Joel Neal, MD, PhD

All Publications

• Efficacy and safety of sintilimab in combination with chemotherapy for recurrent extensive-stage small cell lung cancer: a real-world retrospective study. Journal of thoracic disease Wang, J., Liang, S., Xu, L., Kong, Y., Seki, N., Ganti, A. K., Neal, J. W., Li, J., Xu, F., Li, K., Xu, Y., Wu, L., Chen, B. 2024; 16 (6): 3897-3908

  Abstract

  Background: Immune checkpoint inhibitors (ICIs) no longer are approved for second-line or later treatment of extensive-stage small cell lung cancer (ES-SCLC), and have not been studied in combination with chemotherapy. Exploring the efficacy and safety of second-line or later immunotherapy for ES-SCLC is an urgent clinical question that needs to be addressed, and combination therapies are an important research direction. This study intended to investigate the efficacy and safety of the sintilimab in combination with chemotherapy as a second-line and beyond treatment option for ES-SCLC.Methods: Medical records of patients who received treatment with sintilimab in combination with chemotherapy or chemotherapy alone as a second-line or beyond therapy were retrospectively analyzed. The study evaluated efficacy and safety. Indicators of efficacy included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Safety indicators included adverse events (AEs).Results: This cohort comprised of 46 patients: 24 in the sintilimab combination chemotherapy group and 22 in the chemotherapy group. Chemotherapy received by both groups was either albumin-bound paclitaxel or irinotecan. Compared with the chemotherapy group, the sintilimab combination chemotherapy group had higher ORR and DCR (ORR: 37.5% vs. 9.1%, P=0.04; DCR: 75.0% vs. 40.9%, P=0.04), and significantly prolonged PFS and OS [median PFS (mPFS): 5.07 vs. 2.45 months, P=0.006; median OS (mOS): 14.43 vs. 10.34 months, P=0.009]. Also, there was no significant increase in the incidence of AEs in the sintilimab combination chemotherapy group, which was well tolerated by patients.Conclusions: Sintilimab in combination with chemotherapy is superior to single-agent chemotherapeutic treatment as second-line or later therapy in ES-SCLC patients who have not received prior immunotherapy. These results need to be confirmed in future clinical trials.

  View details for DOI 10.21037/jtd-24-769

  View details for PubMedID 38983156

• Molecular Characteristics and Pretreatment Neutrophil-to-Lymphocyte Ratio as Predictors of Durable Clinical Benefit from Immune Checkpoint Inhibition in Non-Small Cell Lung Cancer. Clinical lung cancer Shah, A. T., Blanchard, I., Padda, S. K., Wakelee, H. A., Neal, J. W. 2024

  Abstract

  Prior research in non-small cell lung cancer (NSCLC) has shown that tumors with specific driver mutations may be less likely to respond to immune checkpoint inhibitors (ICI). In this analysis, we evaluated the characteristics of patients with durable clinical benefit (DCB) to ICI compared to those with no durable clinical benefit (NDB), with emphasis on the role of molecular alterations in EGFR, ALK, and ROS1 and pretreatment neutrophil-to-lymphocyte ratio (NLR).We retrospectively collected clinical characteristics and outcomes for patients who initiated ICI monotherapy for advanced NSCLC at Stanford University between April 2015 and May 2018. Patients were classified as having DCB if time on ICI therapy was greater than or equal to 180 days, or NDB if less than 180 days. Outcomes included best radiographic benefit while on ICI and survival from time of ICI initiation.Of 123 patients treated with ICI for NSCLC, 28 patients had DCB (23%), while 95 had NDB (77%). Median overall survival from initiation of ICI in the 33 patients with molecular alterations in EGFR (n = 31), ALK, or ROS1 and NLR of 5.9 or higher was 2.0 months, compared to 8.1 months in patients with these genomic alterations and NLR less than 5.9. Median overall survival in patients without alterations in EGFR, ALK, or ROS1 and NLR of 5.9 or higher was 4.3 months, compared to 12.1 months in patients with NLR less than 5.9 (P = .023).Elevation in pretreatment NLR was associated with significantly lower overall median survival from initiation of ICI, particularly when in combination with NSCLC with alterations in EGFR, ALK, or ROS1. This finding could influence clinical practice as NLR is readily available through routine blood testing.

  View details for DOI 10.1016/j.cllc.2024.06.006

  View details for PubMedID 38987048

• A process to reanalyze clinical DNA sequencing data for biomarker matching in the Lung-MAP Master Protocol. The oncologist Neal, J. W., Minichiello, K., Brennick, R., Huang, R. S., Hiemenz, M. C., Amler, C., Patel, J., Herbst, R., Reckamp, K. L., Borghaei, H., Highleyman, L., Redman, M. W., Pasquina, L. W., Kozono, D. E. 2024

  Abstract

  For cancer clinical trials that require central confirmation of tumor genomic profiling, exhaustion of tissue from standard-of-care testing may prevent enrollment. For Lung-MAP, a master protocol that requires results from a defined centralized clinical trial assay to assign patients to a therapeutic substudy, we developed a process to repurpose existing commercial vendor raw genomic data for eligibility: genomic data reanalysis (GDR). Molecular results for substudy assignment were successfully generated for 369 of the first 374 patients (98.7%) using GDR for Lung-MAP, with a median time from request to result of 9 days. During the same period, 691 of 791 (87.4%) tissue samples received successfully yielded results, in a median of 14 days beyond sample acquisition. GDR is a scalable bioinformatic pipeline that expedites reanalysis of existing data for clinical trials in which validated integral biomarker testing is required for participation.

  View details for DOI 10.1093/oncolo/oyae062

  View details for PubMedID 38597608

• CONTACT-01: A Randomized Phase III Trial of Atezolizumab + Cabozantinib Versus Docetaxel for Metastatic Non-Small Cell Lung Cancer After a Checkpoint Inhibitor and Chemotherapy. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Neal, J., Pavlakis, N., Kim, S. W., Goto, Y., Lim, S. M., Mountzios, G., Fountzilas, E., Mochalova, A., Christoph, D. C., Bearz, A., Quantin, X., Palmero, R., Antic, V., Chun, E., Edubilli, T. R., Lin, Y. C., Huseni, M., Ballinger, M., Graupner, V., Curran, D., Vervaet, P., Newsom-Davis, T. 2024: JCO2302166

  Abstract

  Although checkpoint inhibitors have improved first-line treatment for non-small cell lung cancer (NSCLC), a therapeutic need remains for patients whose disease does not respond or who experience disease progression after anti-PD-L1/PD-1 immunotherapy. CONTACT-01 (ClinicalTrials.gov identifier: NCT04471428) evaluated atezolizumab plus cabozantinib versus docetaxel in patients with metastatic NSCLC who developed disease progression after concurrent or sequential treatment with anti-PD-L1/PD-1 and platinum-containing chemotherapy.This multicenter, open-label, phase III trial randomly assigned patients 1:1 to atezolizumab 1,200 mg intravenously once every 3 weeks (q3w) plus cabozantinib 40 mg orally once daily or docetaxel 75 mg/m2 intravenously once every 3 weeks. The primary end point was overall survival (OS).One hundred eighty-six patients were assigned atezolizumab plus cabozantinib, and 180 docetaxel. Minimum OS follow-up was 10.9 months. Median OS was 10.7 months (95% CI, 8.8 to 12.3) with atezolizumab plus cabozantinib and 10.5 months (95% CI, 8.6 to 13.0) with docetaxel (stratified hazard ratio [HR], 0.88 [95% CI, 0.68 to 1.16]; P = .3668). Median progression-free survival was 4.6 months (95% CI, 4.1 to 5.6) and 4.0 months (95% CI, 3.1 to 4.4), respectively (stratified HR, 0.74 [95% CI, 0.59 to 0.92]). Serious adverse events (AEs) occurred in 71 (38.4%) patients receiving atezolizumab plus cabozantinib and 58 (34.7%) receiving docetaxel. Grade 3/4 treatment-related AEs occurred in 73 (39.5%) patients receiving atezolizumab plus cabozantinib and 58 (34.7%) receiving docetaxel. Grade 5 AEs occurred in 14 (7.6%) and 10 (6.0%) patients in the atezolizumab plus cabozantinib and docetaxel arms, respectively (treatment-related in four [2.2%] and one [0.6%], respectively).Atezolizumab plus cabozantinib after disease progression following anti-PD-L1/PD-1 immunotherapy and platinum-containing chemotherapy for metastatic NSCLC did not improve OS compared with docetaxel. Safety was consistent with known profiles of these agents.

  View details for DOI 10.1200/JCO.23.02166

  View details for PubMedID 38552197

• Systematic analysis of off-label and off-guideline cancer therapy usage in a real-world cohort of 165,912US patients. Cell reports. Medicine Liu, R., Wang, L., Rizzo, S., Garmhausen, M. R., Pal, N., Waliany, S., McGough, S., Lin, Y. G., Huang, Z., Neal, J., Copping, R., Zou, J. 2024: 101444

  Abstract

  Patients with cancer may be given treatments that are not officially approved (off-label) or recommended by guidelines (off-guideline). Here we present a data science framework to systematically characterize off-label and off-guideline usages using real-world data from de-identified electronic health records (EHR). We analyze treatment patterns in 165,912US patients with 14 common cancer types. We find that 18.6% and 4.4% of patients have received at least one line of off-label and off-guideline cancer drugs, respectively. Patients with worse performance status, in later lines, or treated at academic hospitals are significantly more likely to receive off-label and off-guideline drugs. To quantify how predictable off-guideline usage is, we developed machine learning models to predict which drug a patient is likely to receive based on their clinical characteristics and previous treatments. Finally, we demonstrate that our systematic analyses generate hypotheses about patients' response to treatments.

  View details for DOI 10.1016/j.xcrm.2024.101444

  View details for PubMedID 38428426

• Consolidation Osimertinib versus Durvalumab versus Observation following Concurrent Chemoradiation in Unresectable EGFR-Mutant Non-Small-Cell Lung Cancer: A Multicenter Retrospective Cohort Study. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Nassar, A. H., Kim, S. Y., Aredo, J. V., Feng, J., Shepherd, F., Xu, C., Kaldas, D., Gray, J. E., Dilling, T. J., Neal, J. W., Wakelee, H. A., Liu, Y., Lin, S. H., Abuali, T., Amini, A., Nie, Y., Patil, T., Lobachov, A., Bar, J., Fitzgerald, B., Fujiwara, Y., Marron, T. U., Thummalapalli, R., Yu, H., Owen, D. H., Sharp, J., Farid, S., Rocha, P., Arriola, E., D'Aiello, A., Cheng, H., Whitaker, R., Parikh, K., Ashara, Y., Chen, L., Sankar, K., Harris, J. P., Nagasaka, M., Ayanambakkam, A., Manana, A. I., Ragavan, M., Lin, J. J., Piotrowska, Z., Wilgucki, M., Reuss, J., Luders, H., Grohe, C., Espinar, J. B., Feiner, E., Punekar, S. R., Gupta, S., Leal, T., Kwiatkowski, D. J., Mak, R. H., Adib, E., Naqash, A. R., Goldberg, S. B. 2024

  Abstract

  Durvalumab improves survival when used as consolidation therapy after chemoradiation (CRT) in patients with stage III NSCLC. However, the optimal consolidation therapy for patients with EGFR-mutant (EGFRmut) stage III NSCLC remains unknown.In this multi-institutional international retrospective analysis across 24 institutions, we evaluated outcomes in patients with stage III EGFRmut NSCLC treated with concurrent CRT followed by consolidation therapy with osimertinib, durvalumab, or observation between 2015 and 2022. Kaplan-Meier method was used to estimate real-world progression-free survival (rwPFS, primary endpoint) and overall survival (OS, secondary endpoint). Treatment-related adverse events (trAE) during consolidation treatment were defined using Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Multivariable Cox regression analysis was used.Of 136 patients with stage III EGFRmut NSCLC treated with definitive concurrent CRT, 56 received consolidation durvalumab, 33 received consolidation osimertinib, and 47 received observation alone. Baseline characteristics were similar across the 3 cohorts. With a median follow-up of 46 months for the entire cohort, the median duration of treatment was not reached (NR) for osimertinib (Inter-quartile range [IQR]: NR-NR) and was 5.5 (IQR:2.4-10.8) months with durvalumab. After adjusting for nodal status, stage III A/B/C, and age, patients treated with consolidation osimertinib had significantly longer 24-month rwPFS compared to those in the durvalumab or observation cohorts (osimertinib: 86%, durvalumab: 30%, observation: 27%, p<0.001 for both comparisons). There was no difference in rwPFS between durvalumab and the observation cohort. No significant difference in OS across the 3 cohorts was detected, possibly due to the limited follow-up. Any grade trAE occurred in 52% (2 [6.1%] grade ≥3) and 48% (10 [18%] grade ≥3) of patients treated with osimertinib and durvalumab, respectively. Of 45 patients who progressed on consolidation durvalumab, 37 (82%) subsequently received EGFR tyrosine kinase inhibitors (TKIs). Of these, 14 (38%) patients developed trAEs including 5 pneumonitis (14%; 2 [5.4%] grade ≥3) and 5 diarrhea (14%; 1 [2.7%] grade ≥3).This study suggests that among patients with stage III unresectable NSCLC with a sensitizing EGFR mutation, consolidation osimertinib was associated with significantly longer rwPFS than durvalumab or observation. No unanticipated safety signals were observed with consolidation osimertinib.

  View details for DOI 10.1016/j.jtho.2024.01.012

  View details for PubMedID 38278303

• HER2-Mutant Advanced and/or Metastatic Non-Small-Cell Lung Cancer: A US Electronic Health Records Database Analysis of Clinical Characteristics, Treatment Practice Patterns, and Outcomes. Clinical lung cancer Waliany, S., Neal, J. W., Engel-Nitz, N., Lam, C., Lin, F., Park, L., Le, L., Nagasaka, M. 2024

  Abstract

  Real-world data for advanced/metastatic non-small-cell lung cancer (NSCLC) with mutations in human epidermal growth factor 2 (HER2) are scarce. We aimed to assess treatment patterns and outcomes among patients with HER2-mutant advanced/metastatic NSCLC.This retrospective nationwide electronic health record study evaluated patient characteristics, treatment patterns, treatment duration, and overall survival for adults with HER2-mutant advanced/metastatic NSCLC without epidermal growth factor receptor mutation.Of 55 included patients, median (quartile 1 [Q1]-quartile 3 [Q3]) age was 63.0 (58.0-72.0) years, 42 (76%) were women, and 39 (71%) were current/former smokers. In first-line therapy, 14 regimens were used for median (Q1-Q3) duration of 3.1 (2.4-6.2) months, with most patients (n = 39, 71%) receiving platinum-based chemotherapy alone or in combination with other agents. Median (95% CI) overall survival from first-line treatment initiation was 19.0 (12.2-not estimable) months, with no significant association with age, sex, or smoking status. Thirty-five (64%) patients received second-line therapy for median (Q1-Q3) duration of 3.3 (2.0-5.2) months. Fourteen second-line regimens were used; most commonly immunotherapy alone or in combination with other agents (n = 16, 46%). Sixteen (46%) patients received third-line therapy for median (Q1-Q3) duration of 1.9 (1.3-2.7) months. Nine third-line regimens were used, with 7 (44%) patients receiving HER2-directed agents.First- and second-line treatments for HER2-mutant NSCLC varied widely and treatment duration was short. The approval of trastuzumab deruxtecan for NSCLC supports wider HER2 testing to identify eligible patients for HER2-directed therapy.

  View details for DOI 10.1016/j.cllc.2024.01.002

  View details for PubMedID 38403548

• Immunotherapy-Associated Atherosclerosis: A Comprehensive Review of Recent Findings and Implications for Future Research. Current treatment options in cardiovascular medicine Chan, A., Torelli, S., Cheng, E., Batchelder, R., Waliany, S., Neal, J., Witteles, R., Nguyen, P., Cheng, P., Zhu, H. 2023; 25 (12): 715-735

  Abstract

  Even as immune checkpoint inhibitors (ICIs) have transformed the lifespan of many patients, they may also trigger acceleration of long-term cardiovascular disease. Our review aims to examine the current landscape of research on ICI-mediated atherosclerosis and address key questions regarding its pathogenesis and impact on patient management.Preclinical mouse models suggest that T cell dysregulation and proatherogenic cytokine production are key contributors to plaque development after checkpoint inhibition. Clinical data also highlight the significant burden of atherosclerotic cardiovascular disease (ASCVD) in patients on immunotherapy, although the value of proactively preventing and treating ASCVD in this population remains an open area of inquiry. Current treatment options include dietary/lifestyle modification and traditional medications to manage hypertension, hyperlipidemia, and diabetes risk factors; no current targeted therapies exist.Early identification of high-risk patients is crucial for effective preventive strategies and timely intervention. Future research should focus on refining screening tools, elucidating targetable mechanisms driving ICI atherosclerosis, and evaluating long-term cardiovascular outcomes in cancer survivors who received immunotherapy. Moreover, close collaboration between oncologists and cardiologists is essential to optimize patient outcomes.

  View details for DOI 10.1007/s11936-023-01024-0

  View details for PubMedID 38213548

  View details for PubMedCentralID PMC10776491

• Phenotyping EMT and MET cellular states in lung cancer patient liquid biopsies at a personalized level using mass cytometry. Scientific reports Karacosta, L. G., Pancirer, D., Preiss, J. S., Benson, J. A., Trope, W., Shrager, J. B., Sung, A. W., Neal, J. W., Bendall, S. C., Wakelee, H., Plevritis, S. K. 2023; 13 (1): 21781

  Abstract

  Malignant pleural effusions (MPEs) can be utilized as liquid biopsy for phenotyping malignant cells and for precision immunotherapy, yet MPEs are inadequately studied at the single-cell proteomic level. Here we leverage mass cytometry to interrogate immune and epithelial cellular profiles of primary tumors and pleural effusions (PEs) from early and late-stage non-small cell lung cancer (NSCLC) patients, with the goal of assessing epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) states in patient specimens. By using the EMT-MET reference map PHENOSTAMP, we observe a variety of EMT states in cytokeratin positive (CK+) cells, and report for the first time MET-enriched CK+ cells in MPEs. We show that these states may be relevant to disease stage and therapy response. Furthermore, we found that the fraction of CD33+ myeloid cells in PEs was positively correlated to the fraction of CK+ cells. Longitudinal analysis of MPEs drawn 2 months apart from a patient undergoing therapy, revealed that CK+ cells acquired heterogeneous EMT features during treatment. We present this work as a feasibility study that justifies deeper characterization of EMT and MET states in malignant cells found in PEs as a promising clinical platform to better evaluate disease progression and treatment response at a personalized level.

  View details for DOI 10.1038/s41598-023-46458-5

  View details for PubMedID 38065965

  View details for PubMedCentralID 2689101

• Efficacy of Mobocertinib and Amivantamab in Patients With Advanced Non-Small Cell Lung Cancer With EGFR Exon 20 Insertions Previously Treated With Platinum-Based Chemotherapy: An Indirect Treatment Comparison. Clinical lung cancer Ou, S. I., Prawitz, T., Lin, H. M., Hong, J. L., Tan, M., Proskorovsky, I., Hernandez, L., Jin, S., Zhang, P., Lin, J., Patel, J., Nguyen, D., Neal, J. W. 2023

  Abstract

  Exon 20 insertions (ex20ins) mutations of the EGFR gene account for 1% to 2% of all non-small-cell lung cancers (NSCLCs). Targeted therapies have been developed to treat this cancer type but have not been studied in head-to-head trials. Our objective was to use a matching-adjusted indirect comparison (MAIC) to assess the efficacy of mobocertinib and amivantamab in patients with NSCLC EGFR ex20ins mutations who were previously treated with platinum-based chemotherapy.An unanchored MAIC was conducted to estimate the treatment effects of mobocertinib and amivantamab using individual-level data from the mobocertinib phase I/II single-arm trial (NCT02716116) and published data from the amivantamab single-arm CHRYSALIS trial (NCT02609776). Confirmed overall response rate (cORR), progression-free survival (PFS), overall survival (OS), and duration of response (DoR) were assessed.Both trials were comparable in terms of study population, study design, and outcome definitions and included 114 patients who received mobocertinib and 114 patients who received amivantamab. After MAIC weighting, all reported baseline characteristics were balanced between mobocertinib and amivantamab. The weighted odds ratio (OR) [95% confidence interval (CI)] comparing mobocertinib to amivantamab was 0.56 (0.30-1.04) for independent review committee (IRC)-assessed cORR and 0.98 (0.53-1.82) for investigator (INV)-assessed cORR. The weighted hazard ratio (HR) comparing mobocertinib to amivantamab was 0.74 (0.51-1.07) for IRC-assessed PFS, 0.92 (0.57-1.48) for OS, and 0.59 (0.30-1.18) for INV-assessed DoR.MAIC analysis showed that mobocertinib and amivantamab had similar efficacy in patients with NSCLC harboring EGFR ex20ins mutations whose disease progressed during or after platinum-based chemotherapy. These findings may benefit patients by supporting future treatment options.

  View details for DOI 10.1016/j.cllc.2023.11.011

  View details for PubMedID 38114357

• Osimertinib-Associated Cardiomyopathy In Patients With Non-Small Cell Lung Cancer: A Case Series JACC: CardioOncology Franquiz, M., Waliany, S., Xu, A., Hnatiuk, A., Wu, S., Cheng, P., Wakelee, H., Neal, J., Witteles, R., Zhu, H. 2023: 839-841

  View details for DOI 10.1016/j.jaccao.2023.07.006

  View details for PubMedCentralID PMC10774774

• Patient Selection and Outcomes for Hypofractionated Accelerated Radiation and Concurrent Chemotherapy for Non-Small-Cell Lung Cancer. Clinical lung cancer Hui, C., Marquez, C., Lau, B., Das, M., Myall, N. J., Roy, M., Wakelee, H. A., Neal, J. W., Kovalchuk, N., Chin, A., Diehn, M., Loo, B. W., Xiang, M., Vitzthum, L. K. 2023

  Abstract

  Adoption of hypofractionated accelerated radiation therapy (HART) with concurrent chemotherapy has been limited by toxicity concerns. We aimed to describe outcomes of patients treated with HART and concurrent chemotherapy and to evaluate dosimetry to organs at risk to guide patient selection.We evaluated a retrospective cohort of NSCLC patients treated with concurrent chemotherapy with HART (>2.2 Gy per fraction) or standard fractionated radiation therapy (SFRT; 2-2.2 Gy fractions). Dosimetric parameters to key organs at risk were compared, and toxicity, patterns of recurrence and survival were calculated for the cohorts.Fifty-three patients treated with HART were compared with 100 patients treated with SFRT. Median dose per fraction for the HART cohort was 2.75 Gy (range 2.4-3 Gy). HART patients had significantly lower doses to the lung, heart, and esophagus due to patient selection. The HART group and had rates of grade 2+ pneumonitis (9.4 vs. 19%, P = .16) and grade 2+ esophagitis (20.8 vs. 45%, P < .01) that compared favorably to SFRT. Cumulative incidence of in-field recurrence trended lower in the HART cohort (7.6% vs. 23.1%, P = .058). Among the HART group, 88.7% (47/53) met the newly proposed lung constraints based on the degree of hypofractionation CONCLUSION: In select patients with favorable dosimetry to organs at risk, definitive HART with concurrent chemotherapy achieved excellent local control with low toxicity. These results are being used to inform a prospective study on the safety and efficacy of HART with concurrent chemotherapy for select NSCLC patients.

  View details for DOI 10.1016/j.cllc.2023.11.008

  View details for PubMedID 38065707

• Personalized Accelerated ChEmoRadiation (PACER) for Lung Cancer: Protocol for a Bayesian Optimal Phase I/II Trial. Clinical lung cancer Hui, C., Brown, E., Wong, S., Das, M., Wakelee, H., Neal, J., Ramchandran, K., Myall, N. J., Pham, D., Xing, L., Yang, Y., Kovalchuk, N., Yuan, Y., Lu, Y., Xiang, M., Chin, A., Diehn, M., Loo, B. W., Vitzthum, L. K. 2023

  Abstract

  Prior attempts to escalate radiation dose for non-small cell lung cancer (NSCLC) have not improved survival. Given the high risk for cardiopulmonary toxicity with treatment and heterogenous presentation of locally advanced NSCLC, it is unlikely that a single dose regimen is optimal for all patients. This phase I/II trial aims to evaluate a novel treatment approach where the level of accelerated hypofractionation is determined by the predicted toxicity from dose to organs at risk (OARs).Patients ≥ 18 years old with lung cancer planned for fractionated radiotherapy to the lung with concurrent chemotherapy will be eligible. Radiation therapy (RT) will be delivered to a total dose of 60 to 66 Gy in 30, 25, or 20 fractions depending on the ability to meet constraints to key organs at risk including the lungs, heart, and esophagus. The primary endpoint is high grade pulmonary, esophageal, or cardiac toxicity. A Bayesian optimized design is used to determine stopping boundaries and evaluate the primary endpoint.PACER will evaluate the safety and feasibility of personalized accelerated chemoradiotherapy for lung cancer.

