- Lung Cancer
- Neuroendocrine Tumors
Clinical Assistant Professor, Medicine - Oncology
Honors & Awards
Humanism in Hematology/Oncology Award, Division of Oncology, Stanford Hospital and Clinics (2019)
Methods in Clinical Cancer Research Workshop, ASCO/AACR (2019)
Charles Dorsey Armstrong Award for Excellence in Patient Care by a Senior Resident, Department of Internal Medicine, Stanford Hospital and Clinics (2015)
Board Certification, Hematology, American Board of Internal Medicine (2019)
Board Certification, Oncology, American Board of Internal Medicine (2019)
Board Certification, Internal Medicine, American Board of Internal Medicine (2015)
Fellowship: Stanford University Hematology and Oncology Fellowship (2019) CA
Residency, Stanford University, Internal Medicine Residency, CA (2015)
Medical Education: Stanford University School of Medicine (2012) CA
Afatinib and Necitumumab in Patients With EGFR Mutation Positive Advanced or Metastatic Non-small Cell Lung Cancer
This phase I trial studies the side effects and best dose of afatinib and necitumumab and to see how well they work in treating patients with EGFR mutation positive non-small cell lung cancer that has spread to other places in the body. Afatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as necitumumab, may interfere with the ability of tumor cells to grow and spread. Giving afatinib and necitumumab may work better in treating patients with EGFR mutation positive non-small cell lung cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
Overall Survival Among Patients With De Novo Stage IV Metastatic and Distant Metastatic Recurrent Non-Small Cell Lung Cancer.
JAMA network open
2023; 6 (9): e2335813
Despite recent breakthroughs in therapy, advanced lung cancer still poses a therapeutic challenge. The survival profile of patients with metastatic lung cancer remains poorly understood by metastatic disease type (ie, de novo stage IV vs distant recurrence).To evaluate the association of metastatic disease type on overall survival (OS) among patients with non-small cell lung cancer (NSCLC) and to identify potential mechanisms underlying any survival difference.Cohort study of a national US population based at a tertiary referral center in the San Francisco Bay Area using participant data from the National Lung Screening Trial (NLST) who were enrolled between 2002 and 2004 and followed up for up to 7 years as the primary cohort and patient data from Stanford Healthcare (SHC) for diagnoses between 2009 and 2019 and followed up for up to 13 years as the validation cohort. Participants from NLST with de novo metastatic or distant recurrent NSCLC diagnoses were included. Data were analyzed from January 2021 to March 2023.De novo stage IV vs distant recurrent metastatic disease.OS after diagnosis of metastatic disease.The NLST and SHC cohort consisted of 660 and 180 participants, respectively (411 men [62.3%] vs 109 men [60.6%], 602 White participants [91.2%] vs 111 White participants [61.7%], and mean [SD] age of 66.8 [5.5] vs 71.4 [7.9] years at metastasis, respectively). Patients with distant recurrence showed significantly better OS than patients with de novo metastasis (adjusted hazard ratio [aHR], 0.72; 95% CI, 0.60-0.87; P < .001) in NLST, which was replicated in SHC (aHR, 0.64; 95% CI, 0.43-0.96; P = .03). In SHC, patients with de novo metastasis more frequently progressed to the bone (63 patients with de novo metastasis [52.5%] vs 19 patients with distant recurrence [31.7%]) or pleura (40 patients with de novo metastasis [33.3%] vs 8 patients with distant recurrence [13.3%]) than patients with distant recurrence and were primarily detected through symptoms (102 patients [85.0%]) as compared with posttreatment surveillance (47 patients [78.3%]) in the latter. The main finding remained consistent after further adjusting for metastasis sites and detection methods.In this cohort study, patients with distant recurrent NSCLC had significantly better OS than those with de novo disease, and the latter group was associated with characteristics that may affect overall survival. This finding can help inform future clinical trial designs to ensure a balance for baseline patient characteristics.
View details for DOI 10.1001/jamanetworkopen.2023.35813
View details for PubMedID 37751203
Pharmacovigilance Analysis of HeartFailure Associated With Anti-HER2 Monotherapies and Combination Regimens for Cancer.
