligand hepatocyte growth factor/scatter factor (HGF) influence cell motility and lead to tumor growth, invasion, and angiogenesis. Alterations in MET have been observed in non-small cell lung cancer (NSCLC) tumors, with increased expression associated with more aggressive cancer, as well as acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). MET inhibitors act via two basic mechanisms. Small molecule inhibitors antagonize ATP in the intracellular tyrosine kinase domain of MET, with studies on the following agents reviewed here: tivantinib (ARQ-197), cabozantinib (XL-184), crizotinib (PF-02341066), amuvatinib (MP470), MGCD265, foretinib (EXEL-2880), MK2461, SGX523, PHA665752, JNJ-38877605, SU11274, and K252A. The monoclonal monovalent antibody fragment onartuzumab (MetMAb) is also discussed here, which binds to and prevents the extracellular activation of the receptor by ligand. MET inhibition may both overcome the negative prognostic effect of MET tumor expression as well as antagonize MET-dependent acquired resistance to EGFR inhibitors. Here we discuss MET inhibitors in combination with other therapies in lung cancer.

    View details for DOI 10.3978/j.issn.2218-6751.2012.10.08

    View details for PubMedID 25806189

    View details for PubMedCentralID PMC4367550

  • A Phase I Study of Erlotinib and Hydroxychloroquine in Advanced Non-Small-Cell Lung Cancer JOURNAL OF THORACIC ONCOLOGY Goldberg, S. B., Supko, J. G., Neal, J. W., Muzikansky, A., Digumarthy, S., Fidias, P., Temel, J. S., Heist, R. S., Shaw, A. T., McCarthy, P. O., Lynch, T. J., Sharma, S., Settleman, J. E., Sequist, L. V. 2012; 7 (10): 1602-1608

    Abstract

    This investigator-initiated study explores the safety, maximum tolerated dose, clinical response, and pharmacokinetics of hydroxychloroquine (HCQ) with and without erlotinib in patients with advanced non-small-cell lung cancer.Patients with prior clinical benefit from an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor were randomized to HCQ or HCQ plus erlotinib in a 3 + 3 dose-escalation schema.Twenty-seven patients were treated, eight with HCQ (arm A) and 19 with HCQ plus erlotinib (arm B). EGFR mutations were detected in 74% of the patients and 85% had received two or more prior therapies. Arm A had no dose-limiting toxicities, but the maximum tolerated dose was not reached as this arm closed early to increase overall study accrual. In arm B, one patient each experienced grade 3 rash, nail changes, skin changes, nausea, dehydration, and neutropenia; one had grade 4 anemia; and one developed fatal pneumonitis, all considered unrelated to HCQ. There were no dose-limiting toxicities, therefore the highest tested dose for HCQ with erlotinib 150 mg was 1000 mg daily. One patient had a partial response to erlotinib/HCQ, for an overall response rate of 5% (95% confidence interval, 1-25). This patient had an EGFR mutation and remained on therapy for 20 months. Administration of HCQ did not alter the pharmacokinetics of erlotinib.HCQ with or without erlotinib was safe and well tolerated. The recommended phase 2 dose of HCQ was 1000 mg when given in combination with erlotinib 150 mg.

    View details for DOI 10.1097/JTO.0b013e318262de4a

    View details for Web of Science ID 000308919400023

    View details for PubMedID 22878749

  • Complex Role of Histone Deacetylase Inhibitors in the Treatment of Non-Small-Cell Lung Cancer JOURNAL OF CLINICAL ONCOLOGY Neal, J. W., Sequist, L. V. 2012; 30 (18): 2280-2282

    View details for DOI 10.1200/JCO.2011.41.0860

    View details for Web of Science ID 000305413200022

    View details for PubMedID 22508823

  • Ipilimumab in Combination With Paclitaxel and Carboplatin As First-Line Treatment in Stage IIIB/IV Non-Small-Cell Lung Cancer: Results From a Randomized, Double-Blind, Multicenter Phase II Study JOURNAL OF CLINICAL ONCOLOGY Lynch, T. J., Bondarenko, I., Luft, A., Serwatowski, P., Barlesi, F., Chacko, R., Sebastian, M., Neal, J., Lu, H., Cuillerot, J., Reck, M. 2012; 30 (17): 2046-2054