  View details for DOI 10.1016/j.cllc.2023.11.004

  View details for PubMedID 38040540

• Demographic and Genomic Characteristics of Non-Small Cell Lung Cancer Patients with ARID1A Alterations Al-Obeidi, E., Williams, A., Burkert, N., Pepin, K., Hicks, J. K., Gray, J. E., Stewart, S., Weipert, C., Waqar, S., Spigel, D., Salgia, R., Massarelli, E., Baik, C. S., Neal, J. W., Ramchandran, K., Xia, B., Carpenter, E. L., Aggarwal, C., Riess, J. W., Gandara, D. ELSEVIER SCIENCE INC. 2023: S489

  View details for Web of Science ID 001098831601328

• Molecular Distribution of Patients with Non-Small Cell Lung Cancer Eligible for Lung Cancer Screening Aredo, J. V., Neal, J. W., Kunder, C. A., Ramchandran, K. J., Das, M. S., Myall, N. J., Han, S. S., Wakelee, H. A. ELSEVIER SCIENCE INC. 2023: S102-S103

  View details for Web of Science ID 001098831600116

• Second Primary Lung Cancer Among Lung Cancer Survivors Who Never Smoked. JAMA network open Choi, E., Su, C. C., Wu, J. T., Aredo, J. V., Neal, J. W., Leung, A. N., Backhus, L. M., Lui, N. S., Le Marchand, L., Stram, D. O., Liang, S. Y., Cheng, I., Wakelee, H. A., Han, S. S. 2023; 6 (11): e2343278

  Abstract

  Lung cancer among never-smokers accounts for 25% of all lung cancers in the US; recent therapeutic advances have improved survival among patients with initial primary lung cancer (IPLC), who are now at high risk of developing second primary lung cancer (SPLC). As smoking rates continue to decline in the US, it is critical to examine more closely the epidemiology of lung cancer among patients who never smoked, including their risk for SPLC.To estimate and compare the cumulative SPLC incidence among lung cancer survivors who have never smoked vs those who have ever smoked.This population-based prospective cohort study used data from the Multiethnic Cohort Study (MEC), which enrolled participants between April 18, 1993, and December 31, 1996, with follow-up through July 1, 2017. Eligible individuals for this study were aged 45 to 75 years and had complete smoking data at baseline. These participants were followed up for IPLC and further SPLC development through the Surveillance, Epidemiology, and End Results registry. The data were analyzed from July 1, 2022, to January 31, 2023.Never-smoking vs ever-smoking exposure at MEC enrollment.The study had 2 primary outcomes: (1) 10-year cumulative incidence of IPLC in the entire study cohort and 10-year cumulative incidence of SPLC among patients with IPLC and (2) standardized incidence ratio (SIR) (calculated as the SPLC incidence divided by the IPLC incidence) by smoking history.Among 211 414 MEC participants, 7161 (3.96%) developed IPLC over 4 038 007 person-years, and 163 (2.28%) developed SPLC over 16 470 person-years. Of the participants with IPLC, the mean (SD) age at cohort enrollment was 63.6 (7.7) years, 4031 (56.3%) were male, and 3131 (43.7%) were female. The 10-year cumulative IPLC incidence was 2.40% (95% CI, 2.31%-2.49%) among ever-smokers, which was 7 times higher than never-smokers (0.34%; 95% CI, 0.30%-0.37%). However, the 10-year cumulative SPLC incidence following IPLC was as high among never-smokers (2.84%; 95% CI, 1.50%-4.18%) as ever-smokers (2.72%; 95% CI, 2.24%-3.20%), which led to a substantially higher SIR for never-smokers (14.50; 95% CI, 8.73-22.65) vs ever-smokers (3.50; 95% CI, 2.95-4.12).The findings indicate that SPLC risk among lung cancer survivors who never smoked is as high as among those with IPLC who ever-smoked, highlighting the need to identify risk factors for SPLC among patients who never smoked and to develop a targeted surveillance strategy.

  View details for DOI 10.1001/jamanetworkopen.2023.43278

  View details for PubMedID 37966839

• Risk Model-Based Lung Cancer Screening and Racial and Ethnic Disparities in the US. JAMA oncology Choi, E., Ding, V. Y., Luo, S. J., Ten Haaf, K., Wu, J. T., Aredo, J. V., Wilkens, L. R., Freedman, N. D., Backhus, L. M., Leung, A. N., Meza, R., Lui, N. S., Haiman, C. A., Park, S. L., Le Marchand, L., Neal, J. W., Cheng, I., Wakelee, H. A., Tammemägi, M. C., Han, S. S. 2023

  Abstract

  The revised 2021 US Preventive Services Task Force (USPSTF) guidelines for lung cancer screening have been shown to reduce disparities in screening eligibility and performance between African American and White individuals vs the 2013 guidelines. However, potential disparities across other racial and ethnic groups in the US remain unknown. Risk model-based screening may reduce racial and ethnic disparities and improve screening performance, but neither validation of key risk prediction models nor their screening performance has been examined by race and ethnicity.To validate and recalibrate the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial 2012 (PLCOm2012) model-a well-established risk prediction model based on a predominantly White population-across races and ethnicities in the US and evaluate racial and ethnic disparities and screening performance through risk-based screening using PLCOm2012 vs the USPSTF 2021 criteria.In a population-based cohort design, the Multiethnic Cohort Study enrolled participants in 1993-1996, followed up through December 31, 2018. Data analysis was conducted from April 1, 2022, to May 19. 2023. A total of 105 261 adults with a smoking history were included.The 6-year lung cancer risk was calculated through recalibrated PLCOm2012 (ie, PLCOm2012-Update) and screening eligibility based on a 6-year risk threshold greater than or equal to 1.3%, yielding similar eligibility as the USPSTF 2021 guidelines.Predictive accuracy, screening eligibility-incidence (E-I) ratio (ie, ratio of the number of eligible to incident cases), and screening performance (sensitivity, specificity, and number needed to screen to detect 1 lung cancer).Of 105 261 participants (60 011 [57.0%] men; mean [SD] age, 59.8 [8.7] years), consisting of 19 258 (18.3%) African American, 27 227 (25.9%) Japanese American, 21 383 (20.3%) Latino, 8368 (7.9%) Native Hawaiian/Other Pacific Islander, and 29 025 (27.6%) White individuals, 1464 (1.4%) developed lung cancer within 6 years from enrollment. The PLCOm2012-Update showed good predictive accuracy across races and ethnicities (area under the curve, 0.72-0.82). The USPSTF 2021 criteria yielded a large disparity among African American individuals, whose E-I ratio was 53% lower vs White individuals (E-I ratio: 9.5 vs 20.3; P < .001). Under the risk-based screening (PLCOm2012-Update 6-year risk ≥1.3%), the disparity between African American and White individuals was substantially reduced (E-I ratio: 15.9 vs 18.4; P < .001), with minimal disparities observed in persons of other minoritized groups, including Japanese American, Latino, and Native Hawaiian/Other Pacific Islander. Risk-based screening yielded superior overall and race and ethnicity-specific performance to the USPSTF 2021 criteria, with higher overall sensitivity (67.2% vs 57.7%) and lower number needed to screen (26 vs 30) at similar specificity (76.6%).The findings of this cohort study suggest that risk-based lung cancer screening can reduce racial and ethnic disparities and improve screening performance across races and ethnicities vs the USPSTF 2021 criteria.

  View details for DOI 10.1001/jamaoncol.2023.4447

  View details for PubMedID 37883107

• Risk model-based management for second primary lung cancer among lung cancer survivors through a validated risk prediction model. Cancer Choi, E., Luo, S. J., Ding, V. Y., Wu, J. T., Kumar, A. V., Wampfler, J., Tammemägi, M. C., Wilkens, L. R., Aredo, J. V., Backhus, L. M., Neal, J. W., Leung, A. N., Freedman, N. D., Hung, R. J., Amos, C. I., Le Marchand, L., Cheng, I., Wakelee, H. A., Yang, P., Han, S. S. 2023

  Abstract

  Recent therapeutic advances and screening technologies have improved survival among patients with lung cancer, who are now at high risk of developing second primary lung cancer (SPLC). Recently, an SPLC risk-prediction model (called SPLC-RAT) was developed and validated using data from population-based epidemiological cohorts and clinical trials, but real-world validation has been lacking. The predictive performance of SPLC-RAT was evaluated in a hospital-based cohort of lung cancer survivors.The authors analyzed data from 8448 ever-smoking patients diagnosed with initial primary lung cancer (IPLC) in 1997-2006 at Mayo Clinic, with each patient followed for SPLC through 2018. The predictive performance of SPLC-RAT and further explored the potential of improving SPLC detection through risk model-based surveillance using SPLC-RAT versus existing clinical surveillance guidelines.Of 8448 IPLC patients, 483 (5.7%) developed SPLC over 26,470 person-years. The application of SPLC-RAT showed high discrimination area under the receiver operating characteristics curve: 0.81). When the cohort was stratified by a 10-year risk threshold of ≥5.6% (i.e., 80th percentile from the SPLC-RAT development cohort), the observed SPLC incidence was significantly elevated in the high-risk versus low-risk subgroup (13.1% vs. 1.1%, p < 1 × 10-6 ). The risk-based surveillance through SPLC-RAT (≥5.6% threshold) outperformed the National Comprehensive Cancer Network guidelines with higher sensitivity (86.4% vs. 79.4%) and specificity (38.9% vs. 30.4%) and required 20% fewer computed tomography follow-ups needed to detect one SPLC (162 vs. 202).In a large, hospital-based cohort, the authors validated the predictive performance of SPLC-RAT in identifying high-risk survivors of SPLC and showed its potential to improve SPLC detection through risk-based surveillance.Lung cancer survivors have a high risk of developing second primary lung cancer (SPLC). However, no evidence-based guidelines for SPLC surveillance are available for lung cancer survivors. Recently, an SPLC risk-prediction model was developed and validated using data from population-based epidemiological cohorts and clinical trials, but real-world validation has been lacking. Using a large, real-world cohort of lung cancer survivors, we showed the high predictive accuracy and risk-stratification ability of the SPLC risk-prediction model. Furthermore, we demonstrated the potential to enhance efficiency in detecting SPLC using risk model-based surveillance strategies compared to the existing consensus-based clinical guidelines, including the National Comprehensive Cancer Network.

  View details for DOI 10.1002/cncr.35069

  View details for PubMedID 37877788

• The effect of neighborhood socioeconomic disadvantage on smoking status, quit attempts, and receipt of cessation support among adults with cancer: Results from nine ECOG-ACRIN Cancer Research Group (EA) trials. Cancer Walter, A. W., Lee, J. W., Streck, J. M., Gareen, I. F., Herman, B. A., Kircher, S. M., Carlos, R. C., Kumar, S. K., Mayer, I. A., Saba, N. F., Fenske, T. S., Neal, J. W., Atkins, M. B., Hodi, F. S., Kyriakopoulos, C. E., Tempany-Afdhal, C. M., Shanafelt, T. D., Wagner, L. I., Land, S. R., Ostroff, J. S., Park, E. R. 2023

  Abstract

  Tobacco use is associated with adverse outcomes among patients diagnosed with cancer. Socioeconomic determinants influence access and utilization of tobacco treatment; little is known about the relationship between neighborhood socioeconomic disadvantage (NSD) and tobacco assessment, assistance, and cessation among patients diagnosed with cancer.A modified Cancer Patient Tobacco Use Questionnaire (C-TUQ) was administered to patients enrolled in nine ECOG-ACRIN clinical trials. We examined associations of NSD with (1) smoking status, (2) receiving tobacco cessation assessment and support, and (3) cessation behaviors. NSD was classified by tertiles of the Area Deprivation Index. Associations between NSD and tobacco variables were evaluated using logistic regression.A total of 740 patients completing the C-TUQ were 70% male, 94% White, 3% Hispanic, mean age 58.8 years. Cancer diagnoses included leukemia 263 (36%), lymphoma 141 (19%), prostate 131 (18%), breast 79 (11%), melanoma 69 (9%), myeloma 53 (7%), and head and neck 4 (0.5%). A total of 402 (54%) never smoked, 257 (35%) had formerly smoked, and 81 (11%) were currently smoking. Patients in high disadvantaged neighborhoods were approximately four times more likely to report current smoking (odds ratio [OR], 3.57; 95% CI, 1.69-7.54; p = .0009), and more likely to report being asked about smoking (OR, 4.24; 95% CI, 1.64-10.98; p = .0029), but less likely to report receiving counseling (OR, 0.11; 95% CI, 0.02-0.58; p = .0086) versus those in the least disadvantaged neighborhoods.Greater neighborhood socioeconomic disadvantage was associated with smoking but less cessation support. Increased cessation support in cancer care is needed, particularly for patients from disadvantaged neighborhoods.

  View details for DOI 10.1002/cncr.35039

  View details for PubMedID 37795845

• Real-World Response and Outcomes in Patients With NSCLC With EGFR Exon 20 Insertion Mutations. JTO clinical and research reports Ou, S. I., Lin, H. M., Hong, J. L., Yin, Y., Jin, S., Lin, J., Mehta, M., Nguyen, D., Neal, J. W. 2023; 4 (10): 100558

  Abstract

  This study describes treatment patterns and outcomes in patients with NSCLC with EGFR exon 20 insertions (EGFRex20ins) in the United States.The Flatiron Health electronic health record database was used to select three cohorts among patients diagnosed with NSCLC with EGFRex20ins (January 1, 2011-February 29, 2020): (1) first-line (1L) or patients receiving 1L therapy after documented EGFRex20ins; (2) second or later-line (≥2L) or patients receiving ≥2L therapy after documented EGFRex20ins; and (3) ≥2L postplatinum trial-aligned, or ≥2L patients previously treated with platinum chemotherapy whose baseline characteristics aligned with key eligibility criteria (initiating new treatment after documented EGFRex20ins and ≥1 previous treatment excluding mobocertinib or amivantamab) of the mobocertinib trial NCT02716116. Real-world end points were confirmed overall response rate, overall survival, and progression-free survival.Of 237 patients with EGFRex20ins-mutated NSCLC, 129 and 114 patients were included in the 1L and ≥2L cohorts, respectively. In 1L patients, platinum chemotherapy plus nonplatinum chemotherapy (31.0%) and EGFR tyrosine kinase inhibitors (28.7%) were the most common regimens. In ≥2L patients, immuno-oncology monotherapy (28.1%) and EGFR tyrosine kinase inhibitors (17.5%) were the most common index treatments. For any 1L, ≥2L, and ≥2L postplatinum trial-aligned patients, the confirmed overall response rate was 18.6%, 9.6%, and 14.0%, respectively; the median overall survival was 17.0, 13.6, and 11.5 months; the median progression-free survival was 5.2, 3.7, and 3.3 months, respectively.The outcomes for patients with NSCLC with EGFRex20ins were poor. This real-world study provides a benchmark on treatment outcomes in this patient population and highlights the unmet need for improved therapeutic options.

  View details for DOI 10.1016/j.jtocrr.2023.100558

  View details for PubMedID 37744306

  View details for PubMedCentralID PMC10514080

• CNS Control after First-Line Osimertinib in Patients with Metastatic EGFR-Mutant NSCLC. International journal of radiation oncology, biology, physics Hui, C., Wakelee, H. A., Neal, J. W., Ramchandran, K. J., Das, M., Nagpal, S., Roy, M., Huang, J., Pollom, E., Myall, N. 2023; 117 (2S): e110

  Abstract

  Although osimertinib (osi) has excellent intracranial activity in EGFR-mutant metastatic non-small cell lung cancer (NSCLC), there is no consensus regarding whether to continue osi for central nervous system (CNS) control with second-line chemotherapy (chemo) at the time of systemic progression. We aimed to compare CNS outcomes after first-line osi in patients receiving second-line chemo with or without continuation of osi.We retrospectively reviewed patients with EGFR-mutant NSCLC with brain metastases (BrM) at the time of initiating first-line osi who experienced progression and started second-line chemo. Cumulative incidence of local and distant CNS progression, and extracranial (EC) progression was calculated from time of second-line chemo initiation with death as a competing risk. Overall survival (OS) was analyzed using Kaplan-Meier.We included 52 patients with a median follow up of 9.6 months (range 0.4-36.4). Median OS and CNS progression-free survival (PFS) from the time of starting second-line chemo was 12.5 months (95% CI 8.1-16.9), and 5.3 months (95% CI 3.35-7.26), respectively. The 1-year cumulative incidence of local, distant CNS progression, any CNS progression, and EC progression was 14.4% (95% CI 4.5-24.2), 42.8% (95% CI 22.8-56.8), 42.8% (95% CI 22.8-56.8) and 66.8% (95% CI 53.5-80.2), respectively. After progression on first-line osi, 25 (48.1%) and 27 patients (51.9%) continued and discontinued osi, respectively. Patients who continued osi had significantly higher BrM burden than those who did not, with 17 (68%), 3 (12%), and 5 (20%) versus 26 (96%), 0, and 1 (3.7%) patient having <10 or >11 parenchymal brain lesions, or leptomeningeal disease (LMD) at the time of second line therapy, respectively (p<0.01). In those who continued osi vs those who did not, median OS (10.8 vs 12.5 months; p = 0.37), median intracranial PFS (5.3 vs 4.8 months; p = 0.99), 1-year cumulative incidence of local (8.4% versus 20 % p = 0.26), and 1-year distant CNS progression (24.8% vs 60%; p = 0.08) was not significantly different. CNS complications such as symptomatic, hospitalizations, and steroid initiation for CNS disease, and progression of LMD were not significantly different between the two groups. Eventually, 10 patients underwent salvage RT post first-line osi and median time to salvage RT was 7.8 months (range 2-9.4). Of patients who underwent salvage RT, 2 patients (20%) had continued osi with second-line chemo. Twelve patients (44.4%) who did not continue osi eventually re-started osi for progressive disease.Patients who continued osi had significantly higher BrM tumor burden. Despite these patients being at higher risk for CNS progression, time to CNS progression and incidence of CNS complications were not significantly different in the two cohorts. Patients who discontinued osi were more likely to undergo salvage RT. Continuation of osi may allow patients to defer salvage RT.

  View details for DOI 10.1016/j.ijrobp.2023.06.888

  View details for PubMedID 37784648

• Individualized Stereotactic Ablative Radiotherapy for Lung Tumors: The iSABR Phase 2 Nonrandomized Controlled Trial. JAMA oncology Gensheimer, M. F., Gee, H., Shirato, H., Taguchi, H., Snyder, J. M., Chin, A. L., Vitzthum, L. K., Maxim, P. G., Wakelee, H. A., Neal, J., Das, M., Chang, D. T., Kidd, E., Hancock, S. L., Shultz, D. B., Horst, K. C., Le, Q. T., Wong, S., Brown, E., Nguyen, N., Liang, R., Loo, B. W., Diehn, M. 2023

  Abstract

  Stereotactic ablative radiotherapy (SABR) is used for treating lung tumors but can cause toxic effects, including life-threatening damage to central structures. Retrospective data suggested that small tumors up to 10 cm3 in volume can be well controlled with a biologically effective dose less than 100 Gy.To assess whether individualizing lung SABR dose and fractionation by tumor size, location, and histological characteristics may be associated with local tumor control.This nonrandomized controlled trial (the iSABR trial, so named for individualized SABR) was a phase 2 multicenter trial enrolling participants from November 15, 2011, to December 5, 2018, at academic medical centers in the US and Japan. Data were analyzed from December 9, 2020, to May 10, 2023. Patients were enrolled in 3 groups according to cancer type: initial diagnosis of non-small cell lung cancer (NSCLC) with an American Joint Committee on Cancer 7th edition T1-3N0M0 tumor (group 1), a T1-3N0M0 new primary NSCLC with a history of prior NSCLC or multiple NSCLCs (group 2), or lung metastases from NSCLC or another solid tumor (group 3).Up to 4 tumors were treated with once-daily SABR. The dose ranged from 25 Gy in 1 fraction for peripheral tumors with a volume of 0 to 10 cm3 to 60 Gy in 8 fractions for central tumors with a volume greater than 30 cm3.Per-group freedom from local recurrence (same-lobe recurrence) at 1 year, with censoring at time of distant recurrence, death, or loss to follow-up.In total, 217 unique patients (median [IQR] age, 72 [64-80] years; 129 [59%] male; 150 [69%] current or former smokers) were enrolled (some multiple times). There were 240 treatment courses: 79 in group 1, 82 in group 2, and 79 in group 3. A total of 285 tumors (211 [74%] peripheral and 74 [26%] central) were treated. The most common dose was 25 Gy in 1 fraction (158 tumors). The median (range) follow-up period was 33 (2-109) months, and the median overall survival was 59 (95% CI, 49-82) months. Freedom from local recurrence at 1 year was 97% (90% CI, 91%-99%) for group 1, 94% (90% CI, 87%-97%) for group 2, and 96% (90% CI, 89%-98%) for group 3. Freedom from local recurrence at 5 years ranged from 83% to 93% in the 3 groups. The proportion of patients with grade 3 to 5 toxic effects was low, at 5% (including a single patient [1%] with grade 5 toxic effects).The results of this nonrandomized controlled trial suggest that individualized SABR (iSABR) used to treat lung tumors may allow minimization of treatment dose and is associated with excellent local control. Individualized dosing should be considered for use in future trials.ClinicalTrials.gov Identifier: NCT01463423.

  View details for DOI 10.1001/jamaoncol.2023.3495

  View details for PubMedID 37707820

• Overall Survival Among Patients With De Novo Stage IV Metastatic and Distant Metastatic Recurrent Non-Small Cell Lung Cancer. JAMA network open Su, C. C., Wu, J. T., Choi, E., Myall, N. J., Neal, J. W., Kurian, A. W., Stehr, H., Wood, D., Henry, S. M., Backhus, L. M., Leung, A. N., Wakelee, H. A., Han, S. S. 2023; 6 (9): e2335813

  Abstract

  Despite recent breakthroughs in therapy, advanced lung cancer still poses a therapeutic challenge. The survival profile of patients with metastatic lung cancer remains poorly understood by metastatic disease type (ie, de novo stage IV vs distant recurrence).To evaluate the association of metastatic disease type on overall survival (OS) among patients with non-small cell lung cancer (NSCLC) and to identify potential mechanisms underlying any survival difference.Cohort study of a national US population based at a tertiary referral center in the San Francisco Bay Area using participant data from the National Lung Screening Trial (NLST) who were enrolled between 2002 and 2004 and followed up for up to 7 years as the primary cohort and patient data from Stanford Healthcare (SHC) for diagnoses between 2009 and 2019 and followed up for up to 13 years as the validation cohort. Participants from NLST with de novo metastatic or distant recurrent NSCLC diagnoses were included. Data were analyzed from January 2021 to March 2023.De novo stage IV vs distant recurrent metastatic disease.OS after diagnosis of metastatic disease.The NLST and SHC cohort consisted of 660 and 180 participants, respectively (411 men [62.3%] vs 109 men [60.6%], 602 White participants [91.2%] vs 111 White participants [61.7%], and mean [SD] age of 66.8 [5.5] vs 71.4 [7.9] years at metastasis, respectively). Patients with distant recurrence showed significantly better OS than patients with de novo metastasis (adjusted hazard ratio [aHR], 0.72; 95% CI, 0.60-0.87; P < .001) in NLST, which was replicated in SHC (aHR, 0.64; 95% CI, 0.43-0.96; P = .03). In SHC, patients with de novo metastasis more frequently progressed to the bone (63 patients with de novo metastasis [52.5%] vs 19 patients with distant recurrence [31.7%]) or pleura (40 patients with de novo metastasis [33.3%] vs 8 patients with distant recurrence [13.3%]) than patients with distant recurrence and were primarily detected through symptoms (102 patients [85.0%]) as compared with posttreatment surveillance (47 patients [78.3%]) in the latter. The main finding remained consistent after further adjusting for metastasis sites and detection methods.In this cohort study, patients with distant recurrent NSCLC had significantly better OS than those with de novo disease, and the latter group was associated with characteristics that may affect overall survival. This finding can help inform future clinical trial designs to ensure a balance for baseline patient characteristics.