2023; 5 (1): 85-98
Background: Trastuzumab improves outcomes in patients with HER2-overexpressing malignancies but is associated with decreases in left ventricular ejection fraction. Heart failure (HF) risks from other anti-HER2 therapies are less clear.Objectives: Using World Health Organization pharmacovigilance data, the authors compared HF odds across anti-HER2 regimens.Methods: In VigiBase, 41,976 patients had adverse drug reactions (ADRs) with anti-HER2 monoclonal antibodies (trastuzumab, n=16,900; pertuzumab, n=1,856), antibody-drug conjugates (trastuzumab emtansine [T-DM1], n=3,983; trastuzumab deruxtecan, n=947), and tyrosine kinase inhibitors (afatinib, n=10,424; lapatinib, n=5,704; neratinib, n=1,507; tucatinib, n=655); additionally, 36,052 patients had ADRs with anti-HER2-based combination regimens. Most patients had breast cancer (monotherapies, n=17,281; combinations, n=24,095). Outcomes included comparison of HF odds with each monotherapy relative to trastuzumab, within each therapeutic class, and among combination regimens.Results: Of 16,900 patients with trastuzumab-associated ADRs, 2,034 (12.04%) had HF reports (median time to onset 5.67months; IQR: 2.85-9.32months) compared with 1% to 2% with antibody-drug conjugates. Trastuzumab had higher odds of HF reporting relative to other anti-HER2 therapies collectively in the overall cohort (reporting OR [ROR]: 17.37; 99% CI: 14.30-21.10) and breast cancer subgroup (ROR: 17.10; 99% CI: 13.12-22.27). Pertuzumab/T-DM1 had 3.4 times higher odds of HF reporting than T-DM1 monotherapy; tucatinib/trastuzumab/capecitabine had similar odds as tucatinib. Among metastatic breast cancer regimens, HF odds were highest with trastuzumab/pertuzumab/docetaxel (ROR: 1.42; 99% CI: 1.17-1.72) and lowest with lapatinib/capecitabine (ROR: 0.09; 99% CI: 0.04-0.23).Conclusions: Trastuzumab and pertuzumab/T-DM1 had higher odds of HF reporting than other anti-HER2 therapies. These data provide large-scale, real-world insight into which HER2-targeted regimens would benefit from left ventricular ejection fraction monitoring.
View details for DOI 10.1016/j.jaccao.2022.09.007
View details for PubMedID 36875913
Use of Machine Learning and Lay Care Coaches to Increase Advance Care Planning Conversations for Patients With Metastatic Cancer.
JCO oncology practice
Patients with metastatic cancer benefit from advance care planning (ACP) conversations. We aimed to improve ACP using a computer model to select high-risk patients, with shorter predicted survival, for conversations with providers and lay care coaches. Outcomes included ACP documentation frequency and end-of-life quality measures.In this study of a quality improvement initiative, providers in four medical oncology clinics received Serious Illness Care Program training. Two clinics (thoracic/genitourinary) participated in an intervention, and two (cutaneous/sarcoma) served as controls. ACP conversations were documented in a centralized form in the electronic medical record. In the intervention, providers and care coaches received weekly e-mails highlighting upcoming clinic patients with < 2 year computer-predicted survival and no prior prognosis documentation. Care coaches contacted these patients for an ACP conversation (excluding prognosis). Providers were asked to discuss and document prognosis.In the four clinics, 4,968 clinic visits by 1,251 patients met inclusion criteria (metastatic cancer with no prognosis previously documented). In their first visit, 28% of patients were high-risk (< 2 year predicted survival). Preintervention, 3% of both intervention and control clinic patients had ACP documentation during a visit. By intervention end (February 2021), 35% of intervention clinic patients had ACP documentation compared with 3% of control clinic patients. Providers' prognosis documentation rate also increased in intervention clinics after the intervention (2%-27% in intervention clinics, P < .0001; 0%-1% in control clinics). End-of-life care intensity was similar in intervention versus control clinics, but patients with ≥ 1 provider ACP edit met fewer high-intensity care measures (P = .04).Combining a computer prognosis model with care coaches increased ACP documentation.
View details for DOI 10.1200/OP.22.00128
View details for PubMedID 36395436
Local Control of Brain Metastases with Osimertinib Alone in Patients with EGFR-Mutant Non-Small Cell Lung Cancer
ELSEVIER SCIENCE INC. 2022: E54-E55
View details for Web of Science ID 000892639300120
Local control of brain metastases with osimertinib alone in patients with EGFR-mutant non-small cell lung cancer.
Journal of neuro-oncology
Although osimertinib has excellent intracranial activity in metastatic non-small cell lung cancer (NSCLC) with exon 19 deletion or L858R EGFR alterations, measures of local control of brain metastases are less well-reported. We describe lesion-level outcomes of brain metastases treated with osimertinib alone.We retrospectively reviewed patients with EGFR-mutant NSCLC with untreated brain metastasis measuring ≥ 5 mm at the time of initiating osimertinib. Cumulative incidence of local recurrence in brain (LRiB) was calculated with death as a competing risk, and univariable and multivariable analyses were conducted to identify factors associated with LRiB.We included 284 brain metastases from 37 patients. Median follow-up was 20.1 months. On initial MRI after starting osimertinib, patient-level response was complete response (CR) in 11 (15%), partial response (PR) in 33 (45%), stable disease (SD) in 18 (25%) and progressive disease (PD) in 11 (15%). The 1-year cumulative incidence of LRiB was 14% (95% CI 9.9-17.9) and was significantly different in patients with a CR (0%), PR (4%), and SD (11%; p = 0.02). Uncontrolled primary tumor (adjusted hazard ratio [aHR] 3.78, 95% CI 1.87-7.66; p < 0.001), increasing number of prior systemic therapies (aHR 2.12, 95% CI 1.49-3.04; p < 0.001), and higher ECOG score (aHR 7.8, 95% CI 1.99-31.81; p = 0.003) were associated with LRiB.Although 1-year cumulative incidence of LRiB is < 4% with a CR or PR, 1-year cumulative incidence of LRiB is over 10% for patients with less than a PR to osimertinib on initial MRI. These patients should be followed closely for need for additional treatment such as stereotactic radiosurgery.