    Abstract

    Ipilimumab, which is an anti-cytotoxic T-cell lymphocyte-4 monoclonal antibody, showed a survival benefit in melanoma with adverse events (AEs) managed by protocol-defined guidelines. A phase II study in lung cancer assessed the activity of ipilimumab plus paclitaxel and carboplatin.Patients (N = 204) with chemotherapy-naive non-small-cell lung cancer (NSCLC) were randomly assigned 1:1:1 to receive paclitaxel (175 mg/m(2)) and carboplatin (area under the curve, 6) with either placebo (control) or ipilimumab in one of the following two regimens: concurrent ipilimumab (four doses of ipilimumab plus paclitaxel and carboplatin followed by two doses of placebo plus paclitaxel and carboplatin) or phased ipilimumab (two doses of placebo plus paclitaxel and carboplatin followed by four doses of ipilimumab plus paclitaxel and carboplatin).Treatment was administered intravenously every 3 weeks for ≤ 18 weeks (induction). Eligible patients continued ipilimumab or placebo every 12 weeks as maintenance therapy. Response was assessed by using immune-related response criteria and modified WHO criteria. The primary end point was immune-related progression-free survival (irPFS). Other end points were progression-free survival (PFS), best overall response rate (BORR), immune-related BORR (irBORR), overall survival (OS), and safety.The study met its primary end point of improved irPFS for phased ipilimumab versus the control (hazard ratio [HR], 0.72; P = .05), but not for concurrent ipilimumab (HR, 0.81; P = .13). Phased ipilimumab also improved PFS according to modified WHO criteria (HR, 0.69; P = .02). Phased ipilimumab, concurrent ipilimumab, and control treatments were associated with a median irPFS of 5.7, 5.5, and 4.6 months, respectively, a median PFS of 5.1, 4.1, and 4.2 months, respectively, an irBORR of 32%, 21% and 18%, respectively, a BORR of 32%, 21% and 14%, respectively, and a median OS of 12.2, 9.7, and 8.3 months. Overall rates of grade 3 and 4 immune-related AEs were 15%, 20%, and 6% for phased ipilimumab, concurrent ipilimumab, and the control, respectively. Two patients (concurrent, one patient; control, one patient) died from treatment-related toxicity.Phased ipilimumab plus paclitaxel and carboplatin improved irPFS and PFS, which supports additional investigation of ipilimumab in NSCLC.

    View details for DOI 10.1200/JCO.2011.38.4032

    View details for Web of Science ID 000305159200009

    View details for PubMedID 22547592

  • First-line treatment of EGFR-mutant non-small-cell lung cancer: the role of erlotinib and other tyrosine kinase inhibitors. Biologics : targets & therapy Nguyen, K. H., Neal, J. W. 2012; 6: 337-345

    Abstract

    Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) were initially established as second- or third-line treatment of advanced non-small-cell lung cancer (NSCLC). Subsequent studies, including IPASS, OPTIMAL, and EURTAC, have demonstrated that these TKIs are effective first-line therapeutic options in patients with tumors harboring activating mutations in the EGFR gene. The TKIs are better tolerated than conventional chemotherapy, with frequent yet mild side effects such as rash and diarrhea, and rarely interstitial lung disease. Because most patients on TKIs develop resistance due to a variety of mechanisms, the use of TKIs in the acquired-resistance setting and in the setting of earlier-staged cancers is being extensively studied. Here we review the major trials leading to the established use of EGFR TKIs in NSCLC, followed by discussion of recently completed and ongoing trials using the next-generation EGFR inhibitor afatinib.

    View details for DOI 10.2147/BTT.S26558

    View details for PubMedID 23055691

  • Current Management of Small Cell Lung Cancer CLINICS IN CHEST MEDICINE Neal, J. W., Gubens, M. A., Wakelee, H. A. 2011; 32 (4): 853-?