  View details for DOI 10.1001/jamanetworkopen.2023.35813

  View details for PubMedID 37751203

• Representativeness of Patients Enrolled in the Lung Cancer Master Protocol (Lung-MAP). JCO precision oncology Vaidya, R., Unger, J. M., Qian, L., Minichiello, K., Herbst, R. S., Gandara, D. R., Neal, J. W., Leal, T. A., Patel, J. D., Dragnev, K. H., Waqar, S. N., Edelman, M. J., Sigal, E. V., Adam, S. J., Malik, S., Blanke, C. D., LeBlanc, M. L., Kelly, K., Gray, J. E., Redman, M. W. 2023; 7: e2300218

  Abstract

  PURPOSE: Lung Cancer Master Protocol (Lung-MAP), a public-private partnership, established infrastructure for conducting a biomarker-driven master protocol in molecularly targeted therapies. We compared characteristics of patients enrolled in Lung-MAP with those of patients in advanced non-small-cell lung cancer (NSCLC) trials to examine if master protocols improve trial access.METHODS: We examined patients enrolled in Lung-MAP (2014-2020) according to sociodemographic characteristics. Proportions for characteristics were compared with those for a set of advanced NSCLC trials (2001-2020) and the US advanced NSCLC population using SEER registry data (2014-2018). Characteristics of patients enrolled in Lung-MAP treatment substudies were examined in subgroup analysis. Two-sided tests of proportions at an alpha of .01 were used for all comparisons.RESULTS: A total of 3,556 patients enrolled in Lung-MAP were compared with 2,215 patients enrolled in other NSCLC studies. Patients enrolled in Lung-MAP were more likely to be 65 years and older (57.2% v 46.3%; P < .0001), from rural areas (17.3% v 14.4%; P = .004), and from socioeconomically deprived neighborhoods (42.2% v 36.7%, P < .0001), but less likely to be female (38.6% v 47.2%; P < .0001), Asian (2.8% v 5.1%; P < .0001), or Hispanic (2.4% v 3.8%; P = .003). Among patients younger than 65 years, Lung-MAP enrolled more patients using Medicaid/no insurance (27.6% v 17.8%; P < .0001). Compared with the US advanced NSCLC population, Lung-MAP under represented patients 65 years and older (57.2% v 69.8%; P < .0001), females (38.6% v 46.0%; P < .0001), and racial or ethnic minorities (14.8% v 21.5%; P < .0001).CONCLUSION: Master protocols may improve access to trials using novel therapeutics for older patients and socioeconomically vulnerable patients compared with conventional trials, but specific patient exclusion criteria influenced demographic composition. Further research examining participation barriers for under represented racial or ethnic minorities in precision medicine clinical trials is warranted.

  View details for DOI 10.1200/PO.23.00218

  View details for PubMedID 37677122

• Improved Survival Outcomes in Patients With MET-Dysregulated Advanced NSCLC Treated With MET Inhibitors: Results of a Multinational Retrospective Chart Review. Clinical lung cancer Wolf, J., Souquet, P. J., Goto, K., Cortot, A., Baik, C., Heist, R., Kim, T. M., Han, J. Y., Neal, J. W., Mansfield, A. S., Gilloteau, I., Nwana, N., Waldron-Lynch, M., Davis, K. L., Giovannini, M., Awad, M. M. 2023

  Abstract

  We evaluated the disease and patient characteristics, treatment, and MET testing patterns, predictive biomarkers and survival outcomes in patients with MET-dysregulated metastatic non-small-cell lung cancer (NSCLC) in a real-world setting.This was a multinational, retrospective, noninterventional chart review study. Data from medical records of patients with advanced/metastatic EGFR wild-type, MET-dysregulated NSCLC (December 2017-September 2018) were abstracted into electronic data collection forms.Overall, 211 patient charts were included in this analysis; 157 patients had MET exon 14 skipping mutations (METex14; with or without concomitant MET amplification) and 54 had MET amplification only. All patients were tested for METex14, whereas MET amplification was evaluated in 168 patients. No overlap was reported between MET dysregulation and ALK, ROS1 or RET rearrangements, or HER2 exon 20 insertions. Overall, 56 of 211 patients (26.5%) received MET inhibitor (METi) therapy in any treatment-line setting (31.2% in the METex14 cohort; 13% in the MET-amplified only cohort). In the METex14 cohort, median OS in patients receiving METi was 25.4 months versus 10.7 months in patients who did not (HR [95% CI]: 0.532 [0.340-0.832]; P = .0055). In the MET-amplified only cohort, median OS was 20.6 months in patients treated with METi compared with 7.6 months in those without METi (HR [95% CI]: 0.388 [0.152-0.991]; P = .0479).MET alterations in NSCLC typically occur in the absence of other oncogenic driver mutations and are associated with poor survival outcomes. Notably, METi therapies are associated with improved survival outcomes in patients with MET-dysregulated NSCLC.

  View details for DOI 10.1016/j.cllc.2023.08.011

  View details for PubMedID 37741716

• Adjuvant osimertinib for resected EGFR-mutated non-small cell lung cancer: a game-changer? Translational lung cancer research Patel, S. R., Neal, J. W. 2023; 12 (7): 1631-1635

  View details for DOI 10.21037/tlcr-23-273

  View details for PubMedID 37577327

  View details for PubMedCentralID PMC10413020

• Cigarette and alternative tobacco product use among adult cancer survivors enrolled in 9 ECOG-ACRIN clinical trials. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Streck, J. M., Lee, J., Walter, A. W., Rosen, R. L., Gareen, I. F., Kircher, S. M., Herman, B. A., Carlos, R. C., Kumar, S., Mayer, I. A., Saba, N. F., Fenske, T. S., Neal, J. W., Atkins, M. B., Hodi, F. S., Kyriakopoulos, C. E., Tempany, C., Shanafelt, T. D., Wagner, L. I., Land, S. R., Park, E. R., Ostroff, J. S. 2023

  Abstract

  BACKGROUND: While cigarette smoking has declined among the US general population, sale and use of non-cigarette alternative tobacco products (ATPs; e.g., e-cigarettes, cigars) and dual use of cigarettes/ATPs are rising. Little is known about ATP use patterns in cancer survivors enrolled in clinical trials. We investigated prevalence of tobacco product use, and factors associated with past 30-day use, among cancer patients in national trials.METHODS: Cancer survivors (N=756) enrolled in 9 ECOG-ACRIN clinical trials (2017-2021) completed a modified Cancer Patient Tobacco Use Questionnaire (C-TUQ) which assessed baseline cigarette and ATP use since cancer diagnosis and in the past 30-days (30d).RESULTS: Patients were on average 59 years old, 70% male, and the mean time since cancer diagnosis was 26 months. Since diagnosis, cigarettes (21%) were the most common tobacco product used, followed by smokeless tobacco use (5%), cigars (4%), and e-cigarettes (2%). In the past 30d, 12% of patients reported smoking cigarettes, 4% cigars, 4% using smokeless tobacco, and 2% e-cigarettes. Since cancer diagnosis, 5.5% of the sample reported multiple tobacco product use, and 3.0% reported multiple product use in the past 30d. Males (vs. females) (OR 4.33; p=0<.01) and individuals not living with another person who smokes (vs. living with) (OR 8.07; p=0<.01) were more likely to use ATPs only vs. cigarettes only in the past 30d.CONCLUSIONS: Among cancer patients, cigarettes were the most prevalent tobacco product reported.IMPACT: Regardless, ATPs and multiple tobacco product use should be routinely assessed in cancer care settings.

  View details for DOI 10.1158/1055-9965.EPI-23-0420

  View details for PubMedID 37410096

• Early-Stage Lung Cancer: Using Circulating Tumor DNA to Get Personal. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Bestvina, C. M., Garassino, M. C., Neal, J. W., Wakelee, H. A., Diehn, M., Vokes, E. E. 2023: JCO2300258

  View details for DOI 10.1200/JCO.23.00258

  View details for PubMedID 37352477

• Adjuvant osimertinib for resected EGFR-mutated non-small cell lung cancer: a game-changer? TRANSLATIONAL LUNG CANCER RESEARCH Patel, S. R., Neal, J. W. 2023

  View details for DOI 10.21037/tlcr-23-273

  View details for Web of Science ID 001015487200001

• EGFR tyrosine kinase inhibitors (TKIs) versus durvalumab (durva) following concurrent chemoradiation (CRT) in unresectable EGFR-mutant non-small-cell lung cancer (NSCLC) Nassar, A., Adib, E., Feng, J., Aredo, J. V., Parikh, K., Harris, J., Manana, A., Ragavan, M., Lin, J., Piotrowska, Z., Fitzgerald, B., Grohe, C., Sankar, K., Neal, J. W., Wakelee, H. A., Shepherd, F. A., Herbst, R. S., Naqash, A., Goldberg, S. B., Kim, S. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for Web of Science ID 001053772003642

• ECOG-ACRIN LUNG-MAP S1900E substudy: A phase II study of sotorasib in participants (Pts) with previously treated stage IV or recurrent KRAS G12C mutant non-squamous (Non-sq) non-small cell lung cancer (NSCLC). Padda, S., Redman, M., Gerber, D. E., Stinchcombe, T., Waqar, S., Leal, T., Minichiello, K., Reckamp, K. L., Herbst, R. S., Borghaei, H., Brahmer, J. R., Gray, J., Kelly, K., Ramalingam, S. S., Neal, J. W. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for Web of Science ID 001053772005492

• Mobocertinib efficacy in patients with NSCLC and EGFR exon 20 insertion mutations (ex20ins) identified by next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) Neal, J. W., Li, Y., Yu, Z., Fram, R. J., Danes, C., Vincent, S., Piotrowska, Z. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for Web of Science ID 001053772003749

• Risk factors for venous thromboembolism (VTE) among patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) receiving amivantamab plus lazertinib versus either agent alone. Girard, N., Cho, B., Spira, A. I., Shu, C. A., Sanborn, R. E., Neal, J. W., Marmarelis, M., Sabari, J. K., Waqar, S., Nagasaka, M., Yang, J., Lu, S., Kambuj, P., Sanchez, J., Ojeda, L., Xie, J., Mahadevia, P., Bauml, J., Knoblauch, R. E., Hayashi, H. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for Web of Science ID 001053772003804

• The effect of ctDNA tumor fraction (TF) on overall survival and concordance between tissue genomics and ctDNA in Lung-MAP Mack, P. C., Redman, M., Kozono, D. E., Callis, S., Tukachinsky, H., Tolba, K. A., Neal, J. W., Waqar, S., Dragnev, K. H., Aggarwal, C., Hirsch, F. R., Patel, J. D., Herbst, R. S., Chiang, A. C., Reckamp, K. L., Kelly, K., Borghaei, H., Gray, J., Gandara, D. R. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for Web of Science ID 001053772003702

• Predicting benefit from immune checkpoint inhibitors in patients with non-small-cell lung cancer by CT-based ensemble deep learning: a retrospective study. The Lancet. Digital health Saad, M. B., Hong, L., Aminu, M., Vokes, N. I., Chen, P., Salehjahromi, M., Qin, K., Sujit, S. J., Lu, X., Young, E., Al-Tashi, Q., Qureshi, R., Wu, C. C., Carter, B. W., Lin, S. H., Lee, P. P., Gandhi, S., Chang, J. Y., Li, R., Gensheimer, M. F., Wakelee, H. A., Neal, J. W., Lee, H. S., Cheng, C., Velcheti, V., Lou, Y., Petranovic, M., Rinsurongkawong, W., Le, X., Rinsurongkawong, V., Spelman, A., Elamin, Y. Y., Negrao, M. V., Skoulidis, F., Gay, C. M., Cascone, T., Antonoff, M. B., Sepesi, B., Lewis, J., Wistuba, I. I., Hazle, J. D., Chung, C., Jaffray, D., Gibbons, D. L., Vaporciyan, A., Lee, J. J., Heymach, J. V., Zhang, J., Wu, J. 2023

  Abstract

  Only around 20-30% of patients with non-small-cell lung cancer (NCSLC) have durable benefit from immune-checkpoint inhibitors. Although tissue-based biomarkers (eg, PD-L1) are limited by suboptimal performance, tissue availability, and tumour heterogeneity, radiographic images might holistically capture the underlying cancer biology. We aimed to investigate the application of deep learning on chest CT scans to derive an imaging signature of response to immune checkpoint inhibitors and evaluate its added value in the clinical context.In this retrospective modelling study, 976 patients with metastatic, EGFR/ALK negative NSCLC treated with immune checkpoint inhibitors at MD Anderson and Stanford were enrolled from Jan 1, 2014, to Feb 29, 2020. We built and tested an ensemble deep learning model on pretreatment CTs (Deep-CT) to predict overall survival and progression-free survival after treatment with immune checkpoint inhibitors. We also evaluated the added predictive value of the Deep-CT model in the context of existing clinicopathological and radiological metrics.Our Deep-CT model demonstrated robust stratification of patient survival of the MD Anderson testing set, which was validated in the external Stanford set. The performance of the Deep-CT model remained significant on subgroup analyses stratified by PD-L1, histology, age, sex, and race. In univariate analysis, Deep-CT outperformed the conventional risk factors, including histology, smoking status, and PD-L1 expression, and remained an independent predictor after multivariate adjustment. Integrating the Deep-CT model with conventional risk factors demonstrated significantly improved prediction performance, with overall survival C-index increases from 0·70 (clinical model) to 0·75 (composite model) during testing. On the other hand, the deep learning risk scores correlated with some radiomics features, but radiomics alone could not reach the performance level of deep learning, indicating that the deep learning model effectively captured additional imaging patterns beyond known radiomics features.This proof-of-concept study shows that automated profiling of radiographic scans through deep learning can provide orthogonal information independent of existing clinicopathological biomarkers, bringing the goal of precision immunotherapy for patients with NSCLC closer.National Institutes of Health, Mark Foundation Damon Runyon Foundation Physician Scientist Award, MD Anderson Strategic Initiative Development Program, MD Anderson Lung Moon Shot Program, Andrea Mugnaini, and Edward L C Smith.

  View details for DOI 10.1016/S2589-7500(23)00082-1

  View details for PubMedID 37268451

• Phase II Randomized Trial of Carboplatin, Pemetrexed, and Bevacizumab With and Without Atezolizumab in Stage IV Nonsquamous Non-Small-Cell Lung Cancer Patients Who Harbor a Sensitizing EGFR Mutation or Have Never Smoked. Clinical lung cancer Bodor, J. N., Patel, J. D., Wakelee, H. A., Levy, B. P., Borghaei, H., Pellini, B., Costello, M. R., Dowell, J. E., Finley, G., Huang, C. H., Neal, J. W., Nieva, J. J., Puri, S., Socinski, M. A., Thomas, C., Ross, E. A., Litwin, S., Clapper, M. L., Treat, J. 2023

  Abstract

  INTRODUCTION: Patients with non-small-cell lung cancer (NSCLC) who have never smoked or have tumors with mutations in EGFR generally derive minimal benefit from single-agent PD-1/PD-L1 checkpoint inhibitors. Prior data indicate that adding PD-L1 inhibition to anti-VEGF and cytotoxic chemotherapy may be a promising approach to overcoming immunotherapy resistance in these patients, however prospective validation is needed. This trial in progress (NCT03786692) is evaluating patients with stage IV NSCLC who have never smoked or who have tumors with sensitizing EGFR alterations to determine if a 4-drug combination of atezolizumab, carboplatin, pemetrexed, and bevacizumab can improve outcomes compared to carboplatin, pemetrexed and bevacizumab without atezolizumab.METHODS: This is a randomized, phase II, multicenter study evaluating carboplatin, pemetrexed, bevacizumab with and without atezolizumab in 117 patients with stage IV nonsquamous NSCLC. Randomization is 2 to 1 favoring the atezolizumab containing arm. Eligible patients include: 1) those with tumors with sensitizing EGFR alterations in exons 19 or 21 or 2) patients who have never smoked and have wild-type tumors (ie, no EGFR, ALK or ROS1 alterations). Patients are defined as having never smoked if they have smoked less than 100 cigarettes in a lifetime. Patients with EGFR-mutated tumors must have disease progression or intolerance to prior tyrosine kinase inhibitor (TKI) therapy. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), response rate, duration of response, and time to response.CONCLUSION: This phase II trial is accruing patients at U.S. sites through the National Comprehensive Cancer Network (NCCN). The trial opened in August 2019 and accrual is expected to be completed in the Fall of 2024.

  View details for DOI 10.1016/j.cllc.2023.05.003

  View details for PubMedID 37451930

• Dissecting metastasis using preclinical models and methods. Nature reviews. Cancer Hebert, J. D., Neal, J. W., Winslow, M. M. 2023

  Abstract

  Metastasis has long been understood to lead to the overwhelming majority of cancer-related deaths. However, our understanding of the metastatic process, and thus our ability to prevent or eliminate metastases, remains frustratingly limited. This is largely due to the complexity of metastasis, which is a multistep process that likely differs across cancer types and is greatly influenced by many aspects of the in vivo microenvironment. In this Review, we discuss the key variables to consider when designing assays to study metastasis: which source of metastatic cancer cells to use and where to introduce them into mice to address different questions of metastasis biology. We also examine methods that are being used to interrogate specific steps of the metastatic cascade in mouse models, as well as emerging techniques that may shed new light on previously inscrutable aspects of metastasis. Finally, we explore approaches for developing and using anti-metastatic therapies, and how mouse models can be used to test them.

  View details for DOI 10.1038/s41568-023-00568-4

  View details for PubMedID 37138029

  View details for PubMedCentralID 5308465

• Pulmonary Hemorrhage in Patients Treated with Thoracic Stereotactic Ablative Radiotherapy and Anti-Angiogenic Agents. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Lau, B., Wu, Y. F., No, H. J., Ko, R. B., Devine, M., Das, M. S., Neal, J. W., Wakelee, H. A., Ramchandran, K., Gensheimer, M. F., Diehn, M., Chin, A. L., Loo, B. W., Vitzthum, L. K. 2023

  Abstract

  Severe pulmonary hemorrhage can occur in patients treated with thoracic stereotactic ablative radiotherapy (SABR) and vascular endothelial growth factor inhibitors (VEGFi). There is limited understanding of which patients are at risk for toxicity with the combination of thoracic SABR and VEGFis or how the risk differs over either therapy alone.We evaluated a prospectively maintained cohort of 690 patients with 818 pulmonary tumors treated with highly conformal SABR. Rates of any grade and grade-three-plus (G3+) pulmonary hemorrhage were compared between patients treated with or without VEGFi therapy across tumor locations. Outcomes were compared between patients treated with SABR + VEGFi and a propensity-matched cohort of those treated with VEGFi therapy alone.Treatment with VEGFi + SABR was associated with higher rates of G3+ pulmonary hemorrhage compared to those treated with SABR alone for the overall cohort (3-year incidence: 7.9% vs 0.6%, p<0.01) and those with central tumors (19.1% vs 3.3%, p=0.04). When further subdivided, there were significantly higher toxicity rates with VEGFi for the ultracentral (9.0% vs 45.0%, p = 0.044), but not central non-abutting tumors (0.0% vs 1.3% p = 0.69). There was an increased incidence of G3+ hemorrhage in patients treated with VEGFi + SABR compared to VEGFi alone (9.6 vs 1.3%, p=0.04).The combination of VEGFi and SABR was associated with an increased risk of high-grade pulmonary hemorrhage over either therapy alone. Low rates of toxicity were observed when excluding patients with SABR to ultracentral tumors and applying highly conformal SABR techniques.

  View details for DOI 10.1016/j.jtho.2023.04.007

  View details for PubMedID 37085030

• Brief Report: High Levels of CD47 Expression in Thymic Epithelial Tumors. JTO clinical and research reports Sun, T. Y., Nguyen, B., Chen, S. B., Natkunam, Y., Padda, S., van de Rijn, M., West, R., Neal, J. W., Wakelee, H., Riess, J. W. 2023; 4 (4): 100498

  Abstract

  CD47 is a tumor antigen that inhibits phagocytosis leading to immune evasion. Anti-CD47 therapy is a promising new immunotherapy across numerous tumor types, but it has not been tested in thymic epithelial tumors (TETs): thymomas and thymic carcinomas. TETs are rare tumors that are difficult to treat, especially with programmed cell death protein 1/programmed death-ligand 1 checkpoint inhibitors, owing to the excessive rates of immune-related adverse events. This study investigated the levels of CD47 expression in TETs to explore the possibility of anti-CD47 therapy.A total of 67 thymic tumors (63 thymomas and 4 thymic carcinomas) and 14 benign thymus controls and their clinical data were included. Samples were stained for CD47 expression (rabbit monoclonal antibody SP279, Abcam, Waltham, MA) and scored for both intensity and H-score (intensity multiplied by the percentage of tumor involved). Intensity was defined as follows: 0 = none, 1 = weak, 2 = moderate, and 3 = strong. H-scores ranged from 0 to 300. Samples with an intensity score below 2 or an H-score below 150 were considered CD47low, whereas the rest were CD47high.Compared with normal thymic tissues, TETs were more frequently CD47 positive and had significantly higher levels of CD47 expression. CD47 was positive in 79.1% of TETs compared with 57.1% of normal thymus. The level of CD47 expression was 16-fold higher in TETs (mean H-score 75.0 versus 4.6, p = 0.003). Multivariate analysis adjusted for age, sex, stage, resection status, and performance status revealed that CD47-high tumors were highly correlated with WHO histology type (p = 0.028). The most frequent CD47high tumors, in contrast to CD47low tumors, were types A (28.6% versus 7.5%) and AB (57.1% versus 13.2%), and the least frequent were B1 (7.1% versus 24.5%), B2 (0% versus 35.8%), B3 (7.1% versus 11.3%), and C (0% versus 7.5%).In contrast to normal thymus, TETs had significantly higher levels of CD47 expression. Tumor samples with high CD47 expression were mostly WHO types A and AB. This is the first study to explore CD47 expression in thymic cancers and lends support for ongoing investigation of anti-CD47 macrophage checkpoint inhibitor therapy in these tumors.

  View details for DOI 10.1016/j.jtocrr.2023.100498

  View details for PubMedID 37020927

  View details for PubMedCentralID PMC10067933

• Comparative effectiveness of mobocertinib and standard of care in patients with NSCLC with EGFR exon 20 insertion mutations: An indirect comparison. Lung cancer (Amsterdam, Netherlands) Ou, S. I., Lin, H. M., Hong, J. L., Yin, Y., Jin, S., Lin, J., Mehta, M., Zhang, P., Nguyen, D., Neal, J. W. 2023; 179: 107186

  Abstract

  Mobocertinib is a novel, first-in-class, irreversible, oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) designed to selectively target in-frame EGFR exon 20 insertions (ex20ins). Comparative effectiveness data for mobocertinib versus real-world treatments are lacking in this rare population. This study compared data for mobocertinib reported in a Phase I/II single-arm clinical trial with an external control group consisting of patients who received available treatment in the real-world setting in the United States (US).The mobocertinib group included platinum-pretreated patients with advanced EGFR ex20ins non-small cell lung cancer (NSCLC) receiving mobocertinib 160 mg QD in an ongoing, single-arm, phase 1/2 clinical trial (NCT02716116; n = 114). The real-world data (RWD) group included platinum-pretreated patients with advanced EGFR ex20ins-mutant NSCLC from the Flatiron Health database (n = 50). Inverse probability treatment weighting based on the propensity score method controlled for potential confounding between groups. Confirmed overall response rate (cORR), progression-free survival (PFS), and overall survival (OS) were compared between groups.After weighting, baseline characteristics were balanced. Patients in the RWD group received EGFR TKI (20 %), immuno-oncology therapy (40 %), or any regimens containing chemotherapy (40 %) in the second- or later-line setting. In the mobocertinib and RWD groups, respectively, cORR was 35.1 % and 11.9 % (odds ratio: 3.75 [95 % confidence interval (CI): 2.05, 6.89]); median PFS was 7.3 and 3.3 months (hazard ratio [HR]: 0.57 [95 % CI: 0.36, 0.90]); and median OS was 24.0 and 12.4 months (HR: 0.53 [95 % CI: 0.33, 0.83]) after weighting.Mobocertinib showed substantially improved outcomes versus an external control group using available therapies in platinum-pretreated patients with EGFR ex20ins-mutant NSCLC. In the absence of comparative evidence from randomized trials, these findings help elucidate potential benefits of mobocertinib in this rare population.