View details for DOI 10.1007/s11060-022-04145-x
View details for PubMedID 36227422
Predictive Model to Guide Brain Magnetic Resonance Imaging Surveillance in Patients With Metastatic Lung Cancer: Impact on Real-World Outcomes.
JCO precision oncology
2022; 6: e2200220
Brain metastasis is common in lung cancer, and treatment of brain metastasis can lead to significant morbidity. Although early detection of brain metastasis may improve outcomes, there are no prediction models to identify high-risk patients for brain magnetic resonance imaging (MRI) surveillance. Our goal is to develop a machine learning-based clinicogenomic prediction model to estimate patient-level brain metastasis risk.A penalized regression competing risk model was developed using 330 patients diagnosed with lung cancer between January 2014 and June 2019 and followed through June 2021 at Stanford HealthCare. The main outcome was time from the diagnosis of distant metastatic disease to the development of brain metastasis, death, or censoring.Among the 330 patients, 84 (25%) developed brain metastasis over 627 person-years, with a 1-year cumulative brain metastasis incidence of 10.2% (95% CI, 6.8 to 13.6). Features selected for model inclusion were histology, cancer stage, age at diagnosis, primary site, and RB1 and ALK alterations. The prediction model yielded high discrimination (area under the curve 0.75). When the cohort was stratified by risk using a 1-year risk threshold of > 14.2% (85th percentile), the high-risk group had increased 1-year cumulative incidence of brain metastasis versus the low-risk group (30.8% v 6.1%, P < .01). Of 48 high-risk patients, 24 developed brain metastasis, and of these, 12 patients had brain metastasis detected more than 7 months after last brain MRI. Patients who missed this 7-month window had larger brain metastases (58% v 33% largest diameter > 10 mm; odds ratio, 2.80, CI, 0.51 to 13) versus those who had MRIs more frequently.The proposed model can identify high-risk patients, who may benefit from more intensive brain MRI surveillance to reduce morbidity of subsequent treatment through early detection.
View details for DOI 10.1200/PO.22.00220
View details for PubMedID 36201713
Simultaneous Cases of Carfilzomib-Induced Thrombotic Microangiopathy in 2 Patients With Multiple Myeloma.
Federal practitioner : for the health care professionals of the VA, DoD, and PHS
2022; 39 (Suppl 3): S56-S62
In patients with multiple myeloma, thrombotic microangiopathy is a rare adverse event associated with proteasome inhibitors, such as bortezomib, carfilzomib, and ixazomib.Two patients with multiple myeloma who presented with carfilzomib-induced thrombotic microangiopathy received eculizumab with subsequent stabilization of renal function.Given the overall rarity of this adverse event, the simultaneous presentation of these 2 cases was unexpected. These cases underscores the need for heightened awareness in clinical practice of thrombotic microangiopathy. The potential role of eculizumab as a therapeutic treatment in the setting of thrombotic microangiopathy requires further investigation.
View details for DOI 10.12788/fp.0284
View details for PubMedID 36426106
View details for PubMedCentralID PMC9662305
- Resistance to EGFR Tyrosine Kinase Inhibitor Therapy in Non-Small-Cell Lung Cancer via Newly Acquired Targetable Oncogenic Driver Alterations With an Emphasis on BRAF: Case Series and Literature Review of Treatment. JCO precision oncology 2022; 6: e2100551
Clinical Activity of Mitogen-Activated Protein Kinase-Targeted Therapies in Patients With Non-V600 BRAF-Mutant Tumors.