    Abstract

    Confined to one side of the chest, limited stage small cell lung cancer is treated with a combination of chemotherapy and radiotherapy, yet has a long-term survival rate of only 15%. Extensive stage disease has initial response rates to chemotherapy exceeding 70%. However, the disease almost invariably progresses and becomes fatal. Many recent clinical trials have failed to show superiority of newer chemotherapeutics or targeted therapies compared with the standard chemotherapy backbone of platinum plus etoposide. Numerous promising targeted therapies and other agents are still in development.

    View details for DOI 10.1016/j.ccm.2011.07.002

    View details for Web of Science ID 000297822700017

    View details for PubMedID 22054891

  • Targeting FGFR, Ephrins, Mer, MET, and PDGFR-alpha in Non-small Cell Lung Cancer JOURNAL OF THORACIC ONCOLOGY Riess, J. W., Neal, J. W. 2011; 6 (11): S1797-S1798
  • One Allele's Loss Is Another's Gain: Alterations of NKX2-8 in Non-Small Cell Lung Cancer CLINICAL CANCER RESEARCH Neal, J. W., Shaw, A. T. 2011; 17 (4): 638-639

    Abstract

    Large-scale genetic changes such as loss or gain of chromosomes are important drivers of solid tumor carcinogenesis. Recent technological advances in genomic profiling have allowed quantitative detection of gene copy numbers, leading to identification of the 14q13.3 gene locus as functionally important in non-small cell lung cancers.

    View details for DOI 10.1158/1078-0432.CCR-10-3081

    View details for Web of Science ID 000287913200002

    View details for PubMedID 21163872

  • Outcomes After Combined Modality Therapy for EGFR-Mutant and Wild-Type Locally Advanced NSCLC ONCOLOGIST Mak, R. H., Doran, E., Muzikansky, A., Kang, J., Neal, J. W., Baldini, E. H., Choi, N. C., Willers, H., Jackman, D. M., Sequist, L. V. 2011; 16 (6): 886-895

    Abstract

    Epidermal growth factor receptor (EGFR) mutations identify a unique biological subtype of non-small cell lung cancer (NSCLC). Treatment outcomes for EGFR-mutant locally advanced NSCLC patients have not been well described.We retrospectively examined outcomes after combined modality therapy including thoracic radiation therapy (RT) in 123 patients with locally advanced NSCLC and known EGFR mutation status. Outcomes were compared using Kaplan-Meier analysis, the log-rank test, and multivariate Cox regression models.All 123 patients underwent thoracic RT; 25% had tumors with EGFR mutations and 94% had stage III disease. Overall, 81% received chemotherapy concurrent with RT and 55% underwent surgical resection. With a median follow-up of 27.5 months, the overall survival (OS) rate was significantly higher in patients with EGFR-mutant tumors than in those with wild-type EGFR tumors (2-year estimate: 92.6% versus 69.0%; p = .04). The 2-year relapse-free survival and distant recurrence rates did not differ significantly by genotype. The 2-year locoregional recurrence rate (LRR) was significantly lower in EGFR-mutant than in wild-type EGFR patients (17.8% versus 41.7%; p = .005). EGFR-mutant genotype was associated with a lower risk for LRR on multivariate analysis, but not OS, after adjusting for surgery and other potential confounders.We observed that EGFR-mutant patients with locally advanced NSCLC treated with RT had lower rates of LRR than wild-type EGFR patients, raising the hypothesis that EGFR mutations may confer sensitivity to RT and/or chemotherapy. The association between mutation status and OS after combined modality therapy was less robust. Our data may serve as a useful baseline estimate of outcomes by EGFR genotype for future prospective studies.