  View details for DOI 10.1016/j.lungcan.2023.107186

  View details for PubMedID 37075617

• CONTACT-01: Efficacy and safety from a phase III study of atezolizumab (atezo) plus cabozantinib (cabo) vs docetaxel (doc) monotherapy in patients (pts) with metastatic NSCLC (mNSCLC) previously treated with checkpoint inhibitors and chemotherapy Neal, J., Pavlakis, N., Kim, S., Goto, Y., Lim, S. M., Mountzios, G., Fountzilas, E., Mochalova, A., Christoph, D. C., Bearz, A., Quantin, X., Palmero, R., Antic, V., Chun, E., Edubilli, T., Lin, Y., Huseni, M., Scheffold, C., Vervaet, P., Newsom-Davis, T. ELSEVIER SCIENCE INC. 2023: S39-S40

  View details for Web of Science ID 000995007600007

• Real-world risk of brain metastases in stage III non-small cell lung cancer in the era of PET and MRI staging. Frontiers in oncology Alhusaini, S., Lanman, T. A., Ko, R. B., Therkelsen, K. E., Eyben, R. V., Diehn, M., Soltys, S. G., Pollom, E. L., Chin, A., Vitzthum, L., Wakelee, H. A., Padda, S. K., Ramchandran, K., Loo, B. W., Neal, J. W., Nagpal, S. 2023; 13: 1139940

  Abstract

  The 2-year incidence of brain metastases (BrMs) in stage III non-small lung cell cancer (NSCLC) has been estimated to be around 30%. However, recent clinical trials have demonstrated considerably lower BrMs rates in this patient population. In this study, we aimed to review the real-world incidence, surveillance, and treatment patterns of BrMs in stage III NSCLC.Using a retrospective single-center study design, we identified patients with stage III NSCLC who received radiation with curative intent over a 10-year period. Outcome variables included BrMs incidence, overall survival (OS), and survival from date of BrMs. Additionally, we assessed patterns of BrMs surveillance in stage III NSCLC and treatment.We identified a total of 279 stage III NSCLC patients, of which 160 with adequate records were included in the final analyses [adenocarcinoma (n = 96), squamous cell carcinoma (n = 53), other histology subtype (n = 11)]. The median OS for the entire cohort was 41 months (95% CI, 28-53), while the median time from BrMs to death was 19 months (95% CI, 9-21). Twenty-three patients (14.4%) received planned surveillance brain MRIs at 6, 12, and 24 months after completion of treatment. The remaining 137 patients (85.6%) received brain MRIs at systemic recurrence (restaging) or when neurologically symptomatic. A total of 37 patients (23%) developed BrMs, with a 2-year cumulative BrMs incidence of 17% (95% CI, 11-23). A higher incidence of BrMs was identified in patients with adenocarcinoma relative to those with squamous cell carcinoma (p < 0.01). Similarly, a higher 2-year BrMs incidence was observed in patients who received planned surveillance brain MRI relative to those who did not, although statistical significance was not reached. Stereotactic radiosurgery (SRS) treated 29 of BrMs patients (78.4%) and was preferred over WBRT, which treated only 3 patients (8.1%).At our center, BrMs incidence in stage III NSCLC patients was lower than historically reported but notably higher than the incidence described in recent clinical trials. Routine BrMs surveillance potentially allows earlier detection of asymptomatic BrMs. However, asymptomatic BrMs were mostly detected on restaging MRI at the time of recurrence.

  View details for DOI 10.3389/fonc.2023.1139940

  View details for PubMedID 37035171

  View details for PubMedCentralID PMC10080021

• Efficacy of osimertinib in patients with lung cancer positive for uncommon EGFR exon 19 deletion mutations. Clinical cancer research : an official journal of the American Association for Cancer Research Grant, M. J., Aredo, J. V., Starrett, J. H., Stockhammer, P., van Alderwerelt van Rosenburgh, I. K., Wurtz, A., Piper-Valillo, A. J., Piotrowska, Z., Falcon, C., Yu, H. A., Aggarwal, C., Scholes, D., Patil, T., Nguyen, C., Phadke, M., Li, F. Y., Neal, J., Lemmon, M. A., Walther, Z., Politi, K., Goldberg, S. B. 2023

  Abstract

  The uncommon EGFR exon 19 deletion (ex19del), L747_A750>P, demonstrates reduced sensitivity to osimertinib compared to the common ex19del, E746_A750del in preclinical models. The clinical efficacy of osimertinib in patients with non-small cell lung cancer (NSCLC) harboring L747_A750>P and other uncommon ex19dels is not known.The AACR GENIE database was interrogated to characterize the frequency of individual ex19dels relative to other variants, and a multi-center retrospective cohort was used to compare clinical outcomes for patients with tumors harboring E746_A750del, L747_A750>P, and other uncommon ex19dels who received osimertinib in the first line (1L) or in second or later lines of therapy and were T790M+ (≥2L).Ex19dels comprised 45% of EGFR mutations, with 72 distinct variants ranging in frequency from 28.1% (E746_A750del) to 0.03%, with L747_A750>P representing 1.8% of the EGFR mutant cohort. In our multi-institution cohort (N=200), E746_A750del was associated with significantly prolonged progression free survival (PFS) with 1L osimertinib vs. L747_A750>P (median 21.3 months [95% CI 17.0-31.7] vs. 11.7 months [10.8-29.4], adjusted hazard ratio [HR] 0.52 [0.28-0.98] p=0.043). Osimertinib efficacy in patients with other uncommon ex19dels varied based on the specific mutation present.The ex19del L747_A750>P is associated with inferior PFS compared to the common E746_A750del mutation in patients treated with 1L osimertinib. Understanding differences in osimertinib efficacy among EGFR ex19del.

  View details for DOI 10.1158/1078-0432.CCR-22-3497

  View details for PubMedID 36913537

• Osimertinib in NSCLC With Atypical EGFR-Activating Mutations: A Retrospective Multicenter Study. JTO clinical and research reports Ji, J., Aredo, J. V., Piper-Vallillo, A., Huppert, L., Rotow, J. K., Husain, H., Stewart, S., Cobb, R., Wakelee, H. A., Blakely, C. M., Wong, M. L., Gubens, M. A., Madani, M. H., Digumarthy, S. R., McCoach, C., Piotrowska, Z., Neal, J. W., Riess, J. W. 2023; 4 (3): 100459

  Abstract

  Introduction: EGFR mutations drive a subset of NSCLC. Patients harboring the common EGFR mutations, deletion ofexon 19 and L858R, respond well to osimertinib, a third-generation tyrosine kinase inhibitor. Nevertheless, the effect of osimertinib on NSCLC with atypical EGFR mutations is not well described. This multicenter retrospective study evaluates the efficacy of osimertinib among patients with NSCLC harboring atypical EGFR mutations.Methods: Patients with metastatic NSCLC treated with osimertinib, harboring at least one atypical EGFR mutation, excluding concurrent deletion of exon 19, L858R, or T790M mutations, from six U.S. academic cancer centers were included. Baseline clinical characteristics were collected. The primary end point was the time to treatment discontinuation (TTD) of osimertinib. Objective response rate by the Response Evaluation Criteria in Solid Tumors version 1.1 was also assessed.Results: A total of 50 patients with NSCLC with uncommon EGFR mutations were identified. The most frequent EGFR mutations were L861Q (40%, n= 18), G719X (28%, n= 14), and exon 20 insertion (14%, n= 7). The median TTD of osimertinib was 9.7 months (95% confidence interval [CI]: 6.5-12.9 mo) overall and 10.7 months (95% CI: 3.2-18.1 mo) in the first-line setting (n= 20). The objective response rate was 31.7% (95% CI: 18.1%-48.1%) overall and 41.2% (95% CI: 18.4%-67.1%) in the first-line setting. The median TTD varied among patients with L861Q (17.2 mo), G719X (7.8 mo), and exon 20 insertion (1.5 mo) mutations.Conclusions: Osimertinib has activity in patients with NSCLC harboring atypical EGFR mutations. Osimertinib activity differs by the type of atypical EGFR-activating mutation.

  View details for DOI 10.1016/j.jtocrr.2022.100459

  View details for PubMedID 36879929

• Second Primary Lung Cancer among Lung Cancer Survivors Who Never Smoked Choi, E., Su, C., Wu, J., Aredo, J., Neal, J., Leung, A., Backhus, L., Marchand, L., Liang, S. Y., Cheng, I., Wakelee, H., Han, S. ELSEVIER SCIENCE INC. 2023: E1

  View details for Web of Science ID 000989330100001

• Pharmacovigilance Analysis of HeartFailure Associated With Anti-HER2 Monotherapies and Combination Regimens for Cancer. JACC. CardioOncology Waliany, S., Caswell-Jin, J., Riaz, F., Myall, N., Zhu, H., Witteles, R. M., Neal, J. W. 2023; 5 (1): 85-98

  Abstract

  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

• Immunotherapy-Associated Atherosclerosis: A Comprehensive Review of Recent Findings and Implications for Future Research Current Treatment Options in Cardiovascular Medicine Chan, A., Torelli, S., Cheng, E., Batchelder, R., Waliany, S., Neal, J., Witteles, R., Nguyen, P., Cheng, P., Zhu, H. 2023

  View details for DOI 10.1007/s11936-023-01024-0

• Diagnosis and treatment of pericardial mesothelioma by mediastinal mass resection: a case report ANNALS OF TRANSLATIONAL MEDICINE Liang, L., Zhang, X., Ke, X., Song, Y., Brcic, L., Neal, J. W., Xu, G., Chen, C. 2022

  View details for DOI 10.21037/atm-22-4719

  View details for Web of Science ID 000905165300001

• The Role of Single-Cell Profiling and Deep Immunophenotyping in Understanding Immune Therapy Cardiotoxicity. JACC. CardioOncology Huang, Y. V., Waliany, S., Lee, D., Galdos, F. X., Witteles, R. M., Neal, J. W., Fan, A. C., Maecker, H. T., Nguyen, P. K., Wu, S. M., Zhu, H. 2022; 4 (5): 629-634

  Abstract

  • ICIs used in cancer therapy can cause serious cardiac immune-related side effects. • Single-cell multi-omics are powerful tools in understanding cell subsets/phenotypes. • Multi-omics technology can elucidate disease mechanisms in ICI-induced myocarditis.

  View details for DOI 10.1016/j.jaccao.2022.08.012

  View details for PubMedID 36636436

  View details for PubMedCentralID PMC9830194

• Diagnosis and treatment of pericardial mesothelioma by mediastinal mass resection: a case report. Annals of translational medicine Liang, L., Zhang, X., Ke, X., Song, Y., Brcic, L., Neal, J. W., Xu, G., Chen, C. 2022; 10 (24): 1407

  Abstract

  Pericardial mesothelioma (PeM) is a rare disease with non-specific symptoms at the onset, because of its rarity, the relevant literature is limited to case reports and small case series, with no cases exceeding 100 in more than 20 years. As the most common initial symptoms are chest tightness and shortness of breath, early diagnosis is difficult, and the beginning of treatment is easily delayed. We present a rare case of difficult-to-diagnose PeM in which the diagnosis was clarified by surgery and the patient achieved a long survival, providing clinicians with our experience in treating this disease at an early stage of diagnosis and early treatment.A 65-year-old female patient attended Affiliated Hospital of Zunyi Medical University, complaining about chest tightness and shortness of breath after activity for the last 2 months, accompanied by edema of the lower limbs in last month. A well circumscribed anterior-mediastinal, partially cystic mass was observed on the chest computed tomography. The patient's heart was compressed by the mass, and the patient had cardiac tamponade symptoms. Cardiac ultrasound showed the enlargement of the right heart, a widened pulmonary artery, pulmonary hypertension, and severe tricuspid regurgitation. The nature of the mass could not be determined prior to the surgery. Anterior superior mediastinal tumour resection and partial pericardial resection and closed thoracic drainage in a median open chest were performed, and pathohistological analysis revealed localized pericardial, epithelioid mesothelioma. In a follow-up after 19 months patient was generally well and without specific discomfort.Differential diagnosis of the anterior mediastinal mass is broad. In patients with a mediastinal tumour who have significant symptoms, are difficult to diagnose and can tolerate surgery, the thoracic surgeon can use surgery as early as possible to make a definitive diagnosis, save the patient's life, and/or improve the patient's quality of life, experienced pathologist is essential to make fast and correct diagnosis.

  View details for DOI 10.21037/atm-22-4719

  View details for PubMedID 36660732

  View details for PubMedCentralID PMC9843392

• Use of Machine Learning and Lay Care Coaches to Increase Advance Care Planning Conversations for Patients With Metastatic Cancer. JCO oncology practice Gensheimer, M. F., Gupta, D., Patel, M. I., Fardeen, T., Hildebrand, R., Teuteberg, W., Seevaratnam, B., Asuncion, M. K., Alves, N., Rogers, B., Hansen, J., DeNofrio, J., Shah, N. H., Parikh, D., Neal, J., Fan, A. C., Moore, K., Ruiz, S., Li, C., Khaki, A. R., Pagtama, J., Chien, J., Brown, T., Tisch, A. H., Das, M., Srinivas, S., Roy, M., Wakelee, H., Myall, N. J., Huang, J., Shah, S., Lee, H., Ramchandran, K. 2022: OP2200128

  Abstract

  Patients with metastatic cancer benefit from advance care planning (ACP) conversations. We aimed to improve ACP using a computer model to select high-risk patients, with shorter predicted survival, for conversations with providers and lay care coaches. Outcomes included ACP documentation frequency and end-of-life quality measures.In this study of a quality improvement initiative, providers in four medical oncology clinics received Serious Illness Care Program training. Two clinics (thoracic/genitourinary) participated in an intervention, and two (cutaneous/sarcoma) served as controls. ACP conversations were documented in a centralized form in the electronic medical record. In the intervention, providers and care coaches received weekly e-mails highlighting upcoming clinic patients with < 2 year computer-predicted survival and no prior prognosis documentation. Care coaches contacted these patients for an ACP conversation (excluding prognosis). Providers were asked to discuss and document prognosis.In the four clinics, 4,968 clinic visits by 1,251 patients met inclusion criteria (metastatic cancer with no prognosis previously documented). In their first visit, 28% of patients were high-risk (< 2 year predicted survival). Preintervention, 3% of both intervention and control clinic patients had ACP documentation during a visit. By intervention end (February 2021), 35% of intervention clinic patients had ACP documentation compared with 3% of control clinic patients. Providers' prognosis documentation rate also increased in intervention clinics after the intervention (2%-27% in intervention clinics, P < .0001; 0%-1% in control clinics). End-of-life care intensity was similar in intervention versus control clinics, but patients with ≥ 1 provider ACP edit met fewer high-intensity care measures (P = .04).Combining a computer prognosis model with care coaches increased ACP documentation.

  View details for DOI 10.1200/OP.22.00128

  View details for PubMedID 36395436

• Induction EGFR tyrosine kinase inhibitors prior to definitive chemoradiotherapy in unresectable stage III EGFR-mutated non-small cell lung cancer. Cancer treatment and research communications Aredo, J. V., Wakelee, H. A., Hui, A. B., Padda, S. K., Joshi, N. D., Guo, H. H., Chaudhuri, A., Diehn, M., Loo, B. W., Neal, J. W. 2022; 33: 100659

  Abstract

  INTRODUCTION: Increasing evidence suggests that consolidation durvalumab confers limited benefits for patients with stage III EGFR-mutated NSCLC. Induction or maintenance EGFR tyrosine kinase inhibitors (TKIs) added to concurrent chemoradiotherapy (CRT) may optimize definitive treatment, but there are limited data supporting an induction TKI strategy.METHODS: We evaluated the efficacy and safety of induction EGFR TKIs administered before concurrent CRT in a retrospective series of patients with unresectable locally advanced EGFR-mutated NSCLC. Circulating tumor DNA (ctDNA) analysis was performed on a patient subset using CAPP-seq and correlated with outcomes.RESULTS: Of six patients, three received erlotinib and three osimertinib as induction therapy before CRT. Induction TKIs were administered for a median of 2.5 months. The objective response rate after induction TKI was 83%. One patient had a complete response to induction erlotinib and continued erlotinib for 4 years until local progression, which was treated with CRT. Two patients completed maintenance erlotinib after CRT, and another received consolidation durvalumab. After a median follow-up of 20.5 months, only one patient developed disease recurrence, with rising ctDNA coinciding with recurrence. ctDNA remained undetectable in patients without recurrence, or low-level in a patient receiving maintenance erlotinib. Adverse events were mild and expected, and none developed pneumonitis.CONCLUSION: Induction EGFR TKI before CRT may achieve high disease control rates with promising signs of durability in patients with locally advanced EGFR-mutated NSCLC. ctDNA analysis after CRT can correlate well with clinical outcomes. Prospective studies are needed to define the role of induction EGFR TKIs in this setting.

  View details for DOI 10.1016/j.ctarc.2022.100659

  View details for PubMedID 36427429

• PROVIDER INSIGHTS ON MANAGING PATIENTS ON IMMUNOTHERAPY, BARRIERS TO CLINICAL TRIALS, AND BIOMARKER TESTING PREFERENCES Ackbarali, T., Neal, J., Janjigian, Y., Overman, M. BMJ PUBLISHING GROUP. 2022: A970

  View details for DOI 10.1136/jitc-2022-SITC2022.0930

  View details for Web of Science ID 000919423401046

• Amivantamab in combination with lazertinib in patients with atypical epidermal growth factor receptor (EGFR) mutations excluding exon 20 insertion mutations: Initial results from CHRYSALIS-2 Cho, B. C., Wang, Y., Li, Y., Wu, L., Besse, B., Marmarelis, M. E., Goto, K., Lee, J., Lee, S., Zhang, Y., Neal, J., Curtin, J., Bauml, J. M., Mahoney, J., Trani, L., Knoblauch, R. E., Tomasini, P. ELSEVIER. 2022: S1566

  View details for DOI 10.1016/j.annonc.2022.10.359

  View details for Web of Science ID 000897943700326

• Local control of brain metastases with osimertinib alone in patients with EGFR-mutant non-small cell lung cancer. Journal of neuro-oncology Hui, C., Qu, V., Wang, J. Y., von Eyben, R., Chang, Y. C., Chiang, P. L., Liang, C. H., Lu, J. T., Li, G., Hayden-Gephart, M., Wakelee, H., Neal, J., Ramchandran, K., Das, M., Nagpal, S., Soltys, S., Myall, N., Pollom, E. 2022

  Abstract

  Although osimertinib has excellent intracranial activity in metastatic non-small cell lung cancer (NSCLC) with exon 19 deletion or L858R EGFR alterations, measures of local control of brain metastases are less well-reported. We describe lesion-level outcomes of brain metastases treated with osimertinib alone.We retrospectively reviewed patients with EGFR-mutant NSCLC with untreated brain metastasis measuring ≥ 5 mm at the time of initiating osimertinib. Cumulative incidence of local recurrence in brain (LRiB) was calculated with death as a competing risk, and univariable and multivariable analyses were conducted to identify factors associated with LRiB.We included 284 brain metastases from 37 patients. Median follow-up was 20.1 months. On initial MRI after starting osimertinib, patient-level response was complete response (CR) in 11 (15%), partial response (PR) in 33 (45%), stable disease (SD) in 18 (25%) and progressive disease (PD) in 11 (15%). The 1-year cumulative incidence of LRiB was 14% (95% CI 9.9-17.9) and was significantly different in patients with a CR (0%), PR (4%), and SD (11%; p = 0.02). Uncontrolled primary tumor (adjusted hazard ratio [aHR] 3.78, 95% CI 1.87-7.66; p < 0.001), increasing number of prior systemic therapies (aHR 2.12, 95% CI 1.49-3.04; p < 0.001), and higher ECOG score (aHR 7.8, 95% CI 1.99-31.81; p = 0.003) were associated with LRiB.Although 1-year cumulative incidence of LRiB is < 4% with a CR or PR, 1-year cumulative incidence of LRiB is over 10% for patients with less than a PR to osimertinib on initial MRI. These patients should be followed closely for need for additional treatment such as stereotactic radiosurgery.

  View details for DOI 10.1007/s11060-022-04145-x

  View details for PubMedID 36227422

• Predictive Model to Guide Brain Magnetic Resonance Imaging Surveillance in Patients With Metastatic Lung Cancer: Impact on Real-World Outcomes. JCO precision oncology Wu, J., Ding, V., Luo, S., Choi, E., Hellyer, J., Myall, N., Henry, S., Wood, D., Stehr, H., Ji, H., Nagpal, S., Hayden Gephart, M., Wakelee, H., Neal, J., Han, S. S. 2022; 6: e2200220

  Abstract

  Brain metastasis is common in lung cancer, and treatment of brain metastasis can lead to significant morbidity. Although early detection of brain metastasis may improve outcomes, there are no prediction models to identify high-risk patients for brain magnetic resonance imaging (MRI) surveillance. Our goal is to develop a machine learning-based clinicogenomic prediction model to estimate patient-level brain metastasis risk.A penalized regression competing risk model was developed using 330 patients diagnosed with lung cancer between January 2014 and June 2019 and followed through June 2021 at Stanford HealthCare. The main outcome was time from the diagnosis of distant metastatic disease to the development of brain metastasis, death, or censoring.Among the 330 patients, 84 (25%) developed brain metastasis over 627 person-years, with a 1-year cumulative brain metastasis incidence of 10.2% (95% CI, 6.8 to 13.6). Features selected for model inclusion were histology, cancer stage, age at diagnosis, primary site, and RB1 and ALK alterations. The prediction model yielded high discrimination (area under the curve 0.75). When the cohort was stratified by risk using a 1-year risk threshold of > 14.2% (85th percentile), the high-risk group had increased 1-year cumulative incidence of brain metastasis versus the low-risk group (30.8% v 6.1%, P < .01). Of 48 high-risk patients, 24 developed brain metastasis, and of these, 12 patients had brain metastasis detected more than 7 months after last brain MRI. Patients who missed this 7-month window had larger brain metastases (58% v 33% largest diameter > 10 mm; odds ratio, 2.80, CI, 0.51 to 13) versus those who had MRIs more frequently.The proposed model can identify high-risk patients, who may benefit from more intensive brain MRI surveillance to reduce morbidity of subsequent treatment through early detection.