JCO precision oncology
2022; 6: e2200107
PURPOSE: Non-V600 mutations comprise approximately 35% of all BRAF mutations in cancer. Many of these mutations have been identified as oncogenic drivers and can be classified into three classes according to molecular characteristics. Consensus treatment strategies for class 2 and 3 BRAF mutations have not yet been established.METHODS: We performed a systematic review and meta-analysis with published reports of individual patients with cancer harboring class 2 or 3 BRAF mutations from 2010 to 2021, to assess treatment outcomes with US Food and Drug Administration-approved mitogen-activated protein kinase (MAPK) pathway targeted therapy (MAPK TT) according to BRAF class, cancer type, and MAPK TT type. Coprimary outcomes were response rate and progression-free survival.RESULTS: A total of 18,167 studies were screened, identifying 80 studies with 238 patients who met inclusion criteria. This included 167 patients with class 2 and 71 patients with class 3 BRAF mutations. Overall, 77 patients achieved a treatment response. In both univariate and multivariable analyses, response rate and progression-free survival were higher among patients with class 2 compared with class 3 mutations, findings that remain when analyses are restricted to patients with melanoma or lung primary cancers. MEK ± BRAF inhibitors demonstrated greater clinical activity in class 2 compared with class 3 BRAF-mutant tumors than BRAF or EGFR inhibitors.CONCLUSION: This meta-analysis suggests that MAPK TTs have clinical activity in some class 2 and 3 BRAF-mutant cancers. BRAF class may dictate responsiveness to current and emerging treatment strategies, particularly in melanoma and lung cancers. Together, this analysis provides clinical validation of predictions made on the basis of a mutation classification system established in the preclinical literature. Further evaluation with prospective clinical trials is needed for this population.
View details for DOI 10.1200/PO.22.00107
View details for PubMedID 35977349
Characterization of ERBB2 (HER2) Alterations in Metastatic Non-small Cell Lung Cancer and Comparison of Outcomes of Different Trastuzumab-based Regimens.
Clinical lung cancer
About 3%-5% of mNSCLC have ERBB2 (HER2) alterations, but currently, there are no FDA-approved targeted therapies for this indication. We compared treatment response between trastuzumab-based and non-targeted regimens in ERBB2-mutant mNSCLC.This retrospective, single-institution study included patients with mNSCLC with ERBB2 alterations identified by next-generation sequencing. Best overall response was determined using Response Evaluation Criteria in Solid Tumors 1.1.We identified 3 groups of patients: ERBB2-mutant/EGFR-wildtype mNSCLC (n = 33), ERBB2-amplified/EGFR-wildtype mNSCLC without concurrent ERBB2 mutations (n = 6), and ERBB2-altered/EGFR-mutant mNSCLC (n = 8). Observed mutations included A775_G776insYVMA (n = 23), Gly778_Pro780dup (n = 4), Ser310Phe (n = 3), and others (n = 5). Among the 33 with ERBB2-mutant/EGFR-wildtype mNSCLC, those with and without A775_G776insYVMA had significantly different median overall survival (OS) of 17.7 and 52.9 months, respectively (Cox regression multivariable HR: 5.03, 95% CI: 1.37-18.51, P = .02). In those with mNSCLC with A775_G776insYVMA, trastuzumab-based therapies were associated with greater OS (20.3 vs. 9.8 months; multivariable HR: 0.19, 95% CI: 0.04-0.87, P = .032). Objective response and disease control rates (median tumor size change) in the 33 patients with ERBB2-mutant/EGFR-wildtype mNSCLC were 40.0% and 80.0% (-35.8%), respectively, for patients treated with trastuzumab deruxtecan; 0% and 30.0% (-5.2%) for trastuzumab emtansine; and 7.1% and 50.0% (-13.0%) for trastuzumab/chemotherapy combinations.In ERBB2-mutant/EGFR-wildtype mNSCLC, while most trastuzumab-based regimens had modest activity in this real-world analysis, trastuzumab deruxtecan had highest response rates and best tumor size reduction. Receipt of any trastuzumab-based regimen was associated with greater OS with A775_G776insYVMA. There remains an unmet need for approved targeted therapies for ERBB2-mutant/EGFR-wildtype NSCLC.
View details for DOI 10.1016/j.cllc.2022.05.015
View details for PubMedID 35753988
Implementation and efficacy of a fellow-led, case-based noon lecture series.
LIPPINCOTT WILLIAMS & WILKINS. 2022
View details for Web of Science ID 000863680300287
Characterization of Metastatic Non-Small Cell Lung Cancer and Oligometastatic Incidence in an Era of Changing Treatment Paradigms.
International journal of radiation oncology, biology, physics
Due to the limitations of current staging systems and evolving definitions, there are limited data on oligometastatic non-small cell lung cancer (NSCLC) epidemiology. The purpose of this study is to evaluate metastatic disease burden and the incidence of oligometastatic disease using recent clinical trial edibility criteria.A cohort of patients with metastatic NSCLC, diagnosed from 2016 to 2019, were randomly sampled from a curated tumor registry. Definitions for oligometastatic disease were obtained from relevant clinical trials. The Stanford Cancer Institute Research Database (SCIRDB) was used to identify baseline patient factors, systemic and local therapy, extent and location of metastatic lesions, and survival outcomes.Among 120 patients presenting with metastatic NSCLC, the majority had de novo metastatic disease (75%) with a median of 4 metastatic lesions involving 3 organ systems. 37.5% would have been eligible for at least one oligometastatic trial with 28.3% meeting criteria for MDACC, 20.0% for NRG-LU002, 6.7% for SINDAS and 16.7% for SABR-COMET. By adding malignant pleural effusions (MPE) and early progression as exclusionary criteria, only 54.1% of patients with ≤3 synchronous metastases were eligible for consideration of local therapy. Early progression on systemic therapy was associated with worse survival (10.0 vs. 42.4 months, p < 0.001), whereas presence of MPE was not. Of those tumors identified as oligometastatic, 44.4% received local therapy and 28.9% underwent ablative therapy to all sites. There was a trend towards greater overall survival (44.4 vs 24.9 months, p=0.055) and progression free survival (8.0 vs. 5.4 months, p=0.06) in patients meeting eligibility for at least one oligometastatic trial.Around 48% of patients with metastatic NSCLC had ≤3 metastases at presentation and 28% met clinical trial criteria for oligometastatic disease. Future research is needed to better define the oligometastatic state and identify patients most likely to benefit from local therapy.