    View details for DOI 10.1634/theoncologist.2011-0040

    View details for Web of Science ID 000291928900018

    View details for PubMedID 21632451

    View details for PubMedCentralID PMC3228219

  • The SATURN trial: the value of maintenance erlotinib in patients with non-small-cell lung cancer FUTURE ONCOLOGY Neal, J. W. 2010; 6 (12): 1827-1832

    Abstract

    The first-line treatment of advanced non-small-cell lung cancer (NSCLC) generally consists of a maximum of six cycles of platinum-based doublet chemotherapy followed by surveillance for disease progression. Recently, the strategy of starting second-line treatment immediately following the completion of chemotherapy, known as 'maintenance' chemotherapy, has been investigated. The use of maintenance pemetrexed improves both progression-free and overall survival, while the use of maintenance docetaxel did not significantly improve overall survival. The Sequential Tarceva in Unresectable NSCLC (SATURN) study investigated the use of maintenance erlotinib following the completion of first-line chemotherapy. It demonstrated a significant improvement in overall survival from 11.1 months in the placebo group to 12.3 months in patients receiving maintenance erlotinib, with the important caveat that only 21% of patients in the placebo group ever received erlotinib. A subset of patients whose tumors had EGF receptor mutations had a higher magnitude of benefit from maintenance treatment. Therefore, maintenance erlotinib should be considered in the treatment of patients with NSCLC.

    View details for DOI 10.2217/FON.10.156

    View details for Web of Science ID 000297100400007

    View details for PubMedID 21142856

  • Cetuximab monotherapy in patients with advanced non-small cell lung cancer after prior epidermal growth factor receptor tyrosine kinase inhibitor therapy. Journal of thoracic oncology Neal, J. W., Heist, R. S., Fidias, P., Temel, J. S., Huberman, M., Marcoux, J. P., Muzikansky, A., Lynch, T. J., Sequist, L. V. 2010; 5 (11): 1855-1858

    Abstract

    Therapeutic agents directed against the epidermal growth factor receptor (EGFR) signaling pathway have been effective in the treatment of non-small cell lung cancer (NSCLC). Cetuximab is a monoclonal antibody against the EGFR receptor with antitumor activity in NSCLC. This study evaluated the efficacy of cetuximab monotherapy after prior treatment with an oral EGFR tyrosine kinase inhibitor (TKI).Eligible patients had stage IIIB, IV, or recurrent NSCLC with progression on the oral EGFR TKIs gefitinib or erlotinib. Cetuximab was administered intravenously at 400 mg/m on day 1 and then 250 mg/m weekly until disease progression or unacceptable toxicity. The primary end point was response rate.Eighteen patients were enrolled. Patients were heavily pretreated with chemotherapy and TKIs (average number of treatments = 4.2). The response rate was 0/18 (0%), and 28% of patients had confirmed stable disease. Median progression-free survival was 1.8 months (95% confidence interval, 1.6-5.4 months), and median overall survival was 7.5 months (95% confidence interval, 2.2-19 months). Three patients harbored activating EGFR mutations, and one of them had stable disease for nearly 6 months on cetuximab. Common toxicities were mild and included fatigue, skin rash, and nausea/vomiting. Two patients developed interstitial lung disease, life threatening in one case.Cetuximab monotherapy administered after prior EGFR TKI treatment in patients with advanced NSCLC does not yield clinical responses.

    View details for DOI 10.1097/JTO.0b013e3181f0bee0

    View details for PubMedID 20975380

  • AMG-386, a selective angiopoietin-1/-2-neutralizing peptibody for the potential treatment of cancer CURRENT OPINION IN MOLECULAR THERAPEUTICS Neal, J., Wakelee, H. 2010; 12 (4): 487-495

    Abstract

    The VEGF/VEGFR and angiopoietin/Tie-2 signaling pathways are important in the process of vascular endothelial growth (angiogenesis) and in the maintenance of tumor-associated blood vessels. While there are several agents targeting the VEGF/VEGFR signaling pathway, there are none available that target the angiopoietin/Tie-2 signaling pathway. The first such agent to reach clinical trials is AMG-386 (2xCon4C), being developed by Amgen Inc and licensed in Japan to Takeda Bio Development Center Ltd. AMG-386 is an anti-angiopoietin peptibody comprising a peptide with angiopoietin-binding properties that is fused to the Fc (crystallizable fragment) region of an antibody and inhibits the interaction between the ligands angiopoietin-1 and angiopoietin-2 with the Tie-2 receptor. AMG-386 significantly inhibited the growth of tumors in a variety of mouse xenograft models. In phase I trials of AMG-386 as a monotherapy or in combination with chemotherapy in patients with advanced solid tumors, AMG-386 demonstrated only mild toxicities, and one complete response and several partial responses were achieved in patients. Phase II trials of AMG-386 in combination with chemotherapy were ongoing in a variety of solid tumors, including breast, ovarian, colorectal, gastric and renal cell cancers. If safe and effective, AMG-386 could be an exciting addition to other antiangiogenic therapies in solid tumors.