  View details for DOI 10.1200/PO.22.00220

  View details for PubMedID 36201713

• Feasibility of large scale distress screening at an academic center and associated network sites using an adapted patient-reported outcome instrument and reflexive suicide screening. Gupta, D., Savadamuthu, V., Qin, F., Roy, M., Herring, J., Robinson, A., Terrell, C., Neal, J. W., Lahijani, S., Ramchandran, K. LIPPINCOTT WILLIAMS & WILKINS. 2022: 278

  View details for Web of Science ID 000891944700277

• Phase II Randomized Study of Ramucirumab and Pembrolizumab Versus Standard of Care in Advanced Non-Small-Cell Lung Cancer Previously Treated With Immunotherapy-Lung-MAP S1800A (vol 40, pg 2295, 2022) JOURNAL OF CLINICAL ONCOLOGY Reckamp, K. L., Redman, M. W., Dragnev, K. H., Minichiello, K., Villaruz, L. C., Faller, B., Al Baghdadi, T., Hines, S., Everhart, L., Highleyman, L., Papadimitrakopoulou, V., Neal, J. W., Waqar, S. N., Patel, J. D., Gray, J. E., Gandara, D. R., Kelly, K., Herbst, R. S. 2022; 40 (25): 3002

  View details for DOI 10.1200/JCO.22.01464

  View details for Web of Science ID 000846888000016

• Phenotyping Malignant Pleural Effusions with Mass Cytometry: Evidence of EMT and MET States in Late-Stage NSCLC Karacosta, L. G., Pancirer, D., Preiss, J., Shrager, J. B., Sung, A. W., Neal, J. W., Bendall, S. C., Wakelee, H., Plevritis, S. K. ELSEVIER SCIENCE INC. 2022: S577-S578

  View details for Web of Science ID 000858678101493

• Phase 2 EVOKE-02 Study of Sacituzumab Govitecan and Pembrolizumab +/- Platinum in First-Line Metastatic NSCLC Reck, M., Liu, S. V., Owen, S. P., Garon, E. B., Neal, J. W., Vicente, D., Mekan, S. F., Safavi, F., Fernando, N., Mok, T. K. ELSEVIER SCIENCE INC. 2022: S448

  View details for Web of Science ID 000858678101227

• Cabozantinib Plus Atezolizumab in First or Second-Line Advanced NSCLC and Previously-Treated EGFR Mutant Advanced NSCLC Neal, J. W., Lim, F. L., Aix, S. P., Viteri, S., Santoro, A., Spencer, K., Fang, B., Khrizman, P., Kim, J., Subbiah, V., Sudhagoni, R., Samaraweera, L., Andrianova, L., Felip, E. ELSEVIER SCIENCE INC. 2022: S439

  View details for Web of Science ID 000858678101210

• Cabozantinib after prior checkpoint inhibitor therapy in patients with solid tumors: A systematic literature review. Cancer treatment reviews Graham, J., Vogel, A., Cheng, A. L., Bjarnason, G. A., Neal, J. W. 2022; 110: 102453

  Abstract

  We conducted a systematic literature review to identify evidence for cabozantinib activity in patients with solid tumors after prior checkpoint inhibitor (CPI) therapy.The review was conducted according to PRISMA guidelines and registered with PROSPERO (CRD42021259873). MEDLINE®, Embase, and the Cochrane Library were searched on 19 May 2021 to identify publications reporting the efficacy/effectiveness and safety/tolerability of cabozantinib in patients with solid tumors who had received prior CPI-based therapy. Publications were screened by one reviewer with uncertainties resolved by a second and/or the full author group. Risk of bias was assessed using Gradingof Recommendations Assessment, Development and Evaluation (GRADE) for clinical trials and the Newcastle-Ottawa Scale (NOS) for observational studies.Of 669 publications screened, 21 were eligible: 18 reported data on renal cell carcinoma, and one each for hepatocellular carcinoma, metastatic urothelial carcinoma, and non-small cell lung cancer. Of six trial publications, three reported moderate-quality evidence and three low-quality evidence. Of 15 observational studies, NOS scores ranged from 3 to 6, suggesting a high potential for uncertainty. The studies consistently reported clinical activity for cabozantinib after CPI therapy, across treatment lines and tumor types, with no new safety signals. The findings were limited by the quality and quantity of available data.Cabozantinib appears to have anti-tumor activity after prior CPI therapy in patients with solid tumors. Our results are driven largely by studies in renal cell carcinoma. Evidence from ongoing phase 3 trials is required to establish further the role of cabozantinib after CPI therapy.

  View details for DOI 10.1016/j.ctrv.2022.102453

  View details for PubMedID 36037792

• Isolated Nodal Recurrence After Definitive Stereotactic Ablative Radiotherapy for Non-Small Cell Lung Cancer. Practical radiation oncology Devine, M., Merriott, D. J., No, H. J., Lau, B., Say, C., Yoo, C., Yi, E., Ko, R. B., Neal, J. W., Wakelee, H. A., Das, M., Loo, B. W., Diehn, M., Chin, A. L., Vitzthum, L. K. 2022

  Abstract

  Stereotactic ablative radiotherapy (SABR) results in high rates of primary tumor control for early-stage non-small cell lung cancer (NSCLC). For patients with isolated hilar or mediastinal nodal recurrences (INR) after SABR, the optimal salvage treatment strategy is unclear. The purpose of this study is to determine the rate of INR after SABR for early-stage NSCLC and to describe patterns of care and treatment outcomes after salvage therapy.This retrospective cohort study included 342 patients with Stage T1-3N0M0 NSCLC treated with definitive SABR from 2003-2018. We evaluated the incidence of INR and baseline factors between patients who did and did not experience INR. Among patients who experienced INR, we described treatment patterns and outcomes including overall (OS) and progression free survival (PFS) from the time of nodal failure using the Kaplan-Meier method.With a median follow-up of 3.3 years, the 3-year INR rate was 10.6% (6.6% -13.4%). Among the 34 patients experiencing INR, the 3-year rates of OS and PFS were 39.3% (24.4 - 63.3%) and 26.7% (14.1 - 50.3%), respectively. The 34 patients with INR were treated with RT alone (26.7 %), concurrent chemoradiotherapy (CRT) (43.3 %), chemotherapy alone (13.3%), or observation (16.7%). CRT had the best survival outcomes with a 3-year OS and PFS of 81.5% (61.1 - 100.0%) and 63.9% (40.7 - 100.0%), respectively. Of the patients treated with salvage RT or CRT, 14.3% experienced grade 3 toxicity with no patients having grade 4+ toxicity.INR occurred in approximately 10% of patients treated with SABR for early-stage NSCLC. The highest rates of OS an PFS among patients with INR were observed in those treated with salvage chemoradiotherapy.

  View details for DOI 10.1016/j.prro.2022.06.013

  View details for PubMedID 35858658

• Efficacy and safety of first-line anlotinib-based combinations for advanced non-small cell lung cancer: a three-armed prospective study. Translational lung cancer research Chu, T., Zhang, W., Zhang, B., Zhong, R., Zhang, X., Gu, A., Shi, C., Wang, H., Xiong, L., Lu, J., Qian, J., Zhang, Y., Dong, Y., Teng, J., Gao, Z., Wang, W., Shen, Y., Nie, W., Lim, J. U., Mehta, H. J., Neal, J. W., Lou, Y., Xu, J., Zhong, H., Han, B. 2022; 11 (7): 1394-1404

  Abstract

  The evidence of combined therapies of multi-target agents in first-line treatment of advanced non-small cell lung cancer (NSCLC) was limited. This study aimed to evaluate the safety and efficacy of anlotinib combined with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), chemotherapy, or immune checkpoint inhibitor (ICI) in advanced NSCLC.This open-label, three-arm, prospective study (NCT03628521) enrolled untreated locally advanced/metastatic NSCLC patients. Patients with EGFR mutation NSCLC received anlotinib and erlotinib (cohort A). Patients without EGFR/ALK/ROS1 mutation received anlotinib combined with carboplatin plus pemetrexed/gemcitabine (cohort B), or sintilimab (cohort C). The primary outcomes were safety and objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), disease control rate (DCR), and overall survival (OS). Treatments were performed for at least 2 cycles and efficacy was evaluated every 2 cycles using RECIST version 1.1. Safety was assessed throughout the study.A total of 30, 30, and 22 patients were enrolled in cohorts A, B, and C, respectively. There were 3 patients did not complete the treatment in cohort A. In cohorts A and B, ≥ grade 3 treatment-related adverse events (TRAEs) occurred in 77.3% and 60.0% of patients, respectively. The most common TRAEs were rash (10.0%) and decreased platelet count (30.0%) in cohorts A and B, respectively. The ORRs were 92.9% and 60.0% in cohorts A and B, respectively, and DCRs were 96.4% and 96.7%, respectively. The ORR and incidence of ≥ grade 3 TRAEs of cohort C were, which 72.7% and 54.5%, which had been published previously. Median PFSs [95% confidence interval (CI)] were 21.6 (15.6 to 24.9), 13.0 [10.5 to not estimated (NE)], and 15.6 (12.9 to NE) months in cohorts A, B, and C, respectively. Median OS was 28.1 (95% CI: 21.82 to NE) months in cohort B. The 24-month OS rates in cohorts A and C were 87.1% and 83.9%, respectively.Anlotinib-based combinations with EGFR-TKI, chemotherapy, and ICI are well-tolerated and encouraging as first-line therapies for advanced NSCLC, which could be verified in future studies. Anlotinib-based combination might provide multiple choices for first-line treatment in patients with advanced NSCLC.

  View details for DOI 10.21037/tlcr-22-438

  View details for PubMedID 35958322

  View details for PubMedCentralID PMC9359953

• Systematic pan-cancer analysis of mutation-treatment interactions using large real-world clinicogenomics data. Nature medicine Liu, R., Rizzo, S., Waliany, S., Garmhausen, M. R., Pal, N., Huang, Z., Chaudhary, N., Wang, L., Harbron, C., Neal, J., Copping, R., Zou, J. 2022

  Abstract

  Quantifying the effectiveness of different cancer therapies in patients with specific tumor mutations is critical for improving patient outcomes and advancing precision medicine. Here we perform a large-scale computational analysis of 40,903 US patients with cancer who have detailed mutation profiles, treatment sequences and outcomes derived from electronic health records. We systematically identify 458 mutations that predict the survival of patients on specific immunotherapies, chemotherapy agents or targeted therapies across eight common cancer types. We further characterize mutation-mutation interactions that impact the outcomes of targeted therapies. This work demonstrates how computational analysis of large real-world data generates insights, hypotheses and resources to enable precision oncology.

  View details for DOI 10.1038/s41591-022-01873-5

  View details for PubMedID 35773542

• Identification of Pathogenic Immune Cell Subsets Associated With Checkpoint Inhibitor-Induced Myocarditis. Circulation Zhu, H., Galdos, F. X., Lee, D., Waliany, S., Vivian Huang, Y., Ryan, J., Dang, K., Neal, J. W., Wakelee, H. A., Reddy, S. A., Srinivas, S., Lin, L. L., Witteles, R. M., Maecker, H. T., Davis, M. M., Nguyen, P. K., Wu, S. M. 2022: 101161CIRCULATIONAHA121056730

  Abstract

  Immune checkpoint inhibitors (ICIs) are monoclonal antibodies used to activate the immune system against tumor cells. Despite therapeutic benefits, ICIs have the potential to cause immune-related adverse events such as myocarditis, a rare but serious side effect with up to 50% mortality in affected patients. Histologically, patients with ICI myocarditis have lymphocytic infiltrates in the heart, implicating T cell-mediated mechanisms. However, the precise pathological immune subsets and molecular changes in ICI myocarditis are unknown.To identify immune subset(s) associated with ICI myocarditis, we performed time-of-flight mass cytometry on peripheral blood mononuclear cells from 52 individuals: 29 patients with autoimmune adverse events (immune-related adverse events) on ICI, including 8 patients with ICI myocarditis, and 23 healthy control subjects. We also used multiomics single-cell technology to immunophenotype 30 patients/control subjects using single-cell RNA sequencing, single-cell T-cell receptor sequencing, and cellular indexing of transcriptomes and epitopes by sequencing with feature barcoding for surface marker expression confirmation. To correlate between the blood and the heart, we performed single-cell RNA sequencing/T-cell receptor sequencing/cellular indexing of transcriptomes and epitopes by sequencing on MRL/Pdcd1-/- (Murphy Roths large/programmed death-1-deficient) mice with spontaneous myocarditis.Using these complementary approaches, we found an expansion of cytotoxic CD8+ T effector cells re-expressing CD45RA (Temra CD8+ cells) in patients with ICI myocarditis compared with control subjects. T-cell receptor sequencing demonstrated that these CD8+ Temra cells were clonally expanded in patients with myocarditis compared with control subjects. Transcriptomic analysis of these Temra CD8+ clones confirmed a highly activated and cytotoxic phenotype. Longitudinal study demonstrated progression of these Temra CD8+ cells into an exhausted phenotype 2 months after treatment with glucocorticoids. Differential expression analysis demonstrated elevated expression levels of proinflammatory chemokines (CCL5/CCL4/CCL4L2) in the clonally expanded Temra CD8+ cells, and ligand receptor analysis demonstrated their interactions with innate immune cells, including monocytes/macrophages, dendritic cells, and neutrophils, as well as the absence of key anti-inflammatory signals. To complement the human study, we performed single-cell RNA sequencing/T-cell receptor sequencing/cellular indexing of transcriptomes and epitopes by sequencing in Pdcd1-/- mice with spontaneous myocarditis and found analogous expansions of cytotoxic clonal effector CD8+ cells in both blood and hearts of such mice compared with controls.Clonal cytotoxic Temra CD8+ cells are significantly increased in the blood of patients with ICI myocarditis, corresponding to an analogous increase in effector cytotoxic CD8+ cells in the blood/hearts of Pdcd1-/- mice with myocarditis. These expanded effector CD8+ cells have unique transcriptional changes, including upregulation of chemokines CCL5/CCL4/CCL4L2, which may serve as attractive diagnostic/therapeutic targets for reducing life-threatening cardiac immune-related adverse events in ICI-treated patients with cancer.

  View details for DOI 10.1161/CIRCULATIONAHA.121.056730

  View details for PubMedID 35762356

• Long term effect of radiotherapy on risk of second primary lung cancer and overall mortality among lung cancer patients Choi, E., Lam, V. T., Aredo, J. A., Kumar, A. V., Wampfler, J., Wu, J. T., Christiani, D. C., Cheng, I., Amos, C. I., Hung, R. J., Backhus, L. M., Neal, J. W., Wakelee, H. A., Yang, P., Han, S. S. AMER ASSOC CANCER RESEARCH. 2022

  View details for Web of Science ID 000892509507119

• Characterization of ERBB2 (HER2) Alterations in Metastatic Non-small Cell Lung Cancer and Comparison of Outcomes of Different Trastuzumab-based Regimens. Clinical lung cancer Waliany, S., Wakelee, H., Ramchandran, K., Das, M., Huang, J., Myall, N., Li, C., Pagtama, J., Tisch, A. H., Neal, J. W. 2022

  Abstract

  About 3%-5% of mNSCLC have ERBB2 (HER2) alterations, but currently, there are no FDA-approved targeted therapies for this indication. We compared treatment response between trastuzumab-based and non-targeted regimens in ERBB2-mutant mNSCLC.This retrospective, single-institution study included patients with mNSCLC with ERBB2 alterations identified by next-generation sequencing. Best overall response was determined using Response Evaluation Criteria in Solid Tumors 1.1.We identified 3 groups of patients: ERBB2-mutant/EGFR-wildtype mNSCLC (n = 33), ERBB2-amplified/EGFR-wildtype mNSCLC without concurrent ERBB2 mutations (n = 6), and ERBB2-altered/EGFR-mutant mNSCLC (n = 8). Observed mutations included A775_G776insYVMA (n = 23), Gly778_Pro780dup (n = 4), Ser310Phe (n = 3), and others (n = 5). Among the 33 with ERBB2-mutant/EGFR-wildtype mNSCLC, those with and without A775_G776insYVMA had significantly different median overall survival (OS) of 17.7 and 52.9 months, respectively (Cox regression multivariable HR: 5.03, 95% CI: 1.37-18.51, P = .02). In those with mNSCLC with A775_G776insYVMA, trastuzumab-based therapies were associated with greater OS (20.3 vs. 9.8 months; multivariable HR: 0.19, 95% CI: 0.04-0.87, P = .032). Objective response and disease control rates (median tumor size change) in the 33 patients with ERBB2-mutant/EGFR-wildtype mNSCLC were 40.0% and 80.0% (-35.8%), respectively, for patients treated with trastuzumab deruxtecan; 0% and 30.0% (-5.2%) for trastuzumab emtansine; and 7.1% and 50.0% (-13.0%) for trastuzumab/chemotherapy combinations.In ERBB2-mutant/EGFR-wildtype mNSCLC, while most trastuzumab-based regimens had modest activity in this real-world analysis, trastuzumab deruxtecan had highest response rates and best tumor size reduction. Receipt of any trastuzumab-based regimen was associated with greater OS with A775_G776insYVMA. There remains an unmet need for approved targeted therapies for ERBB2-mutant/EGFR-wildtype NSCLC.

  View details for DOI 10.1016/j.cllc.2022.05.015

  View details for PubMedID 35753988

• High-Dose Osimertinib for CNS Progression in EGFR+ NSCLC: A Multi-Institutional Experience. JTO clinical and research reports Piper-Vallillo, A. J., Rotow, J. K., Aredo, J. V., Shaverdashvili, K., Luo, J., Carlisle, J. W., Husain, H., Muzikansky, A., Heist, R. S., Rangachari, D., Ramalingam, S. S., Wakelee, H. A., Yu, H. A., Sequist, L. V., Bauml, J. M., Neal, J. W., Piotrowska, Z. 2022; 3 (6): 100328

  Abstract

  This multicenter review evaluated the efficacy and safety of osimertinib dose escalation for central nervous system (CNS) progression developing on osimertinib 80 mg in EGFR-mutant NSCLC.Retrospective review identified 105 patients from eight institutions with advanced EGFR-mutant NSCLC treated with osimertinib 160 mg daily between October 2013 and January 2020. Radiographic responses were clinically assessed, and Kaplan-Meier analyses were used. We defined CNS disease control as the interval from osimertinib 160 mg initiation to CNS progression or discontinuation of osimertinib 160 mg.Among 105 patients treated with osimertinib 160 mg, 69 were escalated for CNS progression, including 24 treated with dose escalation alone (cohort A), 34 who received dose-escalated osimertinib plus concurrent chemotherapy and/or radiation (cohort B), and 11 who received osimertinib 160 mg without any prior 80 mg exposure. The median duration of CNS control was 3.8 months (95% confidence interval [CI], 1.7-5.8) in cohort A, 5.1 months (95% CI, 3.1-6.5) in cohort B, and 4.2 months (95% CI 1.6-not reached) in cohort C. Across all cohorts, the median duration of CNS control was 6.0 months (95% CI, 5.1-9.0) in isolated leptomeningeal progression (n = 27) and 3.3 months (95% CI, 1.0-3.1) among those with parenchymal-only metastases (n = 23). Patients on osimertinib 160 mg experienced no severe or unexpected side effects.Among patients with EGFR-mutant NSCLC experiencing CNS progression on osimertinib 80 mg daily, dose escalation to 160 mg provided modest benefit with CNS control lasting approximately 3 to 6 months and seemed more effective in patients with isolated leptomeningeal CNS progression.

  View details for DOI 10.1016/j.jtocrr.2022.100328

  View details for PubMedID 35637759

  View details for PubMedCentralID PMC9142556

• Clinicopathological characteristics and prognostic significance of HDAC11 protein expression in non-small cell lung cancer: a retrospective study. Translational lung cancer research Lu, D., Ma, Z., Huang, D., Zhang, J., Li, J., Zhi, P., Zhang, L., Feng, Y., Ge, X., Zhai, J., Jiang, M., Zhou, X., Simone, C. B., Neal, J. W., Patel, S. R., Yan, X., Hu, Y., Wang, J. 2022; 11 (6): 1119-1131

  Abstract

  Background: Although the prognosis of non-small cell lung cancer (NSCLC) can be assessed based on pathological type, disease stage and inflammatory indicators, the prognostic scoring model of NSCLC still needs to improve. HDAC11 is associated with poor prognosis of partial tumors, but its prognostic relationship with NSCLC is poorly understood. In this study, the role of HDAC11 in NSCLC was studied to evaluate relationship with disease prognosis and potential therapeutic target.Methods: The clinicopathological and paracancerous tissues of patients with NSCLC primarily diagnosed in Tangdu Hospital from 2009 to 2013 were collected. Follow-up of patients were made every three months and the last follow-up period was December 2018. The expression of HDAC11 was assessed by immunohistochemistry (IHC). Then, weighted gene co-expression network analysis (WGCNA) was used to analyze the relationship between HDAC11 expression and the prognosis of lung adenocarcinoma (LUAD) patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Kaplan-Meier plotter database was used to verify the connection between hub genes and tumor stage and prognosis. We accessed the relationship between HDAC11 expression and clinicopathological features, and impact on the prognosis.Results: The study assessed 326 patients with NSCLC. Compared with adjacent tissues, HDAC11 expression was upregulated (HR =1.503, 95% CI: 1.172 to 1.927, P=0.001). Kaplan-Meier survival analyses showed that HDAC11 expression was closely related to OS of NSCLC patients (P=0.0011). Univariate and multivariate analyses showed that the independent risk factors of OS were clinical stage, HDAC11 expression, and HDAC11 differentiation (all P≤0.001). HDAC11 was significantly associated with prognosis in LUAD. A total of 1,174 differential genes and WGCNA were obtained to construct a co-expression network in LUAD. The GO and KEGG pathway enrichment analyses showed the relevance with staphylococcus aureus infection, NOD-like receptor signaling pathway, and others. The results of LUAD survival analysis showed that HDAC11-related genes NKX2-5 and FABP7 were significantly associated with LUAD prognosis.Conclusions: The high expression of HDAC11 is related to the poor prognosis of LUAD, and it is expected to become a therapeutic target and prognostic evaluation therapy for LUAD in the future. However, the relevant results need to be further studied and verified.

  View details for DOI 10.21037/tlcr-22-403

  View details for PubMedID 35832445

• Neighborhood socioeconomic disadvantage, tobacco use, and cessation indicators among adults with cancer in the United States: Results from 10 ECOG-ACRIN trials. Walter, A., Lee, J., Gareen, I. F., Kircher, S., Herman, B. A., Streck, J. M., Kumar, S., Mayer, I. A., Saba, N. F., Neal, J. W., Atkins, M. B., Hodi, F., Kyriakopoulos, C., Tempany, C., Shanafelt, T. D., Wagner, L. I., Land, S. R., Ostroff, J. S., Park, E. R. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000863680301814

• Efficacy of osimertinib in patients with EGFR mutant lung cancer harboring the uncommon exon 19 deletion, L747_A750>P. Grant, M. J., Aredo, J. V., Starrett, J., Wurtz, A., Piotrowska, Z., Piper-Vallillo, A., Yu, H., Falcon, C., Patil, T., Nguyen, C., Aggarwal, C., Scholes, D. G., Li, F., Phadke, M., Neal, J. W., Walther, Z., Politi, K. A., Goldberg, S. B. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000863680304358

• EVOKE-02: A phase 2 study of sacituzumab govitecan (SG) plus pembrolizumab (pembro) with or without platinum chemotherapy in first-line metastatic non-small cell lung cancer (NSCLC). Garon, E. B., Liu, S. V., Owen, S., Reck, M., Neal, J. W., Vicente, D., Mekan, S., Safavi, F., Fernando, N., Mok, T. K. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000863680305130

• Cabozantinib (C) plus atezolizumab (A) or C alone in patients (pts) with advanced non-small cell lung cancer (aNSCLC) previously treated with an immune checkpoint inhibitor (ICI): Results from Cohorts 7 and 20 of the COSMIC-021 study. Neal, J. W., Santoro, A., Viteri, S., Aix, S., Fang, B., Lim, F., Gentzler, R. D., Goldschmidt, J. H., Khrizman, P., Massarelli, E., Patel, S. B., Puri, S., Sudhagoni, R., Scheffold, C., Curran, D., Felip, E. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000863680302196

• Representativeness of patients enrolled in the Lung Cancer Master Protocol (Lung-MAP). Vaidya, R., Unger, J. M., Qian, L., Minichiello, K., Herbst, R. S., Gandara, D. R., Neal, J. W., Leal, T., Patel, J. D., Dragnev, K. H., Waqar, S., Edelman, M., Sigal, E. V., Adam, S., Malik, S. M., Blanke, C., LeBlanc, M., Kelly, K., Redman, M. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000863680301843

• Matching-adjusted indirect comparison (MAIC) of mobocertinib versus amivantamab in patients with non-small cell lung cancer (NSCLC) with EGFR exon 20 insertions (ex20ins). Ou, S., Prawitz, T., Lin, H., Hong, J., Tan, M., Proskorovsky, I., Hernandez, L., Jin, S., Zhang, P., Lin, J., Patel, J. D., Nguyen, D., Neal, J. W. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000863680302300

• 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 No, H. J., Raja, N., Von Eyben, R., Das, M., Roy, M., Myall, N., Neal, J., Wakelee, H., Chin, A., Diehn, M., Loo, B. W., Chang, D. T., Pollom, E. L., Vitzthum, L. K. 2022

  Abstract

  Due to the limitations of current staging systems and evolving definitions, there are limited data on oligometastatic non-small cell lung cancer (NSCLC) epidemiology. The purpose of this study is to evaluate metastatic disease burden and the incidence of oligometastatic disease using recent clinical trial edibility criteria.A cohort of patients with metastatic NSCLC, diagnosed from 2016 to 2019, were randomly sampled from a curated tumor registry. Definitions for oligometastatic disease were obtained from relevant clinical trials. The Stanford Cancer Institute Research Database (SCIRDB) was used to identify baseline patient factors, systemic and local therapy, extent and location of metastatic lesions, and survival outcomes.Among 120 patients presenting with metastatic NSCLC, the majority had de novo metastatic disease (75%) with a median of 4 metastatic lesions involving 3 organ systems. 37.5% would have been eligible for at least one oligometastatic trial with 28.3% meeting criteria for MDACC, 20.0% for NRG-LU002, 6.7% for SINDAS and 16.7% for SABR-COMET. By adding malignant pleural effusions (MPE) and early progression as exclusionary criteria, only 54.1% of patients with ≤3 synchronous metastases were eligible for consideration of local therapy. Early progression on systemic therapy was associated with worse survival (10.0 vs. 42.4 months, p < 0.001), whereas presence of MPE was not. Of those tumors identified as oligometastatic, 44.4% received local therapy and 28.9% underwent ablative therapy to all sites. There was a trend towards greater overall survival (44.4 vs 24.9 months, p=0.055) and progression free survival (8.0 vs. 5.4 months, p=0.06) in patients meeting eligibility for at least one oligometastatic trial.Around 48% of patients with metastatic NSCLC had ≤3 metastases at presentation and 28% met clinical trial criteria for oligometastatic disease. Future research is needed to better define the oligometastatic state and identify patients most likely to benefit from local therapy.