View details for DOI 10.1016/j.ijrobp.2022.04.050
View details for PubMedID 35654305
Novel HIVEP1-ALK fusion in a patient with lung adenocarcinoma demonstrating sensitivity to alectinib: a case report.
Translational lung cancer research
2022; 11 (5): 902-909
Background: Anaplastic lymphoma kinase (ALK) fusion is an important oncogenic driver in non-small cell lung cancer (NSCLC). Reports on the intergenic region (IGR) as an ALK fusion partner are rare. Here, we report the case of a patient with advanced NSCLC harboring a human immunodeficiency virus type I enhancer binding protein 1 (HIVEP1)-ALK fusion that responded effectively to alectinib.Case Description: A 60-year-old non-smoking male was referred with a 3-month history of productive cough secondary to lung adenocarcinoma metastatic to mediastinal lymph nodes, brain, liver, and bone (T2N3M1c, stage IVB). Next-generation sequencing identified an IGR (upstream HIVEP1-) ALK fusion, and immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) results were consistent with an ALK-positive tumor. The patient was subsequently started on alectinib, with no obvious adverse reaction. After 1 month of therapy, the patient achieved significantly remission of the clinical symptoms and had led to an ongoing partial response (PR) lasting >33 months.Conclusions: Our experience highlights the efficacy of alectinib in a patient with HIVEP1-ALK fusion positive NSCLC with multiple metastases including brain disease, and the need for multiple genetic testing methods to verify the oncogenicity of ALK fusions prior to treatment. It could provide useful guidance for the treatment of similar cases in the future.
View details for DOI 10.21037/tlcr-22-288
View details for PubMedID 35693284
- In Response to: "Comparing Addition of Radiotherapy in EGFR- and ALK-Positive NSCLC With Brain Metastases: Are We Evaluating the Optimal Endpoint?" Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 1800; 17 (2): e12-e14
Management of brain metastases in lung cancer: evolving roles for radiation and systemic treatment in the era of targeted and immune therapies.
2021; 3 (Suppl 5): v52-v62
Brain metastases are a common occurrence in both non-small cell and small cell lung cancer with the potential to affect quality of life and prognosis. Due to concerns about the accessibility of the central nervous system by systemic chemotherapy agents, the management of brain metastases has historically relied on local therapies including surgery and radiation. However, novel targeted and immune therapies that improve overall outcomes in lung cancer have demonstrated effective intracranial activity. As a result, the management of brain metastases in lung cancer has evolved, with both local and systemic therapies now playing an important role. Factors such as tumor histology (non-small versus small cell), oncogenic driver mutations, and symptom burden from intracranial disease impact treatment decisions. Here, we review the current management of brain metastases in lung cancer, highlighting the roles of stereotactic radiosurgery and novel systemic therapies as well as the ongoing questions that remain under investigation.
View details for DOI 10.1093/noajnl/vdab106
View details for PubMedID 34859233
Brain Metastases in EGFR- and ALK-positive Non-Small Cell Lung Cancer: Outcomes of CNS Penetrant Tyrosine Kinase Inhibitors (TKIs) Alone versus in Combination with Radiation.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
INTRODUCTION: Management of central nervous system (CNS) metastases in patients with driver-mutated non-small cell lung cancer (NSCLC) has traditionally incorporated both tyrosine kinase inhibitors (TKIs) and intracranial radiation. Whether next-generation, CNS-penetrant TKIs can be used alone without upfront radiation, however, remains unknown. This multi-institutional retrospective analysis aimed to compare outcomes in patients with EGFR- or ALK-positive NSCLC who received CNS-penetrant TKI therapy alone versus in combination with radiation for new or progressing intracranial metastases.METHODS: Data was retrospectively collected from 3 academic institutions. Two treatment groups (CNS-penetrant TKI alone vs TKI+CNS RT) were compared for both EGFR- and ALK-positive cohorts. Outcome variables included time to progression, time to intracranial progression, and time to treatment failure, measured from the date of initiation of CNS-penetrant TKI therapy.RESULTS: A total of 147 patients were included (EGFR n=94, ALK n=52, both n=1). In patients receiving radiation, larger metastases, neurological symptoms, and receipt of steroids were more common. There were no significant differences between TKI vs CNS RT+TKI groups for any of the study outcomes, including time to progression (8.5 vs 6.9 months, p=0.13 [EFGR] and 11.4 vs 13.4 months, p=0.98 [ALK]), time to intracranial progression (14.8 vs 20.5 months, p=0.51 [EGFR] and 18.1 vs 21.8 months, p=0.65 [ALK]), or time to treatment failure (13.8 vs 8.6 months, p=0.26 [EGFR] and 13.5 vs 23.2 months, p=0.95 [ALK]).CONCLUSION: These results provide preliminary evidence that intracranial activity of CNS-penetrant TKIs may enable local radiation to be deferred in appropriately selected patients without negatively impacting progression.