    View details for Web of Science ID 000280507000013

    View details for PubMedID 20677100

  • Exciting New Targets in Lung Cancer Therapy: ALK, IGF-1R, HDAC, and Hh CURRENT TREATMENT OPTIONS IN ONCOLOGY Neal, J. W., Sequist, L. V. 2010; 11 (1-2): 36-44

    Abstract

    The anaplastic lymphoma kinase (ALK) inhibitor crizotinib will become an integral addition to the treatment of patients with non-small cell lung cancer (NSCLC) harboring genetic ALK translocations. The insulin-like growth factor receptor (IGF-1R) monoclonal antibody figitumumab, while initially promising, appears to increase toxicity and death in combination with chemotherapy in the treatment of patients with NSCLC of squamous histology; therefore, clinical development of this class of agents will need to proceed with caution. The histone deacetylation (HDAC) inhibitor vorinostat did not demonstrate an improvement in overall survival (OS) compared with placebo in a large randomized trial, but other agents in this class may have greater selectivity and efficacy. Inhibitors of the hedgehog (Hh) signaling pathways have some early clinical promise in both NSCLC and small cell lung cancer (SCLC), and larger studies using these agents are eagerly anticipated.

    View details for DOI 10.1007/s11864-010-0120-6

    View details for Web of Science ID 000281247200004

    View details for PubMedID 20676809

  • Targeted therapies: optimal first-line therapy for NSCLC with EGFR mutations. Nature reviews. Clinical oncology Neal, J. W., Sequist, L. V. 2010; 7 (2): 71-72

    View details for DOI 10.1038/nrclinonc.2009.191

    View details for PubMedID 20118973

  • First-line use of EGFR tyrosine kinase inhibitors in patients with NSCLC containing EGFR mutations. Clinical advances in hematology & oncology : H&O Neal, J. W., Sequist, L. V. 2010; 8 (2): 119-126

    Abstract

    While the small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib and gefitinib have modest clinical benefit in unselected patients with non-small cell lung cancer after platinum-based chemotherapy, an emerging and potentially more elegant strategy is to move these agents to the frontline setting for select patients. Those with somatic mutations in EGFR respond dramatically to EGFR inhibitors, and mounting evidence from recent clinical trials, particularly the Iressa Pan-Asia Study (IPASS) trial, confirms superior response rates, progression-free survival, and tolerability with this targeted therapy compared with conventional chemotherapy. Here, we review the studies supporting the use of EGFR tyrosine kinase inhibitors in the frontline setting in patients with EGFR mutations.

    View details for PubMedID 20386533

  • Induction of FucT-VII by the Ras/MAP kinase cascade in Jurkat T cells BLOOD Barry, S. M., Zisoulis, D. G., Neal, J. W., Clipstone, N. A., Kansas, G. S. 2003; 102 (5): 1771-1778

    Abstract

    Induction of the alpha1,3-fucosyltransferase FucT-VII in T lymphocytes is crucial for selectin ligand formation, but the signaling and transcriptional pathways that govern FucT-VII expression are unknown. Here, using a novel, highly phorbol myristate acetate (PMA)-responsive variant of the Jurkat T-cell line, we identify Ras and downstream mitogen-activated protein (MAP) kinase pathways as essential mediators of FucT-VII gene expression. PMA induced FucT-VII in only a subset of treated cells, similar to expression of FucT-VII in normal activated CD4 T cells. Introduction of constitutively active Ras or Raf by recombinant retroviruses induced FucT-VII expression only in that subset of cells expressing the highest levels of Ras, suggesting that induction of FucT-VII required a critical threshhold of Ras signaling. Both PMA treatment and introduction of active Ras led to rolling on E-selectin. Pharmacologic inhibition studies confirmed the involvement of the classic Ras-Raf-MEK-extracellular signal-regulated kinase (Ras-Raf-MEK-ERK) pathway in FucT-VII induction by PMA, Ras, and Raf. These studies also revealed a second, Ras-induced, Raf-1-independent pathway that participated in induction of FucT-VII. Strong activation of Ras represents a major pathway for induction of FucT-VII gene expression in T cells.