  View details for DOI 10.1016/j.ijrobp.2022.04.050

  View details for PubMedID 35654305

• Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of lung cancer and mesothelioma. Journal for immunotherapy of cancer Govindan, R., Aggarwal, C., Antonia, S. J., Davies, M., Dubinett, S. M., Ferris, A., Forde, P. M., Garon, E. B., Goldberg, S. B., Hassan, R., Hellmann, M. D., Hirsch, F. R., Johnson, M. L., Malik, S., Morgensztern, D., Neal, J. W., Patel, J. D., Rimm, D. L., Sagorsky, S., Schwartz, L. H., Sepesi, B., Herbst, R. S. 2022; 10 (5)

  Abstract

  Immunotherapy has transformed lung cancer care in recent years. In addition to providing durable responses and prolonged survival outcomes for a subset of patients with heavily pretreated non-small cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs)- either as monotherapy or in combination with other ICIs or chemotherapy-have demonstrated benefits in first-line therapy for advanced disease, the neoadjuvant and adjuvant settings, as well as in additional thoracic malignancies such as small-cell lung cancer (SCLC) and mesothelioma. Challenging questions remain, however, on topics including therapy selection, appropriate biomarker-based identification of patients who may derive benefit, the use of immunotherapy in special populations such as people with autoimmune disorders, and toxicity management. Patient and caregiver education and support for quality of life (QOL) is also important to attain maximal benefit with immunotherapy. To provide guidance to the oncology community on these and other important concerns, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). This CPG represents an update to SITC's 2018 publication on immunotherapy for the treatment of NSCLC, and is expanded to include recommendations on SCLC and mesothelioma. The Expert Panel drew on the published literature as well as their clinical experience to develop recommendations for healthcare professionals on these important aspects of immunotherapeutic treatment for lung cancer and mesothelioma, including diagnostic testing, treatment planning, immune-related adverse events, and patient QOL considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers using immunotherapy to treat patients with lung cancer or mesothelioma.

  View details for DOI 10.1136/jitc-2021-003956

  View details for PubMedID 35640927

• Targeting Acquired and Intrinsic Resistance Mechanisms in Epidermal Growth Factor Receptor Mutant Non-Small-Cell Lung Cancer. Drugs Shah, M. P., Neal, J. W. 2022

  Abstract

  Over the past 2 decades, rapid advances in molecular profiling and the development of targeted therapies have dramatically improved the clinical course of advanced non-small-cell lung cancer (NSCLC). Mutations in the epidermal growth factor receptor (EGFR) gene are found in about a third of patients with advanced NSCLC, and the approval of first-generation EGFR targeted kinase inhibitors significantly improved survival when compared with platinum-based doublet chemotherapy (PBC), the previous standard of care. Inevitably, selective pressure from first-generation EGFR inhibitors led to acquired resistance mechanisms, such as the T790M mutation. The advent of third-generation EGFR inhibitors (e.g., osimertinib) successfully overcame the T790M resistance mechanism, and osimertinib subsequently became the first-line therapy for EGFR mutant NSCLC. Currently, research in EGFR mutant NSCLC is primarily focused on targeting resistance mechanisms to osimertinib. Over the past several years, many important acquired and intrinsic mechanisms of resistance to osimertinib have been identified. Acquired resistance mechanisms include C797X, mesenchymal epithelial transition factor (MET) amplification, HER2/HER3 amplification, phosphoinositide 3-kinase (PI3K) pathway mutations, RAS/mitogen-activated protein kinase (MAPK) pathway mutations, cell-cycle gene alterations, oncogenic fusions, and histologic transformations. An important intrinsic resistance mechanism to osimertinib is the EGFR exon 20 insertion mutation, which is sensitive to the newly Food and Drug Administration (FDA)-approved tyrosine kinase inhibitor mobocertinib and the EGFR/MET bispecific antibody amivantamab. This review article aims to (1) summarize the advances in the treatment of EGFR mutant NSCLC, (2) delineate known resistance mechanisms to the current first-line therapy, osimertinib, and (3) describe the development of targeted drugs that aim to overcome these resistance mechanisms.

  View details for DOI 10.1007/s40265-022-01698-z

  View details for PubMedID 35412115

• ANtiangiogenic Second-line Lung cancer Meta-Analysis on individual patient data in non-small cell lung cancer: ANSELMA. European journal of cancer (Oxford, England : 1990) Remon, J., Lacas, B., Herbst, R., Reck, M., Garon, E. B., Scagliotti, G. V., Ramlau, R., Hanna, N., Vansteenkiste, J., Yoh, K., Groen, H. J., Heymach, J. V., Mandrekar, S. J., Okamoto, I., Neal, J. W., Heist, R. S., Planchard, D., Pignon, J., Besse, B., ANSELMA collaborative group, Besse, B., Lacas, B., Pignon, J. P., Remon, J., Berghmans, T., Dahlberg, S., Felip, E., Berghmans, T., Besse, B., Dahlberg, S., Felip, E., Garon, E., Groen, H. J., Hanna, N., Heist, R. S., Herbst, R., Heymach, J. V., Lacas, B., Adjei, A. A., Heist, R., Mandrekar, S. J., Neal, J. W., Okamoto, I., Pignon, J., Ramlau, R., Remon, J., Reck, M., Scagliotti, G. V., Vansteenkiste, J., Yoh, K. 2022; 166: 112-125

  Abstract

  BACKGROUND: Now that immunotherapy plus chemotherapy (CT) is one standard optionin first-line treatment of advanced non-small cell lung cancer (NSCLC), there exists a medical need to assess the efficacy of second-line treatments (2LT) with antiangiogenics (AA). We performed an individual patient data meta-analysis to validate the efficacy of these combinations as 2LT.METHODS: Randomised trials of AA plus standard 2LT compared to 2LT alone that ended accrual before 2015 were eligible. Fixed-effect models were used to compute pooled hazard ratios (HRs) for overall survival (OS, main end-point), progression-free survival (PFS) and subgroup analyses.RESULTS: Sixteen trials were available (8,629 patients, 64% adenocarcinoma). AA significantly prolonged OS (HR=0.93 [95% confidence interval {CI}: 0.89; 0.98], p=0.005) and PFS (0.80 [0.77; 0.84], p<0.0001) compared with 2LT alone. Absolute 1-year OS and PFS benefit for AA were +1.8% [-0.4; +4.0] and +3.5% [+1.9; +5.1], respectively. The OS benefit of AA was higher in younger patients (HR=0.87 [95% CI: 0.76; 1.00], 0.89 [0.81; 0.97], 0.94 [0.87; 1.02] and 1,04 [0.93; 1.17] for patients <50, 50-59, 60-69 and≥70 years old, respectively; trend test: p=0.02)and in patients who started AA within 9 months after starting the first-line therapy (0.88 [0.82; 0.99]) than in patients who started AA later (0.99 [0.91; 1.08]) (interaction: p=0.03). Results were similar for PFS. AA increased the risk of hypertension (p<0.0001), but not the risk of pulmonary thromboembolic events (p=0.21).CONCLUSIONS: In the 2LT of advanced NSCLC, adding AA significantly prolongs OS and PFS, but the benefit is clinically limited, mainly observed in younger patients and after shorter time since the start of first-line therapy.

  View details for DOI 10.1016/j.ejca.2022.02.002

  View details for PubMedID 35286903

• Risk factors for immune checkpoint inhibitor-related pneumonitis in non-small cell lung cancer TRANSLATIONAL LUNG CANCER RESEARCH Chao, Y., Zhou, J., Hsu, S., Ding, N., Li, J., Zhang, Y., Xu, X., Tang, X., Wei, T., Zhu, Z., Chu, Q., Neal, J. W., Wu, J., Song, Y., Hu, J. 2022

  View details for DOI 10.21037/tlcr-22-72

  View details for Web of Science ID 000761628800001

• Risk factors for immune checkpoint inhibitor-related pneumonitis in non-small cell lung cancer. Translational lung cancer research Chao, Y., Zhou, J., Hsu, S., Ding, N., Li, J., Zhang, Y., Xu, X., Tang, X., Wei, T., Zhu, Z., Chu, Q., Neal, J. W., Wu, J. T., Song, Y., Hu, J. 2022; 11 (2): 295-306

  Abstract

  Immune checkpoint inhibitors (ICIs) have led to dramatic improvements in survival a subset of patients with non-small cell lung cancer (NSCLC); however, they have been shown to cause life-threatening toxicity such as immune checkpoint inhibitor-related pneumonitis (CIP). Our previous studies have shown that chronic obstructive pulmonary disease (COPD) and circulating cytokines are associated with clinical outcomes in NSCLC patients receiving ICIs. However, the relationship between these factors and the development of CIP is unclear. In this study, we retrospectively assessed NSCLC patients receiving ICIs to identify CIP risk factors.This retrospective cohort study reviewed medical records of NSCLC patients receiving ICIs targeting programmed cell death 1 (PD-1) or its ligand PD-L1 between March 2017 and December 2020 at Zhongshan Hospital Fudan University. CIP was diagnosed by the treating investigator. Clinical characteristics and baseline plasma cytokines were collected. Logistic regression was used to compare clinical characteristics and circulating cytokine levels between patients with and without CIP to identify CIP risk factors.Of 164 NSCLC patients who received ICIs, CIP developed in 20 cases (12.2%). The presence of COPD [odds ratio (OR), 7.194; 95% confidence interval (CI): 1.130 to 45.798; P=0.037] and PD-L1 expression of ≥50% (OR, 7.184; 95% CI: 1.154 to 44.721; P=0.035) were independently associated with a higher incidence of CIP, whereas a higher baseline level of interleukin-8 (IL-8) was associated with a lower incidence of CIP (OR, 0.758; 95% CI: 0.587 to 0.978; P=0.033). The independent risk factors from final multivariate analysis were incorporated into a nomogram to predict the incidence of CIP. The nomogram model receiver operating characteristic (ROC) curve had a good predictive accuracy of 0.883 (95% CI: 0.806 to 0.959).Increased risk of CIP independently associated with history of COPD, tumor PD-L1 expression ≥50%, and low baseline IL-8 level. The nomogram may hold promise for CIP risk assessment in the administration of ICIs.

  View details for DOI 10.21037/tlcr-22-72

  View details for PubMedID 35280322

  View details for PubMedCentralID PMC8902097

• The Role of Single-Cell Profiling and Deep Immunophenotyping in Understanding Immune Therapy Cardiotoxicity JACC: CardioOncology Huang, Y. V., Waliany, S., Lee, D., Galdos, F. X., Witteles, R. M., Neal, J. W., Fan, A. C., Maecker, H. T., Nguyen, P. K., Wu, S. M., Zhu, H. 2022; 4 (5): 629–634

  View details for DOI 10.1016/j.jaccao.2022.08.012

• Afatinib After Progression on Osimertinib in EGFR-Mutated Non-Small Cell Lung Cancer. Cancer treatment and research communications Aredo, J. V., Wakelee, H. A., Neal, J. W., Padda, S. K. 1800; 30: 100497

  Abstract

  INTRODUCTION: After the development of acquired resistance to osimertinib, the standard-of-care treatment for advanced EGFR-mutated NSCLC is chemotherapy. Whether afatinib, a pan-ErbB family tyrosine kinase inhibitor, is active after progression on osimertinib is unknown.METHODS: We conducted a single-institution retrospective analysis of patients with advanced EGFR-mutated NSCLC who received afatinib-containing therapy after progression on osimertinib. Kaplan-Meier analyses evaluated progression-free survival (PFS) and overall survival (OS) from initiation of afatinib.RESULTS: After progression on first (N=3) or second-line plus (N=12) osimertinib, 15 patients received afatinib monotherapy (N=3), afatinib and cetuximab (N=10), or afatinib and bevacizumab (N=2). The objective response rate was 6.7% and disease control rate was 53.3%. Median PFS was 2.5 months and median OS was 7.7 months. Median PFS of ≥ 6 months versus < 6 months on osimertinib was associated with a significantly greater median PFS on afatinib (4.0 versus 1.4 months; P=0.003), although there was no significant difference in median OS (9.3 versus 6.6 months; P=0.123). Best response of stable disease/partial response versus progressive disease on osimertinib was associated with a significantly greater median PFS on afatinib (3.4 versus 1.6 months; P=0.036) and a significantly greater median OS (8.7 versus 4.6 months; P=0.017).CONCLUSION: Afatinib-containing therapy had limited activity in patients with EGFR-mutated NSCLC after progression on osimertinib in this cohort of mostly second-line plus osimertinib. Response and longer PFS to prior osimertinib may be predictive of response to afatinib. Strategies based on osimertinib resistance mechanisms may further define the role of subsequent afatinib.

  View details for DOI 10.1016/j.ctarc.2021.100497

  View details for PubMedID 34920242

• Consolidation Durvalumab Should Not Be Administered to Patients With Stage III EGFR-Mutant NSCLC. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Aredo, J. V., Hellyer, J. A., Neal, J. W., Wakelee, H. A. 2021; 16 (12): 1994-1998

  View details for DOI 10.1016/j.jtho.2021.07.033

  View details for PubMedID 34809803

• A phase 1b study of erlotinib and momelotinib for the treatment of EGFR-mutated, tyrosine kinase inhibitor-naive metastatic non-small cell lung cancer. Cancer chemotherapy and pharmacology Padda, S. K., Reckamp, K. L., Koczywas, M., Neal, J. W., Kawashima, J., Kong, S., Huang, D. B., Kowalski, M., Wakelee, H. A. 2021

  Abstract

  INTRODUCTION: Preclinical evidence suggests the feedforward cytokine loop of interleukin-6/Janus kinases (JAK)/STAT3 plays a role in epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resistance in EGFR-mutated non-small cell lung cancer (NSCLC).METHODS: In this phase 1b study, the JAK1/2 and TANK-binding kinase 1 (TBK1) inhibitor momelotinib was evaluated in combination with erlotinib in patients with EGFR TKI-naive, EGFR-mutated NSCLC. After erlotinib lead-in (50, 75, 100, or 150mg oral daily [QD]), momelotinib was combined and dose escalated in a 3+3 study design. The primary endpoint of maximum tolerated dose (MTD) of momelotinib was determined based on the incidence of dose-limiting toxicities (DLTs) during the first 28-day cycle. Secondary endpoints included efficacy and pharmacokinetics (PK).RESULTS: Eleven patients were enrolled across 3 dose levels of momelotinib (100mg QD, 200mg QD, and 100mg twice daily [BID]). The MTD was momelotinib 200mg QD in combination with erlotinib. Two DLTs of grade 4 neutropenia without fever and grade 3 diarrhea occurred at momelotinib 100mg BID. Most common treatment-emergent adverse events included diarrhea, dry skin, fatigue, and decreased appetite; the vast majority being grades 1-2. The overall response rate was 54.5% (90% CI 27.1-80.0; all partial) and median progression-free survival was 9.2months (90% CI 6.2-12.4). Momelotinib did not affect the PK of erlotinib.CONCLUSIONS: The JAK1/2 and TBK1 inhibitor momelotinib in combination with erlotinib did not appear to enhance benefit over the historical data of erlotinib monotherapy in patients with EGFR-mutated NSCLC. CLINICALTRIALS.GOV IDENTIFIER: NCT02206763.

  View details for DOI 10.1007/s00280-021-04369-0

  View details for PubMedID 34773474

• Chemotherapy Plus Immunotherapy Versus Chemotherapy Plus Bevacizumab Versus Chemotherapy Alone in EGFR-Mutant NSCLC After Progression on Osimertinib. Clinical lung cancer White, M. N., Piper-Vallillo, A. J., Gardner, R. M., Cunanan, K., Neal, J. W., Das, M., Padda, S. K., Ramchandran, K., Chen, T. T., Sequist, L. V., Piotrowska, Z., Wakelee, H. A. 2021

  Abstract

  INTRODUCTION: Patients with EGFR-mutant lung cancer who have had disease progression on osimertinib commonly receive platinum doublet chemotherapy, but whether adding immunotherapy or bevacizumab provides additional benefit is unknown.MATERIALS AND METHODS: This was a retrospective analysis at 2 university-affiliated institutions. Patients with EGFR-mutant lung cancer who had progression on osimertinib and received next-line therapy with platinum doublet chemotherapy (chemo), platinum doublet chemotherapy plus immunotherapy (chemo-IO), or platinum doublet chemotherapy plus bevacizumab (chemo-bev), were identified; patients who continued osimertinib with these regimens were included. Efficacy outcomes including duration on treatment (DOT) and overall survival (OS) from the start of chemotherapy were assessed. Associations of treatment regimen with outcomes were evaluated using adjusted Cox regression models, using pairwise comparisons between groups.RESULTS: 104 patients were included: 57 received chemo, 12 received chemo-IO, and 35 received chemo-bev. In adjusted models, patients who received chemo-IO had worse OS than did those who received chemo (hazard ratio (HR) 2.66, 95% CI 1.25-5.65; P= .011) or those who received chemo-bev (HR 2.37, 95% CI 1.09-5.65; P= .030). A statistically significant difference in OS could not be detected in patients who received chemo-bev versus those who received chemo (HR 1.50, 95% CI 0.84-2.69; P= .17).CONCLUSION: In this retrospective study, giving immunotherapy with platinum doublet chemotherapy after progression on osimertinib was associated with a worse OS compared with platinum doublet chemotherapy alone. Platinum doublet chemotherapy without immunotherapy (with consideration of continuation of osimertinib, in selected cases) is a reasonable choice in this setting, while we await results of clinical trials examining optimal next-line chemotherapy-based regimens in EGFR-mutant lung cancer.

  View details for DOI 10.1016/j.cllc.2021.11.001

  View details for PubMedID 34887193

• Computational Biological Modeling Identifies PD-(L)1 Immunotherapy Sensitivity Among Molecular Subgroups of KRAS-Mutated Non-Small-Cell Lung Cancer. JCO precision oncology Padda, S. K., Aredo, J. V., Vali, S., Singh, N. K., Vasista, S. M., Kumar, A., Neal, J. W., Abbasi, T., Wakelee, H. A. 2021; 5: 153-162

  Abstract

  KRAS-mutated (KRASMUT) non-small-cell lung cancer (NSCLC) is emerging as a heterogeneous disease defined by comutations, which may confer differential benefit to PD-(L)1 immunotherapy. In this study, we leveraged computational biological modeling (CBM) of tumor genomic data to identify PD-(L)1 immunotherapy sensitivity among KRASMUT NSCLC molecular subgroups.In this multicohort retrospective analysis, the genotype clustering frequency ranked method was used for molecular clustering of tumor genomic data from 776 patients with KRASMUT NSCLC. These genomic data were input into the CBM, in which customized protein networks were characterized for each tumor. The CBM evaluated sensitivity to PD-(L)1 immunotherapy using three metrics: programmed death-ligand 1 expression, dendritic cell infiltration index (nine chemokine markers), and immunosuppressive biomarker expression index (14 markers).Genotype clustering identified eight molecular subgroups and the CBM characterized their shared cancer pathway characteristics: KRASMUT/TP53MUT, KRASMUT/CDKN2A/B/CMUT, KRASMUT/STK11MUT, KRASMUT/KEAP1MUT, KRASMUT/STK11MUT/KEAP1MUT, KRASMUT/PIK3CAMUT, KRAS MUT/ATMMUT, and KRASMUT without comutation. CBM identified PD-(L)1 immunotherapy sensitivity in the KRASMUT/TP53MUT, KRASMUT/PIK3CAMUT, and KRASMUT alone subgroups and resistance in the KEAP1MUT containing subgroups. There was insufficient genomic information to elucidate PD-(L)1 immunotherapy sensitivity by the CBM in the KRASMUT/CDKN2A/B/CMUT, KRASMUT/STK11MUT, and KRASMUT/ATMMUT subgroups. In an exploratory clinical cohort of 34 patients with advanced KRASMUT NSCLC treated with PD-(L)1 immunotherapy, the CBM-assessed overall survival correlated well with actual overall survival (r = 0.80, P < .001).CBM identified distinct PD-(L)1 immunotherapy sensitivity among molecular subgroups of KRASMUT NSCLC, in line with previous literature. These data provide proof-of-concept that computational modeling of tumor genomics could be used to expand on hypotheses from clinical observations of patients receiving PD-(L)1 immunotherapy and suggest mechanisms that underlie PD-(L)1 immunotherapy sensitivity.

  View details for DOI 10.1200/PO.20.00172

  View details for PubMedID 34994595

• A Phase II Trial of Individualized Stereotactic Ablative Radiotherapy for Lung Tumors (iSABR) Gensheimer, M. F., Gee, H. E., Von Eyben, R., Shirato, H., Taguchi, H., Wong, S., Brown, E., Nguyen, N., Liang, R., Maxim, P. G., Wakelee, H. A., Neal, J. W., Das, M., Loo, B. W., Diehn, M. ELSEVIER SCIENCE INC. 2021: S89-S90

  View details for Web of Science ID 000715803801515

• Patterns of Care in Patients With Isolated Nodal Recurrence After Definitive Stereotactic Ablative Radiotherapy for Non-Small Cell Lung Cancer Devine, M., Merriott, D. J., Say, C., Yoo, C., Yi, E., Lau, B., Ko, R. B., Shaheen, S., Neal, J. W., Wakelee, H. A., Das, M., Loo, B. W., Diehn, M., Chin, A. L., Vitzthum, L. ELSEVIER SCIENCE INC. 2021: E435

  View details for Web of Science ID 000715803800895

• Pulmonary Hemorrhage in Patients Treated With Thoracic Stereotactic Ablative Radiotherapy and Anti-Angiogenic Agents Lau, B., No, H. J., Wu, Y. F., Ko, R. B., Devine, M., Das, M., Neal, J. W., Ramchandran, K. J., Wakelee, H. A., Shaheen, S., Diehn, M., Chin, A. L., Loo, B. W., Vitzthum, L. ELSEVIER SCIENCE INC. 2021: E423

  View details for Web of Science ID 000715803800868

• A Phase II Trial of Individualized Stereotactic Ablative Radiotherapy for Lung Tumors (iSABR). International journal of radiation oncology, biology, physics Gensheimer, M. F., Gee, H. E., Von Eyben, R., Shirato, H., Taguchi, H., Wong, S., Brown, E., Nguyen, N., Liang, R., Maxim, P. G., Wakelee, H. A., Neal, J. W., Das, M., Loo, B. W., Diehn, M. 2021; 111 (3S): S89-S90

  Abstract

  PURPOSE/OBJECTIVE(S): Stereotactic ablative radiotherapy (SABR) is an effective treatment for lung tumors, but can result in toxicity such as chest wall pain and life-threatening damage to central lung structures. We hypothesized that while larger tumors require higher dose, small tumors up to 10cc in volume can be controlled with biologically effective dose < 100Gy. In this phase II single-arm trial, we tested the hypothesis that individualizing lung SABR dose and fractionation to tumor size, location, and histology would result in excellent local control with acceptable toxicity. The trial was conducted at two centers in the United States and Japan (NCT# redacted for blinded review).MATERIALS/METHODS: Patients in three groups were enrolled: initial diagnosis of non-small cell lung cancer (NSCLC), AJCC 7th edition stage T1-3 N0 M0 (group 1); new primary NSCLC with history of NSCLC, or multiple synchronously diagnosed NSCLCs (group 2); and lung metastases from NSCLC or another primary site (group 3). Up to four tumors could be treated with once-daily SABR. There were six dose/fractionation schedules used, depending on gross tumor volume (≤10cc, 10-30cc, > 30cc) and location (peripheral vs. central). Larger tumors received higher dose and central tumors generally received lower dose per fraction. Dose ranged from 25Gy in one fraction for 0-10cc peripheral tumors to 60Gy in 8 fractions for > 30cc central tumors. Colorectal cancer metastases were treated to higher dose, at least 50Gy in 4 fractions. The primary endpoint was per-group cumulative incidence of local recurrence at 1 year (recurrence of treated tumor within same lobe), with distant recurrence and death as competing risks. Treated tumor recurrence (recurrence with epicenter within 1cm of PTV) and toxicity were also analyzed.RESULTS: A total of 217 patients were enrolled from 2011-2018 (some patients were enrolled multiple times). Median age was 72, 59% were male, and 69% were current/former smokers. There were 240 treatment courses and 285 tumors treated (range 1-3 tumors per course). 211 tumors were peripheral and 74 were central. Tumor size distribution was: ≤10cc, 74%; 10-30cc, 19%; > 30cc, 7%. The most common dose was 25Gy in one fraction (158 tumors). Median follow-up was 30 months (range 2-95). Median overall survival was 57 months. Local recurrence data are currently being updated and will be presented at the meeting. The rate of grade 2 or higher pneumonitis was 16/217 (7%) and grade 3 or higher pneumonitis was 3/217 (1%). The rate of grade 2 or higher chest wall pain was 13/217 (6%). One patient had a grade 5 adverse event, developing pulmonary hemorrhage that was possibly related to radiotherapy, 17 months after treatment of a large central NSCLC.CONCLUSION: Individualized SABR to lung cancers resulted in excellent local control and favorable toxicity profile.