View details for DOI 10.1016/j.jtho.2021.08.009
View details for PubMedID 34455066
Pharmacovigilance analysis of cardiac toxicities associated with targeted therapies for metastatic non-small cell lung carcinoma.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
INTRODUCTION: Targeted therapies have transformed treatment of driver-mutated metastatic non-small cell lung carcinoma (NSCLC). We compared cardiovascular adverse events between and within targeted therapy classes.METHODS: We used WHO pharmacovigilance database VigiBase to compare odds of heart failure, conduction disease, QT prolongation, supraventricular tachycardia (SVT), and ventricular arrhythmias between inhibitors of EGFR (erlotinib, gefitinib, afatinib, osimertinib), BRAF (dabrafenib), MEK (trametinib), and ALK ± ROS1 (alectinib, brigatinib, ceritinib, crizotinib, lorlatinib).RESULTS: Of 98,765 adverse reactions reported with NSCLC targeted therapies, 1,783 (1.8%) were arrhythmias and 1,146 (1.2%) were heart failure. ALK/ROS1 inhibitors were associated with increased odds of conduction disease (reporting odds ratio [ROR] 12.95, 99% CI: 10.14-16.55) and QT prolongation (ROR 5.16, 99% CI: 3.92-6.81) relative to BRAF and EGFR inhibitors. Among ALK/ROS1 inhibitors, crizotinib had highest odds of conduction disease (ROR 1.75, 99% CI: 1.30-2.36) and QT prolongation (ROR 1.91, 99% CI: 1.22-3.00). Dabrafenib (ROR 2.24, 99% CI: 1.86-2.70) and trametinib (ROR 2.44, 99% CI: 2.03-2.92) had higher odds of heart failure than other targeted therapies. Osimertinib was strongly associated with QT prolongation (ROR 6.13, 99% CI: 4.43-8.48), heart failure (ROR 3.64, 99% CI: 2.94-4.50), and SVT (ROR 1.90, 99% CI: 1.26-2.86) relative to other targeted therapies.CONCLUSIONS: ALK/ROS1 inhibitors are associated with higher odds of conduction disease and QT prolongation than other targeted therapies. Osimertinib is strongly associated with QT prolongation, SVT, and heart failure relative to other EGFR inhibitors and targeted therapies. Monitoring for heart failure and arrhythmias should be considered with NSCLC targeted therapies, especially osimertinib.
View details for DOI 10.1016/j.jtho.2021.07.030
View details for PubMedID 34418561
Safety of lorlatinib following alectinib-induced pneumonitis in two patients with ALK-rearranged non-small cell lung cancer: a case series.
Translational lung cancer research
2021; 10 (1): 487–95
Drug-induced interstitial lung disease (DI-ILD) is a rare adverse event associated with targeted therapies that inhibit the anaplastic lymphoma kinase (ALK) protein. Although newer-generation ALK inhibitors such as alectinib significantly improve survival in metastatic ALK-rearranged non-small cell lung cancer (NSCLC), the risk of DI-ILD is similar to that of earlier-generation therapies. Lorlatinib is a third-generation ALK inhibitor that is active in patients with metastatic NSCLC whose tumors have developed secondary resistance to alectinib. While it is associated with low rates of DI-ILD in initial phase 1/2 clinical trials, the safety of lorlatinib in patients with a history of DI-ILD has not been well-described. In this case series, we therefore report two patients with metastatic ALK-rearranged NSCLC who each tolerated lorlatinib following recovery from alectinib-related DI-ILD. Both cases were notable for the acute onset of dyspnea, hypoxia, and diffuse ground-glass opacities within one month of initiating alectinib. With no alternative etiology of pneumonitis identified, both patients were treated empirically for grade 3 DI-ILD with corticosteroids and discontinuation of alectinib. Following rapid clinical recovery and eventual radiographic resolution of opacities, each patient was started on lorlatinib at the time of cancer progression, with neither person developing symptoms or radiographic findings consistent with recurrent DI-ILD. In the following series, we describe these two cases in greater detail and discuss their significance within the context of the prior literature. While further descriptions are needed, our experience suggests that lorlatinib may be a safe therapeutic option in some patients who have recovered from DI-ILD.