    View details for DOI 10.1182/blood-2002-11-3551

    View details for Web of Science ID 000184945200042

    View details for PubMedID 12738675

  • A constitutively active NFATc1 mutant induces a transformed phenotype in 3T3-L1 fibroblasts JOURNAL OF BIOLOGICAL CHEMISTRY Neal, J. W., Clipstone, N. A. 2003; 278 (19): 17246-17254

    Abstract

    The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway is best known for its role in T lymphocyte activation. However, it has become increasingly apparent that this signaling pathway is also involved in the regulation of cell growth and development in a wide variety of different tissues and cell types. Here we have investigated the effects of sustained NFATc1 signaling on the growth and differentiation of the murine 3T3-L1 preadipocyte cell line. Remarkably, we find that expression of a constitutively active NFATc1 mutant (caNFATc1) in these immortalized cells inhibits their differentiation into mature adipocytes and causes them to adopt a transformed cell phenotype, including loss of contact-mediated growth inhibition, reduced serum growth requirements, protection from growth factor withdrawal-induced apoptosis, and formation of colonies in semisolid media. Furthermore, we find that caNFATc1-expressing cells acquire growth factor autonomy and are able to proliferate even in the complete absence of serum. We provide evidence that this growth factor independence is caused by the NFATc1-dependent production of a soluble heat-labile autocrine factor that is capable of promoting the growth and survival of wild type 3T3-L1 cells as well as potently inhibiting their differentiation into mature adipocytes. Finally, we demonstrate that cells expressing caNFATc1 form tumors in nude mice. Taken together, these results indicate that deregulated NFATc1 activity is able to induce the immortalized 3T3-L1 preadipocyte cell line to acquire the well established hallmarks of cellular transformation and thereby provide direct evidence for the oncogenic potential of the NFATc1 transcription factor.

    View details for DOI 10.1074/jbc.M300528200

    View details for Web of Science ID 000182818600107

    View details for PubMedID 12598522

  • Calcineurin mediates the calcium-dependent inhibition of adipocyte differentiation in 3T3-L1 cells JOURNAL OF BIOLOGICAL CHEMISTRY Neal, J. W., Clipstone, N. A. 2002; 277 (51): 49776-49781

    Abstract

    Recent studies have revealed that the calcium-dependent serine/threonine phosphatase calcineurin mediates the effects of intracellular calcium in many different cell types. In this study we investigated the role of calcineurin in the regulation of adipocyte differentiation. We found that the specific calcineurin inhibitors cyclosporin A and FK506 overcame the antiadipogenic effect of calcium ionophore on the differentiation of 3T3-L1 preadipocytes. This finding suggests that calcineurin is responsible for mediating the previously documented Ca(2+)-dependent inhibition of adipogenesis. We further demonstrate that the expression of a constitutively active calcineurin mutant potently inhibits the ability of 3T3-L1 cells to undergo adipocyte differentiation by preventing expression of the proadipogenic transcription factors peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer-binding protein alpha (C/EBPalpha). This calcineurin-mediated block in adipocyte differentiation is rescued by ectopic expression of PPARgamma1. Finally, we demonstrate that inhibition of endogenous calcineurin activity with either FK506 or a specific calcineurin inhibitory peptide enhances differentiation of 3T3-L1 cells in response to suboptimal adipogenic stimuli, suggesting that endogenous calcineurin activity normally sets a signaling threshold that antagonizes efficient adipocyte differentiation. Collectively, these data indicate that calcineurin acts as a Ca(2+)-dependent molecular switch that negatively regulates commitment to adipocyte differentiation by preventing the expression of critical proadipogenic transcription factors.