  View details for DOI 10.1016/j.ijrobp.2021.07.212

  View details for PubMedID 34700657

• Patterns of Care in Patients With Isolated Nodal Recurrence After Definitive Stereotactic Ablative Radiotherapy for Non-Small Cell Lung Cancer. International journal of radiation oncology, biology, physics Devine, M., Merriott, D. J., Say, C., Yoo, C., Yi, E., Lau, B., Ko, R. B., Shaheen, S., Neal, J. W., Wakelee, H. A., Das, M., Loo, B. W., Diehn, M., Chin, A. L., Vitzthum, L. 2021; 111 (3S): e435

  Abstract

  PURPOSE/OBJECTIVE(S): Patients treated with stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer (NSCLC) have high rates of local control but may be at increased risk of nodal recurrence compared to those who undergo surgical resection with more invasive nodal evaluation. The optimal treatment for patients with isolated nodal recurrence (INR) is unclear. The purpose of this study is to determine the rate of INR after SABR for early-stage NSCLC and describe patterns of care and treatment outcomes for patients that experience INR.MATERIALS/METHODS: This retrospective cohort study included 342 patients with stage T1-3N0 NSCLC treated with definitive SABR. We evaluated the estimated rate of INR using the cumulative incidence function with death as a competing risk and compared baseline factors among patients who did or did not experience INR. Among patients that experienced INR, we describe patterns of treatment and outcomes including overall (OS) and progression free survival (PFS) from the time of nodal failure using the Kaplan-Meier method. OS and PFS outcomes were compared between treatment groups using the log-rank test.RESULTS: Of the 342 patients treated with SABR from 2003-2018, 34 developed INR and 19 developed any nodal recurrence. Patients were treated with definitive SABR for T1 (62.6%, n = 214), T2 (25.4%, n = 87) and T3 (12.0%, n = 41) NSCLC with a median BED10 of 87.5. The 3- and 5-year cumulative incidence of INR was 9.3 (95% CI 6.1 - 12.4) and 10.1 (6.8 -13.4) %, respectively. Pathologic nodal staging prior to SBRT was 9.1 and 13.3 % (P = 0.68) for patients who did or did not experience INR, respectively. The median number of involved nodes at the time of recurrence was one with a maximum of four. Among the 30 patients with a known treatment course after INR, patients were treated with RT alone (26.7 %, n = 8), chemotherapy and RT (CRT) (43.3 %, n = 13), chemotherapy alone (13.3%, n = 4) or observation (16.7%, n = 5). RT regimens included standard fractionation (38.0%, n = 8), hypofractionation (52.4%, n = 11) or SABR (9.5%, n = 2). The estimated two-year OS and PFS for patients experiencing INR were 48.0 (32.6 - 70.7) % and 27.6 (14.7 - 52.8) %, respectively. Treatment with CRT was associated with improved OS (2 year est: 91.7 vs 16.7 %, P < 0.01) and PFS (2 year est: 63.9 vs 0 %, P < 0.01) over RT alone. Similarly, CRT was associated with improved OS (91.7 vs 25.0 %, P < 0.01) and PFS (63.9 vs 0%, P < 0.01) over chemotherapy alone. Median follow-up time after INR was 21.7 months.CONCLUSION: INR occurred in approximately 10% of patients treated for early-stage NSCLC with SABR. Treatment paradigms for post-SABR INR varied significantly at our institution and included combined chemotherapy and radiation, chemotherapy alone, SABR and hypofractionated RT. The highest rates of survival in patients with post-SABR INR were observed in those treated with combined chemotherapy and radiation.

  View details for DOI 10.1016/j.ijrobp.2021.07.1235

  View details for PubMedID 34701446

• Impact of Tumor Suppressor Gene Co-Mutations on Differential Response to EGFR TKI Therapy in EGFR L858R and Exon 19 Deletion Lung Cancer. Clinical lung cancer Hellyer, J. A., White, M. N., Gardner, R. M., Cunanan, K., Padda, S. K., Das, M., Ramchandran, K., Neal, J. W., Wakelee, H. A. 2021

  Abstract

  BACKGROUND: In most studies, patients with EGFR L858R mutant non-small cell lung cancer (NSCLC) have a shorter duration of response to EGFR tyrosine kinase inhibitor (TKI) therapy than do patients with EGFR exon 19 deletion NSCLC. The role that co-mutations play in this observation is unknown.METHODS: We performed a single-institution retrospective analysis of patients with EGFR-mutant NSCLC (exon 19 deletion or L858R mutation) who received frontline EGFR TKI for metastatic disease between 2014 and 2019, and who had STAMP next-generation sequencing (NGS), a 130-gene platform. Time to treatment failure (TTF) and overall survival were calculated using Cox models adjusted for age, race, and brain metastases. Co-mutations in key tumor suppressor genes (TP53, RB1, KEAP1, CDKN2A, or CTNNB1) were identified and their effects on outcomes were evaluated. Analyses were stratified according to receipt of osimertinib versus nonosimertinib as frontline EGFR TKI.RESULTS: Of 137 patients, 72 (57%) had EGFR exon 19 deletions and 65 (43%) had EGFR L858R mutations. Median TTF and OS on frontline TKI was shorter for the L858R cohort versus the exon 19 deletion cohort in univariate analysis. In adjusted models, this difference persisted for TTF but was no longer significant for OS. The difference in TTF in L858R mutant tumors was driven by the presence of co-mutations in key tumor suppressor genes.CONCLUSION: Patients with metastatic NSCLC with mutations in EGFR L858R had shorter TTF on frontline TKI compared to patients with EGFR exon 19 deletions. Co-mutations in tumor suppressor genes may play an important role in the differential response to TKI therapy.

  View details for DOI 10.1016/j.cllc.2021.09.004

  View details for PubMedID 34838441

• Use of a computer model and care coaches to increase advance care planning conversations for patients with metastatic cancer Gupta, D., Fardeen, T., Teuteberg, W., Seevaratnam, B., Asuncion, M., Alves, N., Rogers, B., Neal, J. W., Fan, A. C., Parikh, D., Patel, M. I., Shah, S., Srinivas, S., Huang, J. E., Reddy, S. A., Ganjoo, K. N., Bui, N., Hansen, J., Gensheimer, M. F., Ramchandran, K. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1200/JCO.2020.39.28_suppl.8

  View details for Web of Science ID 000707130200008

• Mobocertinib in EGFR Exon 20 InsertionePositive Metastatic NSCLC Patients With Disease Control on Prior EGFR TKI Therapy Spira, A., Ramalingam, S., Neal, J., Piotrowska, Z., Mekhail, T., Tsao, A., Gentzler, R., Riely, G., Bazhenova, L., Gadgeel, S., Nguyen, D., Johnson, M., Vincent, S., Jin, S., Griffin, C., Bunn, V., Lin, J., Churchill, E., Mehta, M., Janne, P. ELSEVIER SCIENCE INC. 2021: S873-S874

  View details for Web of Science ID 000709606500081

• Survival After Distant Recurrent Versus De Novo Stage IV Metastatic Lung Cancer Under Low-Dose Computed Tomography Screening Su, C., Choi, E., Wu, J., Neal, J., Kurian, A., Backhus, L., Leung, A., Wakelee, H., Han, S. ELSEVIER SCIENCE INC. 2021: S1177-S1178

  View details for Web of Science ID 000709606500646

• A Predictive Model to Guide Brain MRI Surveillance in Patients With Metastatic Lung Cancer: Impact on Real World Outcomes Wu, J., Ding, V., Luo, S., Choi, E., Hellyer, J., Myall, N., Henry, S., Wood, D., Stehr, H., Ji, H., Nagpal, S., Gephart, M., Wakelee, H., Neal, J., Han, S. ELSEVIER SCIENCE INC. 2021: S1177

  View details for Web of Science ID 000709606500645

• Implementation of a cloud-based electronic patient-reported outcome (ePRO) platform in patients with advanced cancer. Journal of patient-reported outcomes Generalova, O., Roy, M., Hall, E., Shah, S. A., Cunanan, K., Fardeen, T., Velazquez, B., Chu, G., Bruzzone, B., Cabot, A., Fisher, G. A., Srinivas, S., Fan, A. C., Haraldsdottir, S., Wakelee, H. A., Neal, J. W., Padda, S. K., Johnson, T., Heestand, G. M., Hsieh, R. W., Ramchandran, K. 2021; 5 (1): 91

  Abstract

  BACKGROUND: Patient reported outcomes (PROs) have been associated with improved symptom management and quality of life in patients with cancer. However, the implementation of PROs in an academic clinical practice has not been thoroughly described. Here we report on the execution, feasibility and healthcare utilization outcomes of an electronic PRO (ePRO) application for cancer patients at an academic medical center.METHODS: We conducted a randomized trial comparing an experimental ePRO arm to standard of care in patients with advanced cancer in the thoracic, gastrointestinal, and genitourinary oncology groups at Stanford Cancer Center from March 2018 to November 2019. We describe the pre-implementation, implementation, and post-implementation phases of the ePRO arm, technological barriers, electronic health record (EHR) integration, clinician burden, and patient data privacy and security. Feasibility was pre-specified to be at least 70% completion of all questionnaires. Acceptability was based on patient and clinician feedback. Ambulatory healthcare utilization was assessed by reviewing numbers of phone messages, electronic portal messages, and referrals for supportive care.RESULTS: Of 617 ePRO questionnaires sent to 72 patients, 445 (72%) were completed. Most clinicians (87.5%) and patients (93%) felt neutral or positive about the ePRO tool's ease of use. Exposure to ePRO did not cause a measurable change in ambulatory healthcare utilization, with a median of less than two phone messages and supportive care referrals, and 5-6 portal messages.CONCLUSIONS: Web-based ePRO tools for patients with advanced cancer are feasible and acceptable without increasing clinical burden. Key lessons include the importance of pilot testing, engagement of stakeholders at all levels, and the need for customization by disease group. Future directions for this work include completion of EHR integration, expansion to other centers, and development of integrated workflows for routine clinical practice.

  View details for DOI 10.1186/s41687-021-00358-2

  View details for PubMedID 34524558

• Radiological tumor classification across imaging modality and histology. Nature machine intelligence Wu, J., Li, C., Gensheimer, M., Padda, S., Kato, F., Shirato, H., Wei, Y., Schönlieb, C. B., Price, S. J., Jaffray, D., Heymach, J., Neal, J. W., Loo, B. W., Wakelee, H., Diehn, M., Li, R. 2021; 3: 787-798

  Abstract

  Radiomics refers to the high-throughput extraction of quantitative features from radiological scans and is widely used to search for imaging biomarkers for prediction of clinical outcomes. Current radiomic signatures suffer from limited reproducibility and generalizability, because most features are dependent on imaging modality and tumor histology, making them sensitive to variations in scan protocol. Here, we propose novel radiological features that are specially designed to ensure compatibility across diverse tissues and imaging contrast. These features provide systematic characterization of tumor morphology and spatial heterogeneity. In an international multi-institution study of 1,682 patients, we discover and validate four unifying imaging subtypes across three malignancies and two major imaging modalities. These tumor subtypes demonstrate distinct molecular characteristics and prognoses after conventional therapies. In advanced lung cancer treated with immunotherapy, one subtype is associated with improved survival and increased tumor-infiltrating lymphocytes compared with the others. Deep learning enables automatic tumor segmentation and reproducible subtype identification, which can facilitate practical implementation. The unifying radiological tumor classification may inform prognosis and treatment response for precision medicine.

  View details for DOI 10.1038/s42256-021-00377-0

  View details for PubMedID 34841195

  View details for PubMedCentralID PMC8612063

• 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 Waliany, S., Zhu, H., Wakelee, H., Padda, S. K., Das, M., Ramchandran, K., Myall, N. J., Chen, T., Witteles, R. M., Neal, J. W. 2021

  Abstract

  INTRODUCTION: Targeted therapies have transformed treatment of driver-mutated metastatic non-small cell lung carcinoma (NSCLC). We compared cardiovascular adverse events between and within targeted therapy classes.METHODS: We used WHO pharmacovigilance database VigiBase to compare odds of heart failure, conduction disease, QT prolongation, supraventricular tachycardia (SVT), and ventricular arrhythmias between inhibitors of EGFR (erlotinib, gefitinib, afatinib, osimertinib), BRAF (dabrafenib), MEK (trametinib), and ALK ± ROS1 (alectinib, brigatinib, ceritinib, crizotinib, lorlatinib).RESULTS: Of 98,765 adverse reactions reported with NSCLC targeted therapies, 1,783 (1.8%) were arrhythmias and 1,146 (1.2%) were heart failure. ALK/ROS1 inhibitors were associated with increased odds of conduction disease (reporting odds ratio [ROR] 12.95, 99% CI: 10.14-16.55) and QT prolongation (ROR 5.16, 99% CI: 3.92-6.81) relative to BRAF and EGFR inhibitors. Among ALK/ROS1 inhibitors, crizotinib had highest odds of conduction disease (ROR 1.75, 99% CI: 1.30-2.36) and QT prolongation (ROR 1.91, 99% CI: 1.22-3.00). Dabrafenib (ROR 2.24, 99% CI: 1.86-2.70) and trametinib (ROR 2.44, 99% CI: 2.03-2.92) had higher odds of heart failure than other targeted therapies. Osimertinib was strongly associated with QT prolongation (ROR 6.13, 99% CI: 4.43-8.48), heart failure (ROR 3.64, 99% CI: 2.94-4.50), and SVT (ROR 1.90, 99% CI: 1.26-2.86) relative to other targeted therapies.CONCLUSIONS: ALK/ROS1 inhibitors are associated with higher odds of conduction disease and QT prolongation than other targeted therapies. Osimertinib is strongly associated with QT prolongation, SVT, and heart failure relative to other EGFR inhibitors and targeted therapies. Monitoring for heart failure and arrhythmias should be considered with NSCLC targeted therapies, especially osimertinib.

  View details for DOI 10.1016/j.jtho.2021.07.030

  View details for PubMedID 34418561

• Radiological tumour classification across imaging modality and histology NATURE MACHINE INTELLIGENCE Wu, J., Li, C., Gensheimer, M., Padda, S., Kato, F., Shirato, H., Wei, Y., Schonlieb, C., Price, S., Jaffray, D., Heymach, J., Neal, J. W., Loo, B. W., Wakelee, H., Diehn, M., Li, R. 2021

  View details for DOI 10.1038/s42256-021-00377-0

  View details for Web of Science ID 000685037800005

• The role of ramucirumab with docetaxel in epidermal growth factor receptor mutant and wild-type non-small cell lung cancer. Journal of thoracic disease Ellis-Caleo, T., Neal, J. W. 2021; 13 (8): 4864-4871

  Abstract

  Ramucirumab paired with docetaxel extends progression free survival and overall survival in non-small cell lung cancer (NSCLC) following progression on platinum therapy. There is some data that epidermal growth factor receptor (EGFR) mutant disease would respond better to vascular endothelial growth factor receptor (VEGFR) therapy than EGFR wild type disease.This retrospective, single-institution cohort study reports outcomes of patients who received docetaxel with or without ramucirumab according to EGFR status. Clinical data including age, performance status, metastatic burden and prior treatment history was obtained and reported with time on treatment and overall survival as primary endpoints. Data analysis was performed for three cohorts: EGFR mutant disease receiving docetaxel and ramucirumab (EGFR-doce/ram), EGFR mutant disease receiving docetaxel alone (EGFR-doce) and EGFR wild type disease receiving docetaxel and ramucirumab (WT-doce/ram).Patients in the EGFR-doce/ram cohort had a median time on docetaxel of 1.4 months (95% CI: 0.72-5.2 months) and of 0.8 months (95% CI: 0.2-6.5 months) on ramucirumab. Patients in the EGFR-doce cohort were on docetaxel for a median 1.4 months (95% CI: 0.9-2.4 months). Patients in the WT-doce/ram cohort had a median time on docetaxel of 2.3 months (95% CI: 1.6-4.1 months) and on ramucirumab of 1.4 months (95% CI: 0.8-3.2 months). There was no significant difference between time on ramucirumab or docetaxel between the cohorts. Overall survival for the three cohorts was noted to be 6.7 months (95% CI: 2.5-16.2 months) for the EGFR-doce/ram cohort, 4.9 months (95% CI: 4.2-12.5 months) for the EGFR-doce cohort and 6.6 months (95% CI: 4.3-12.8 months) for the WT-doce/ram cohort. There was no significant difference in overall survival between the cohorts.Our data did not support the initial hypothesis that patients with EGFR mutant disease would do better with the addition of ramucirumab. Our study was limited by small sample size, retrospective nature and inability to control for confounders including prior bevacizumab or immune checkpoint inhibitor (ICI) exposure. This study offers real-world estimates to clinicians and patients about the length of time they can expect to derive benefit from the combination of ramucirumab and docetaxel.

  View details for DOI 10.21037/jtd-21-557

  View details for PubMedID 34527325

  View details for PubMedCentralID PMC8411152

• EGFR exon 20 Insertion NSCLC and Response to Platinum-Based Chemotherapy. Clinical lung cancer Shah, M. P., Aredo, J. V., Padda, S. K., Ramchandran, K. J., Wakelee, H. A., Das, M. S., Neal, J. W. 2021

  Abstract

  INTRODUCTION: In classical EGFR mutant non-small-cell lung cancer (NSCLC), EGFR tyrosine kinase inhibitor (TKI) therapy yields better outcomes than platinum-based chemotherapy. However, EGFR exon 20 insertion (ex20ins) NSCLC is relatively resistant to currently available EGFR TKIs. Though platinum-based chemotherapy is the frontline standard of care for EGFR ex20ins NSCLC, its efficacy is not fully described.STUDY DESIGN: A retrospective, single-center, case series METHODS: Patients were identified through an electronic research database at a single institution and included if they had advanced EGFR ex20ins NSCLC, received platinum-based chemotherapy for metastatic disease, and had scans evaluable for response. Each patient's demographics, tumor characteristics, and clinical course were recorded. Treatment response was evaluated using RECIST v1.1 criteria, and the PFS was calculated by the Kaplan-Meier method.RESULTS: Among 27 patients identified with EGFR ex20ins NSCLC at our institution, 18 (67%) received platinum-based chemotherapy for metastatic disease and had scans evaluable for response. These patients received platinum-based chemotherapy in the first-line (N=17, 94%) and second-line settings (N=1, 6%). The objective response rate (ORR) to platinum-based chemotherapy was 39% (7 of 18 patients; 95% confidence interval [CI] 16-61). The median PFS with platinum-based chemotherapy was 7.1 months (95% CI, 6.3 -13.7), and the median overall survival was 3.2 years (95% CI, 1.92 - NR).CONCLUSIONS: The efficacy of platinum-based chemotherapy in EGFR ex20ins NSCLC is similar to that expected for TKI sensitive EGFR mutant NSCLC. Novel agents designed to specifically target ex20ins mutant EGFR should additionally improve outcomes.