View details for DOI 10.21037/tlcr-20-564
View details for PubMedID 33569330
Advances in the Treatment of Stage III Non-Small Cell Lung Cancer.
Clinics in chest medicine
2020; 41 (2): 211–22
Treatment of stage III non-small cell lung cancer (NSCLC) traditionally has involved combinations of chemotherapy, radiation, and surgical resection. Although the multimodality approach remains standard, only a fraction of patients with stage III lung cancer can undergo complete resection, and long-term prognosis remains poor. The PACIFIC trial generated significant enthusiasm when it demonstrated that the programmed death ligand-1 inhibitor, durvalumab, improved survival in patients with unresectable stage III NSCLC after completion of definitive concurrent chemoradiation. This article reviews the indications for traditional therapies in stage III NSCLC and highlights ongoing advances that have led to the incorporation of novel therapeutic agents.
View details for DOI 10.1016/j.ccm.2020.02.008
View details for PubMedID 32402357
- Real-world treatment patterns and survival of patients with BRAF V600-mutated metastatic non-small cell lung cancer LUNG CANCER 2019; 128: 74–90
Natural Disease History, Outcomes, and Co-mutations in a Series of Patients With BRAF-Mutated Non-small-cell Lung Cancer.
Clinical lung cancer
BACKGROUND: BRAF mutations occur in 1% to 4% of non-small-cell lung cancer (NSCLC) cases. Previous retrospective studies have reported similar outcomes for BRAF-mutated NSCLC as compared with wild-type tumors without a known driver mutation or tumors harboring other mutations. However, select cases of prolonged survival have also been described, and thus, the natural history of BRAF-mutated NSCLC remains an area of ongoing study. The aim of this series was to describe the natural history, clinical outcomes, and occurrence of co-mutations in patients with BRAF-mutated NSCLC.PATIENTS AND METHODS: Patients with BRAF-mutated NSCLC seen at Stanford University Medical Center from January 1, 2006 through July 31, 2015 were reviewed. The Kaplan-Meier method was used to calculate median overall survival, and the generalized Wilcoxon test was used to compare median survivals across subgroups of patients.RESULTS: Within a cohort of 18 patients with BRAF-mutated NSCLC, V600E mutations were most common (72%; 13/18). Clinicopathologic features were similar between patients with V600E versus non-V600E mutations, although there was a trend toward more patients with non-V600E mutations being heavy smokers (80% vs. 31%; P= .12). Co-occurring mutations in TP53 were identified most commonly (28%; 5/18). The median overall survival for the entire cohort was 40.1 months, and the median survival from the onset of metastases (n= 16) was 28.1 months. Survival rates at 2 and 5 years from the onset of metastases were 56% and 13%, respectively.CONCLUSION: The clinical behavior of BRAF-mutated NSCLC is variable, but favorable outcomes can be seen in a subset of patients.
View details for PubMedID 30442523
-Mutant Non-Small Cell Lung Cancer: From Molecular Profiling to Rationally Designed Therapy.
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths globally. However, the identification of oncogenic driver alterations involved in the initiation and maintenance of NSCLC, such as epidermal growth factor receptor mutations and anaplastic lymphoma kinase translocation, has led to the development of novel therapies that directly target mutant proteins and associated signaling pathways, resulting in improved clinical outcomes. As sequencing techniques have improved, the molecular heterogeneity of NSCLC has become apparent, leading to the identification of a number of potentially actionable oncogenic driver mutations. Of these, one of the most promising therapeutic targets is B-Raf proto-oncogene, serine/threonine kinase (BRAF). Mutations in BRAF, observed in 2%-4% of NSCLCs, typically lead to constitutive activation of the protein and, as a consequence, lead to activation of the mitogen-activated protein kinase signaling pathway. Direct inhibition of mutant BRAF and/or the downstream mitogen-activated protein kinase kinase (MEK) has led to prolonged survival in patients with BRAF-mutant metastatic melanoma. This comprehensive review will discuss the clinical characteristics and prognostic implications of BRAF-mutant NSCLC, the clinical development of BRAF and MEK inhibitors from melanoma to NSCLC, and practical considerations for clinicians involving BRAF mutation screening and the choice of targeted therapy. The Oncologist 2017;22:1-11 IMPLICATIONS FOR PRACTICE: Personalized medicine has begun to provide substantial benefit to patients with oncogene-driven non-small cell lung cancer (NSCLC). However, treatment options for patients with oncogenic driver mutations lacking targeted treatment strategies remain limited. Direct inhibition of mutant B-Raf proto-oncogene, serine/threonine kinase (BRAF) and/or downstream mitogen-activated protein kinase kinase has the potential to change the course of the disease for patients with BRAF-mutant NSCLC, as it has in BRAF-mutant melanoma. Optimization of screening strategies for rare mutations and the choice of appropriate agents on an individual basis will be key to providing timely and successful intervention.