    View details for DOI 10.1074/jbc.M207913200

    View details for Web of Science ID 000180028900090

    View details for PubMedID 12351639

  • Glycogen synthase kinase-3 inhibits the DNA binding activity of NFATc JOURNAL OF BIOLOGICAL CHEMISTRY Neal, J. W., Clipstone, N. A. 2001; 276 (5): 3666-3673

    Abstract

    The NFAT family of transcription factors is required for the expression of numerous immunologically important genes and plays a pivotal role in both the initiation and coordination of the immune response. NFAT family members appear to be regulated primarily at the level of their subcellular localization. Here we show that NFATc is additionally regulated at the level of its DNA binding activity. Using gel mobility shift assays, we demonstrate that the intrinsic DNA binding activity of NFATc is negatively regulated by phosphorylation. We found that activation of calcineurin activity in cells and dephosphorylation of NFATc in vitro enhanced NFATc DNA binding activity, whereas phosphorylation of NFATc in vitro inhibited its ability to bind DNA. Through the analysis of NFATc mutants, we identified the conserved Ser-Pro repeat motifs as critical quantitative determinants of NFATc DNA binding activity. In addition, we provide several lines of evidence to suggest that the phosphorylation of the Ser-Pro repeats by glycogen synthase kinase-3 inhibits the ability of NFATc to bind DNA. Taken together, these studies afford new insights into the regulation of NFATc and underscore the potential role of glycogen synthase kinase-3 in the regulation of NFAT-dependent gene expression.

    View details for Web of Science ID 000166784900089

    View details for PubMedID 11063740

  • REGULATION OF THE GLUCOSE-H+ SYMPORTER BY METABOLITE-ACTIVATED ATP-DEPENDENT PHOSPHORYLATION OF HPR IN LACTOBACILLUS-BREVIS JOURNAL OF BACTERIOLOGY Ye, J. J., Neal, J. W., Cui, X. W., Reizer, J., Saier, M. H. 1994; 176 (12): 3484-3492

    Abstract

    Lactobacillus brevis takes up glucose and the nonmetabolizable glucose analog 2-deoxyglucose (2DG), as well as lactose and the nonmetabolizable lactose analoge thiomethyl beta-galactoside (TMG), via proton symport. Our earlier studies showed that TMG, previously accumulated in L. brevis cells via the lactose:H+ symporter, rapidly effluxes from L. brevis cells or vesicles upon addition of glucose and that glucose inhibits further accumulation of TMG. This regulation was shown to be mediated by a metabolite-activated protein kinase that phosphorylase serine 46 in the HPr protein. We have now analyzed the regulation of 2DG uptake and efflux and compared it with that of TMG. Uptake of 2DG was dependent on an energy source, effectively provided by intravesicular ATP or by extravesicular arginine which provides ATP via an ATP-generating system involving the arginine deiminase pathway. 2DG uptake into these vesicles was not inhibited, and preaccumulated 2DG did not efflux from them upon electroporation of fructose 1,6-diphosphate or gluconate 6-phosphate into the vesicles. Intravesicular but not extravesicular wild-type or H15A mutant HPr of Bacillus subtilis promoted inhibition (53 and 46%, respectively) of the permease in the presence of these metabolites. Counterflow experiments indicated that inhibition of 2DG uptake is due to the partial uncoupling of proton symport from sugar transport. Intravesicular S46A mutant HPr could not promote regulation of glucose permease activity when electroporated into the vesicles with or without the phosphorylated metabolites, but the S46D mutant protein promoted regulation, even in the absence of a metabolite. The Vmax but not the Km values for both TMG and 2DG uptake were affected. Uptake of the natural, metabolizable substrates of the lactose, glucose, mannose, and ribose permeases was inhibited by wild-type HPr in the presence of fructose 1,6-diphosphate or by S46D mutant HPr. These results establish that HPr serine phosphorylation by the ATP-dependent, metabolite-activated HPr kinase regulates glucose and lactose permease activities in L. brevis and suggest that other permeases may also be subject to this mode of regulation.

    View details for Web of Science ID A1994NQ76400006

    View details for PubMedID 8206825