View details for DOI 10.1634/theoncologist.2016-0458
View details for PubMedID 28487464
- Adding to the targeted therapy toolbox: BRAF and MEK inhibition in the treatment of BRAF V600E metastatic non-small cell lung cancer TRANSLATIONAL CANCER RESEARCH 2016; 5: S1233-S1240
- Long-Term Survival of a Patient With Non-Small-Cell Lung Cancer Harboring a V600E Mutation in the BRAF Oncogene. Clinical lung cancer 2016; 17 (2): e17-21
Variations in the neurobiology of reading in children and adolescents born full term and preterm
2016; 11: 555-565
Diffusion properties of white matter tracts have been associated with individual differences in reading. Individuals born preterm are at risk of injury to white matter. In this study we compared the associations between diffusion properties of white matter and reading skills in children and adolescents born full term and preterm. 45 participants, aged 9-17 years, included 26 preterms (born < 36 weeks' gestation) and 19 full-terms. Tract fractional anisotropy (FA) profiles were generated for five bilateral white matter tracts previously associated with reading: anterior superior longitudinal fasciculus (aSLF), arcuate fasciculus (Arc), corticospinal tract (CST), uncinate fasciculus (UF) and inferior longitudinal fasciculus (ILF). Mean scores on reading for the two groups were in the normal range and were not statistically different. In both groups, FA was associated with measures of single word reading and comprehension in the aSLF, AF, CST, and UF. However, correlations were negative in the full term group and positive in the preterm group. These results demonstrate variations in the neurobiology of reading in children born full term and preterm despite comparable reading skills. Findings suggest that efficient information exchange required for strong reading abilities may be accomplished via a different balance of neurobiological mechanisms in different groups of readers.
View details for DOI 10.1016/j.nicl.2016.04.003
View details for PubMedID 27158588
Developmental Changes within White Matter Tracts of Healthy Children Age 9 to 16 Years Old
LIPPINCOTT WILLIAMS & WILKINS. 2013: S5
View details for Web of Science ID 000330358800018
- Case series: fractional anisotropy along the trajectory of selected white matter tracts in adolescents born preterm with ventricular dilation. Journal of child neurology 2013; 28 (6): 771-777
Tract Profiles of White Matter Properties: Automating Fiber-Tract Quantification
2012; 7 (11)
Tractography based on diffusion weighted imaging (DWI) data is a method for identifying the major white matter fascicles (tracts) in the living human brain. The health of these tracts is an important factor underlying many cognitive and neurological disorders. In vivo, tissue properties may vary systematically along each tract for several reasons: different populations of axons enter and exit the tract, and disease can strike at local positions within the tract. Hence quantifying and understanding diffusion measures along each fiber tract (Tract Profile) may reveal new insights into white matter development, function, and disease that are not obvious from mean measures of that tract. We demonstrate several novel findings related to Tract Profiles in the brains of typically developing children and children at risk for white matter injury secondary to preterm birth. First, fractional anisotropy (FA) values vary substantially within a tract but the Tract FA Profile is consistent across subjects. Thus, Tract Profiles contain far more information than mean diffusion measures. Second, developmental changes in FA occur at specific positions within the Tract Profile, rather than along the entire tract. Third, Tract Profiles can be used to compare white matter properties of individual patients to standardized Tract Profiles of a healthy population to elucidate unique features of that patient's clinical condition. Fourth, Tract Profiles can be used to evaluate the association between white matter properties and behavioral outcomes. Specifically, in the preterm group reading ability is positively correlated with FA measured at specific locations on the left arcuate and left superior longitudinal fasciculus and the magnitude of the correlation varies significantly along the Tract Profiles. We introduce open source software for automated fiber-tract quantification (AFQ) that measures Tract Profiles of MRI parameters for 18 white matter tracts. With further validation, AFQ Tract Profiles have potential for informing clinical management and decision-making.
View details for DOI 10.1371/journal.pone.0049790
View details for PubMedID 23166771
G328E and G409E sialin missense mutations similarly impair transport activity, but differentially affect trafficking
MOLECULAR GENETICS AND METABOLISM
2007; 92 (4): 371-374
Two disease-associated missense mutations in the sialin gene (G328E and G409E) have recently been identified in patients with lysosomal free sialic acid storage disease. We have assessed the effect of these mutations and find complete loss of measurable transport activity with both and impaired trafficking of the G409E protein. These results suggest that the two residues are important for proper function of sialin and confirm the association of loss of transport with disease causative mutations.
View details for DOI 10.1016/j.ymgme.2007.08.121
View details for Web of Science ID 000252054000012
View details for PubMedID 17933575
View details for PubMedCentralID PMC2171360