  View details for DOI 10.1016/j.cllc.2021.07.001

  View details for PubMedID 34391686

• The role of ramucirumab with docetaxel in epidermal growth factor receptor mutant and wild-type non-small cell lung cancer JOURNAL OF THORACIC DISEASE Ellis-Caleo, T., Neal, J. W. 2021

  View details for DOI 10.21037/jtd-21-557

  View details for Web of Science ID 000683743500001

• Real-world response and outcomes in NSCLC patients with EGFR exon 20 insertion mutations. Ou, S., Lin, H., Hong, J., Yin, Y., Jin, S., Lin, J., Mehta, M., Nguyen, D., Neal, J. W. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1200/JCO.2021.39.15_suppl.9098

  View details for Web of Science ID 000708120605077

• CONTACT-01: A phase III, randomized study of atezolizumab plus cabozantinib versus docetaxel in patients with metastatic non-small cell lung cancer (mNSCLC) previously treated with PD-L1/PD-1 inhibitors and platinum-containing chemotherapy. Neal, J. W., Kundu, P., Tanaka, T., Enquist, I., Patel, S., Balestrini, A., Wang, J., Newsom-Davis, T., Goto, Y., Pavlakis, N., Kim, S. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1200/JCO.2021.39.15_suppl.TPS9134

  View details for Web of Science ID 000708120307045

• Immune Checkpoint Inhibitor Pneumonitis: Heterogeneity in Clinical Management Filsoof, D., Padda, S. K., Garcia, P., Stedman, M., Neal, J. W., Wakelee, H. A., Ramchandran, K., Das, M., Ramsey, M., Bedi, H. S., Sung, A., Raj, R., Anand, S., de Boer, K., Katsumoto, T. R. AMER THORACIC SOC. 2021

  View details for Web of Science ID 000685468901382

• Pragmatic Application of Computed Tomography Lung Texture Analysis in Immune Checkpoint Inhibitor Pneumonitis: An Exploratory Study Filsoof, D., Im, J., Garcia, P., Stedman, M., Anand, S., Neal, J. W., Wakelee, H. A., Ramchandran, K., Das, M., Padda, S. K., Sharifi, H., Mooney, J. J., Tsai, E. B., Lin, M. C., Guo, H., Leung, A., Katsumoto, T. R., de Boer, K., Raj, R. AMER THORACIC SOC. 2021

  View details for Web of Science ID 000685468901148

• Investigating gene expression profiles associated with clinical radiation resistance in KEAP1/NFE2L2 wildtype lung cancer. Binkley, M. S., Jeon, Y., Nesselbush, M., Moding, E. J., Nabet, B., Almanza, D., Yoo, C., Kurtz, D. M., Owen, S., Backhus, L. M., Berry, M. F., Shrager, J. B., Ramchandran, K. J., Padda, S. K., Das, M., Neal, J. W., Wakelee, H. A., Alizadeh, A. A., Loo, B. W., Diehn, M. AMER ASSOC CANCER RESEARCH. 2021

  View details for Web of Science ID 000641160600087

• Chemotherapy with or without immunotherapy or bevacizumab for EGFR-mutated lung cancer after progression on osimertinib White, M., Neal, J. W., Gardner, R. M., Cunanan, K. M., Das, M., Padda, S. K., Ramchandran, K., Chen, T. T., Wakelee, H. ELSEVIER SCIENCE INC. 2021: S773–S774

  View details for Web of Science ID 000634855900139

• Circulating tumor DNA kinetics to identify genomic predictors of rapid response to chemoradiation in non-small cell lung cancer. Moding, E. J., Liu, Y., Hui, A. B., He, J., Qiao, Y., Xu, T., Yao, L., Gandhi, S., Liao, Z., Das, M., Ramchandran, K. J., Padda, S. K., Neal, J. W., Wakelee, H. A., Loo, B. W., Lin, S. H., Alizadeh, A. A., Diehn, M. AMER ASSOC CANCER RESEARCH. 2021

  View details for Web of Science ID 000641160600097

• Myocarditis Surveillance with High-Sensitivity Troponin I During Cancer Treatment with Immune Checkpoint Inhibitors. JACC. CardioOncology Waliany, S., Neal, J. W., Reddy, S., Wakelee, H., Shah, S. A., Srinivas, S., Padda, S. K., Fan, A. C., Colevas, A. D., Wu, S. M., Witteles, R. M., Zhu, H. 2021; 3 (1): 137–39

  View details for DOI 10.1016/j.jaccao.2021.01.004

  View details for PubMedID 33796869

• LUNGMAP Master Protocol (LUNGMAP): Concordance Between Plasma ctDNA and Tissue Molecular Analysis Mack, P., Minichielle, K., Redman, M., Tolba, K., Kozono, D., Waqar, S., Chowdhury, A., Dowlati, A., Neal, J., Dragnev, K., Aggarwal, C., Hirsch, F., Kelly, K., Gandara, D., Herbst, R. ELSEVIER SCIENCE INC. 2021: S163–S164

  View details for Web of Science ID 000631349600179

• Cabozantinib Plus Atezolizumab in NSCLC Patients Previously Treated with a Checkpoint Inhibitor: Results from COSMIC 021 Neal, J., Lim, F., Felip, E., Gentzler, R., Patel, S., Baranda, J., Fang, B., Squillante, C., Simonelli, M., Werneke, S., Curran, D., Ponce Aix, S. ELSEVIER SCIENCE INC. 2021: S230–S231

  View details for Web of Science ID 000631349600302

• ANSELMA: Antiangiogenic Second Line Lung Cancer Meta-Analysis on Individual Patient Data in Non-Small Cell Lung Cancer, Again Relevant in ICI Era Remon, J., Lacas, B., Herbst, R., Reck, M., Garon, E., Scagliotti, G., Ramlau, R., Hanna, N., Vansteenkiste, J., Yoh, K., Groen, H., Heymach, J., Mandrekar, S., Okamoto, I., Neal, J., Heist, R., Pignon, J., Besse, B. ELSEVIER SCIENCE INC. 2021: S244–S245

  View details for Web of Science ID 000631349600332

• Impact of Low-Dose CT Screening for Primary Lung Cancer on Subsequent Risk of Brain Metastasis: Secondary Analysis of NLST Su, C. C., Wu, J., Neal, J., Popat, R., Backhus, L., Leung, A., Nagpal, S., Wakelee, H. A., Han, S. ELSEVIER SCIENCE INC. 2021: S149–S150

  View details for Web of Science ID 000631349600153

• Afatinib and Necitumumab in EGFR mutant NSCLC with Acquired Resistance to 1st or 3rd Generation EGFR Tyrosine Kinase Inhibitors Padda, S., Whisenant, J., Neal, J., York, S., Iams, W., Neuss, M., Reckamp, K., Preiss, J., Berry, L., Shyr, Y., Wakelee, H., Horn, L. ELSEVIER SCIENCE INC. 2021: S626

  View details for Web of Science ID 000631349601560

• Afatinib After Progression on Osimertinib in Patients with EGFR-Mutated Lung Adenocarcinoma Aredo, J., Wakelee, H. A., Neal, J., Padda, S. ELSEVIER SCIENCE INC. 2021: S619

  View details for Web of Science ID 000631349601545

• Tumor Mutation Burden (TMB) by Next Generation Sequencing (NGS) Associates with Survival (OS) in Lung-MAP Immunotherapy Trials S1400I and S1400A Hirsch, F., Hua, X., Wu, M., Neal, J., Cheng, H., Gettinger, S., Bazhenova, L., Papadimitrakopoulou, V., Borghaei, H., Mack, P., Kelly, K., Herbst, R., Gandara, D., Redman, M., Kozono, D. ELSEVIER SCIENCE INC. 2021: S102

  View details for Web of Science ID 000631349600073

• Healthcare Utilization with an Electronic Patient Reported Outcome (ePRO) tool for Symptom Management in Thoracic Cancers Roy, M., Fardeen, T., Generalova, O., Hall, E., Cunanan, K., Das, M., Neal, J., Padda, S., Wakelee, H. A., Ramchandran, K. ELSEVIER SCIENCE INC. 2021: S170–S171

  View details for Web of Science ID 000631349600192

• Randomized Phase II Study of 3 Months or 2 Years of Adjuvant Afatinib in Patients With Surgically Resected Stage I-III EGFR-Mutant Non-Small-Cell Lung Cancer JCO PRECISION ONCOLOGY Neal, J. W., Costa, D. B., Muzikansky, A., Shrager, J. B., Lanuti, M., Huang, J., Ramachandran, K. J., Rangachari, D., Huberman, M. S., Piotrowska, Z., Kris, M. G., Azzoli, C. G., Sequist, L., Chaft, J. E. 2021; 5: 325–32

  View details for DOI 10.1200/PO.20.00301

  View details for Web of Science ID 000636554600002

• Computational Biological Modeling Identifies PD-(L)1 Immunotherapy Sensitivity Among Molecular Subgroups of KRAS-Mutated Non-Small-Cell Lung Cancer JCO PRECISION ONCOLOGY Padda, S. K., Aredo, J., Vali, S., Singh, N. K., Vasista, S. M., Kumar, A., Neal, J. W., Abbasi, T., Wakelee, H. A. 2021; 5: 153–62

  View details for DOI 10.1200/PO.20.00172

  View details for Web of Science ID 000636553300004

• Global analysis of shared T cell specificities in human non-small cell lung cancer enables HLA inference and antigen discovery. Immunity Chiou, S. H., Tseng, D. n., Reuben, A. n., Mallajosyula, V. n., Molina, I. S., Conley, S. n., Wilhelmy, J. n., McSween, A. M., Yang, X. n., Nishimiya, D. n., Sinha, R. n., Nabet, B. Y., Wang, C. n., Shrager, J. B., Berry, M. F., Backhus, L. n., Lui, N. S., Wakelee, H. A., Neal, J. W., Padda, S. K., Berry, G. J., Delaidelli, A. n., Sorensen, P. H., Sotillo, E. n., Tran, P. n., Benson, J. A., Richards, R. n., Labanieh, L. n., Klysz, D. D., Louis, D. M., Feldman, S. A., Diehn, M. n., Weissman, I. L., Zhang, J. n., Wistuba, I. I., Futreal, P. A., Heymach, J. V., Garcia, K. C., Mackall, C. L., Davis, M. M. 2021; 54 (3): 586–602.e8

  Abstract

  To identify disease-relevant T cell receptors (TCRs) with shared antigen specificity, we analyzed 778,938 TCRβ chain sequences from 178 non-small cell lung cancer patients using the GLIPH2 (grouping of lymphocyte interactions with paratope hotspots 2) algorithm. We identified over 66,000 shared specificity groups, of which 435 were clonally expanded and enriched in tumors compared to adjacent lung. The antigenic epitopes of one such tumor-enriched specificity group were identified using a yeast peptide-HLA A∗02:01 display library. These included a peptide from the epithelial protein TMEM161A, which is overexpressed in tumors and cross-reactive epitopes from Epstein-Barr virus and E. coli. Our findings suggest that this cross-reactivity may underlie the presence of virus-specific T cells in tumor infiltrates and that pathogen cross-reactivity may be a feature of multiple cancers. The approach and analytical pipelines generated in this work, as well as the specificity groups defined here, present a resource for understanding the T cell response in cancer.

  View details for DOI 10.1016/j.immuni.2021.02.014

  View details for PubMedID 33691136

• Impact of Low-Dose CT Screening for Primary Lung Cancer on Subsequent Risk of Brain Metastasis. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Su, C. C., Wu, J. T., Neal, J. W., Popat, R. A., Kurian, A. W., Backhus, L. M., Nagpal, S., Leung, A. N., Wakelee, H. A., Han, S. S. 2021

  Abstract

  Brain metastasis (BM) is one of the most common metastases from primary lung cancer (PLC). Recently, the National Lung Screening Trial (NLST) demonstrated the efficacy of low-dose computed tomography (LDCT) screening on LC mortality reduction. However, it remains unknown if early detection of PLC through LDCT may be potentially beneficial in reducing the risk of subsequent metastases. Our study aimed to investigate the impact of LDCT screening for PLC on the risk of developing BM after PLC diagnosis.We used NLST data to identify 1,502 participants who were diagnosed with PLC in 2002-2009 and have follow-up data for BM. Cause-specific competing risk regression was applied to evaluate an association between BM risk and the mode of PLC detection-i.e., LDCT screen-detected versus non-LDCT screen-detected. Subgroup analyses were conducted in early-stage PLC patients and those who underwent surgery for PLC.Of 1502 participants, 41.4% had PLC detected through LDCT-screening versus 58.6% detected through other methods, e.g., chest X-Ray or incidental detection. Patients whose PLC was detected with LDCT-screening had a significantly lower 3-year incidence of BM (6.5%) versus those without (11.9%), with a cause-specific hazard ratio (HR) of 0.53 (p=0.001), adjusting for PLC stage, histology, diagnosis age and smoking status. This significant reduction in BM risk among PLCs detected through LDCT-screening persisted in subgroups of early-stage PLC participants (HR 0.47, p=0.002) and those who underwent surgery (HR 0.37, p=0.001).Early detection of PLC using LDCT-screening is associated with lower risk of BM after PLC diagnosis based on a large population-based study.

  View details for DOI 10.1016/j.jtho.2021.05.010

  View details for PubMedID 34091050

• Indirect comparison of mobocertinib and standard of care in platinum-pretreated patients with NSCLC with EGFR exon 20 insertion Ou, S. I., Lin, H. M., Hong, J., Yin, Y., Jin, S., Lin, J., Mehta, M., Nguyen, D., Neal, J. W. ELSEVIER. 2021: S964-S965

  View details for DOI 10.1016/j.annonc.2021.08.1816

  View details for Web of Science ID 000700527702229

• The Survival Impact of Second Primary Lung Cancer in Patients with Lung Cancer. Journal of the National Cancer Institute Choi, E., Luo, S. J., Aredo, J. V., Backhus, L. M., Wilkens, L. R., Su, C. C., Neal, J. W., Le Marchand, L., Cheng, I., Wakelee, H. A., Han, S. S. 2021

  Abstract

  Lung cancer survivors have a high risk of developing second primary lung cancer (SPLC), but little is known about the survival impact of SPLC diagnosis.We analyzed data from 138,969 patients in the Surveillance, Epidemiology, and End Results (SEER), who were surgically treated for initial primary lung cancer (IPLC) in 1988-2013. Each patient was followed from the date of IPLC diagnosis to SPLC diagnosis (for those with SPLC) and last vital status through 2016. We performed multivariable Cox regression to evaluate the association between overall survival and SPLC diagnosis as a time-varying predictor. To investigate potential effect modification, we tested interaction between SPLC and IPLC stage. Using data from the Multiethnic Cohort Study (MEC) (N = 1,540 IPLC patients with surgery), we evaluated the survival impact of SPLC by smoking status. All statistical tests were 2-sided.A total of 12,115 (8.7%) patients developed SPLC in SEER over 700,421 person-years of follow up. Compared to patients with single primary lung cancer, those with SPLC had statistically significantly reduced overall survival (hazard ratio [HR]=2.12, 95% confidence interval [CI] = 2.06-2.17; P < .001). The effect of SPLC on reduced survival was more pronounced among patients with early-stage IPLC vs. advanced-stage IPLC (HR = 2.14 [95% CI = 2.08-2.20] vs. 1.43 [95% CI = 1.21-1.70], respectively; Pinteraction <0.001). Analysis using MEC data showed that the effect of SPLC on reduced survival was statistically significantly larger among persons who actively smoked at initial diagnosis vs. those who formerly or never smoked (HR = 2.31 [95% CI = 1.48-3.61] vs. 1.41 [95% CI = 0.98-2.03], respectively; Pinteraction=0.04).SPLC diagnosis is statistically significantly associated with decreased survival in SEER and MEC. Intensive surveillance targeting patients with early-stage IPLC and active smoking at IPLC diagnosis may lead to a larger survival benefit.

  View details for DOI 10.1093/jnci/djab224

  View details for PubMedID 34893871

• Distress Screening Through Patient-Reported Outcomes Measurement Information System (PROMIS) at an Academic Cancer Center and Network Site: Implementation of a Hybrid Model. JCO oncology practice Neal, J. W., Roy, M. n., Bugos, K. n., Sharp, C. n., Galatin, P. S., Falconer, P. n., Rosenthal, E. L., Blayney, D. W., Modaressi, S. n., Robinson, A. n., Ramchandran, K. n. 2021: OP2000473

  Abstract

  Cancer care guidelines recommend regular distress screening of patients, with approximately one in three patients with cancer experiencing significant distress. However, the implementation of such programs is variable and inconsistent. We sought to assess the feasibility of implementing a hybrid electronic and paper screening tool for distress in all patients coming to a large academic cancer center and an associated integrated network site.Patients at an academic cancer center (Stanford Cancer Center) and its associated integrated network site received either an electronic or on-paper modified Patient-Reported Outcomes Measurement Information System-Global Health questionnaire, to assess overall health and distress. We used the Reach, Effectiveness, Adoption, Implementation, and Maintenance implementation framework to test and report on the feasibility of using this questionnaire. Iterative workflow changes were made to implement the questionnaire throughout the healthcare system, including processes to integrate with existing electronic health records.From June 2015 to December 2017, 53,954 questionnaires representing 26,242 patients were collected. Approximately 30% of the questionnaires were completed before the visit on an electronic patient portal. The number of patients meeting the positive screen threshold remained around 40% throughout the study period. Following assessment, there were 3,763 referrals to cancer supportive services. Of note, those with a positive screen were more likely to have a referral to supportive care (odds ratio, 6.4; 95% CI, 5.8 to 6.9; P < .0001).The hybrid electronic and on-paper use of a commonly available patient-reported outcome tool, Patient-Reported Outcomes Measurement Information System-Global Health, as a large-scale distress screening method, is feasible at a large integrated cancer center.

  View details for DOI 10.1200/OP.20.00473

  View details for PubMedID 33830852

• Brief Report: Role of Consolidation Durvalumab in patients with EGFR and HER2 Mutant Unresectable Stage III NSCLC. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Hellyer, J. A., Aredo, J. V., Das, M. n., Ramchandran, K. n., Padda, S. K., Neal, J. W., Wakelee, H. A. 2021

  Abstract

  Despite the recent advance of consolidation durvalumab in the treatment of unresectable stage III non-small cell lung cancer (NSCLC), not every patient benefits from durvalumab and predictive markers of response have been difficult to identify.We performed a retrospective analysis of patients with unresectable stage III NSCLC treated with consolidation durvalumab following definitive chemoradiation from January 2018 to March 2020.Thirty-six patients with unresectable stage III NSCLC were treated with consolidation durvalumab. Fourteen of these patients had tumor mutations in the ERBB family including 11 EGFR and 3 ERBB2. The ERBB2/EGFR tumor mutation cohort was more likely to be non-smokers; otherwise the two groups were similar in age, sex, PD-L1 expression and type of prior chemotherapy regimen. Patients in the ERBB2/EGFR cohort had a significantly shorter disease free survival compared to the EGFR/ERBB2 wildtype cohort (7.5 months vs NR, p= 0.04).Consolidation durvalumab appears to be less efficacious in patients with ERBB2/EGFR mutant tumors. Future work should seek to evaluate this in the prospective setting and provide insight into the optimal treatment of ERBB2/EGFR-mutant stage III NSCLC.

  View details for DOI 10.1016/j.jtho.2020.12.020

  View details for PubMedID 33539970

• Combining Osimertinib With Chemotherapy in EGFR-Mutant NSCLC at Progression. Clinical lung cancer White, M. N., Piotrowska, Z. n., Stirling, K. n., Liu, S. V., Banwait, M. K., Cunanan, K. n., Sequist, L. V., Wakelee, H. A., Hausrath, D. n., Neal, J. W. 2021

  Abstract

  Osimertinib is a third-generation EGFR tyrosine kinase inhibitor that has improved survival and central nervous system (CNS) outcomes in patients with non-small cell lung cancer (NSCLC) with activating EGFR mutations. However, little is known about the efficacy and safety of combining osimertinib with chemotherapy.This was a retrospective study performed at 3 institutions. Patients with advanced EGFR-mutated NSCLC who received concurrent osimertinib with chemotherapy in the third-line or beyond were identified by chart review. Efficacy outcomes including duration on treatment (DOT), overall survival (OS), and CNS outcomes were assessed. Safety outcomes were also evaluated.A total of 44 patients met inclusion criteria. Median DOT with osimertinib plus platinum doublet (n = 28) was 6.1 months (95% CI 4.1 months-not reached), and with osimertinib plus single-agent chemotherapy (n = 29) was 2.6 months (95% CI 1.8-4.8 months). Median OS from the start of osimertinib plus chemotherapy was 10.4 months (95% CI 7.0-13.2 months). At initiation of osimertinib plus chemotherapy, 37 patients (84%) had CNS metastases; 9 of these (24%) had CNS disease progression on osimertinib plus chemotherapy. Chemotherapy was delayed or dose reduced due to toxicity in 8 patients (18%); osimertinib was discontinued in 1 patient (2%) for reduced cardiac ejection fraction, and dose reduced in 2 patients (5%).The combination of osimertinib plus chemotherapy appeared safe and showed favorable control of CNS disease in this cohort of patients who had progressed systemically with multiple prior lines of therapy, with DOT and survival outcomes similar to historical chemotherapy controls.

  View details for DOI 10.1016/j.cllc.2021.01.010

  View details for PubMedID 33610453

• Activity and Safety of Mobocertinib (TAK-788) in Previously Treated Non-Small Cell Lung Cancer With EGFR Exon 20 Insertion Mutations From a Phase 1/2 Trial. Cancer discovery Riely, G. J., Neal, J. W., Camidge, D. R., Spira, A. I., Piotrowska, Z. n., Costa, D. B., Tsao, A. S., Patel, J. D., Gadgeel, S. M., Bazhenova, L. n., Zhu, V. W., West, H. L., Mekhail, T. n., Gentzler, R. D., Nguyen, D. n., Vincent, S. n., Zhang, S. n., Lin, J. n., Bunn, V. n., Jin, S. n., Li, S. n., Janne, P. A. 2021

  Abstract

  Mobocertinib, an oral epidermal growth factor receptor (EGFR) inhibitor targeting EGFR gene mutations including exon 20 insertions (EGFRex20ins) in non-small cell lung cancer, was evaluated in a phase 1/2 dose-escalation/expansion trial (ClinicalTrials.gov NCT02716116). Dose escalation identified 160 mg daily as the recommended phase 2 dose and maximum tolerated dose. Among 136 patients treated with 160 mg daily, the most common any grade treatment-related adverse events (TRAEs; >25%) were diarrhea (83%), nausea (43%), rash (33%), and vomiting (26%), with diarrhea (21%) the only grade {greater than or equal to}3 TRAE >5%. Among 28 EGFRex20ins patients treated at 160 mg daily, the investigator-assessed confirmed response rate was 43% (12/28; 95% confidence interval (CI): 24-63%) with median duration of response of 14 months (5.0-not reached), and median progression-free survival of 7.3 months (4.4-15.6). Mobocertinib demonstrated antitumor activity in patients with diverse EGFRex20ins variants with a safety profile consistent with other EGFR inhibitors.

  View details for DOI 10.1158/2159-8290.CD-20-1598

  View details for PubMedID 33632775

• Improved survival and disease control following pembrolizumab-induced immune-related adverse events in high PD-L1 expressing non-small cell lung cancer with brain metastases. Journal of neuro-oncology Zhang, M. n., Rodrigues, A. J., Pollom, E. L., Gibbs, I. C., Soltys, S. G., Hancock, S. L., Neal, J. W., Padda, S. K., Ramchandran, K. J., Wakelee, H. A., Chang, S. D., Lim, M. n., Hayden Gephart, M. n., Li, G. n. 2021

  Abstract

  Immune checkpoint inhibitors have become standard of care for many patients with non-small cell lung cancer (NSCLC). These agents often cause immune-related adverse events (IRAEs), which have been associated with increased overall survival (OS). Intracranial disease control and OS for patients experiencing IRAEs with metastatic NSCLC and brain metastases have not yet been described.We performed a single-institution, retrospective review of patients with NSCLC and existing diagnosis of brain metastasis, who underwent pembrolizumab treatment and developed any grade IRAE. The primary outcome of the study was intracranial time to treatment failure (TTF), defined from time of pembrolizumab initiation to new intracranial disease progression or death. Kaplan-Meier and Cox proportional hazard analyses were performed.A total of 63 patients with NSCLC brain metastasis were identified, and 24 developed IRAEs. Patients with any grade IRAEs had longer OS (21 vs. 10 months, p = 0.004), systemic TTF (15 vs. 4 months, p < 0.001) and intracranial TTF (14 vs. 5 months, p = 0.001), relative to patients without IRAEs. Presence of IRAEs and high PD-L1 (≥ 50%), but not absent/moderate PD-L1 (0-49%), had a positive association for OS, systemic TTF, and intracranial TTF. Following multivariable analysis, IRAE experienced on pembrolizumab was an independent predictor of OS, systemic TTF, and intracranial TTF.In our series of patients with NSCLC and brain metastases treated with pembrolizumab, IRAE presence was associated with a significant increase in OS, systemic TTF, and intracranial TTF. Future studies with increased cohorts will clarify how IRAEs should be interpreted among molecular subtypes.

  View details for DOI 10.1007/s11060-020-03686-3

  View details for PubMedID 33415659

• Durvalumab for Stage III EGFR-Mutated Non-Small Cell Lung Cancer After Definitive Chemoradiotherapy. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Aredo, J. V., Mambetsariev, I. n., Hellyer, J. A., Amini, A. n., Neal, J. W., Padda, S. K., McCoach, C. E., Riess, J. W., Cabebe, E. C., Naidoo, J. n., Abuali, T. n., Salgia, R. n., Loo, B. W., Diehn, M. n., Han, S. S., Wakelee, H. A. 2021

  Abstract

  In 2018, durvalumab was FDA approved as consolidation immunotherapy for patients with stage III non-small cell lung cancer (NSCLC) after definitive chemoradiotherapy (CRT). Whether durvalumab benefits patients with EGFR-mutated NSCLC remains unknown.We conducted a multi-institutional retrospective analysis of patients with unresectable stage III EGFR-mutated NSCLC who completed concurrent CRT. Kaplan-Meier analyses evaluated progression-free survival (PFS) between patients who completed CRT with or without durvalumab.Among 37 patients, 13 initiated durvalumab a median of 20 days after CRT completion. Two patients completed 12 months of treatment, with five patients discontinuing durvalumab due to progression and five due to immune-related adverse events (irAEs). Of 24 patients who completed CRT without durvalumab, 16 completed CRT alone and 8 completed CRT with induction or consolidation EGFR tyrosine kinase inhibitors (TKI). Median PFS was 10.3 months in patients who received CRT and durvalumab versus 6.9 months with CRT alone (log-rank P=0.993). CRT and EGFR TKI was associated with a significantly longer median PFS (26.1 months) compared to CRT and durvalumab or CRT alone (log-rank P=0.023). Six patients treated with durvalumab initiated EGFR TKIs after recurrence, with one developing grade 4 pneumonitis on osimertinib.In this study, patients with EGFR-mutated NSCLC did not benefit with consolidation durvalumab and experienced a high frequency of irAEs. Patients who initiate osimertinib after durvalumab may be susceptible to incident irAEs. Consolidation durvalumab should be approached with caution in this setting and concurrent CRT with induction and/or consolidation EGFR TKIs further investigated as definitive treatment.

  View details for DOI 10.1016/j.jtho.2021.01.1628

  View details for PubMedID 33588109

• Giant Magnetoresistive Nanosensor Analysis of Circulating Tumor DNA Epidermal Growth Factor Receptor Mutations for Diagnosis and Therapy Response Monitoring. Clinical chemistry Nesvet, J. C., Antilla, K. A., Pancirer, D. S., Lozano, A. X., Preiss, J. S., Ma, W. n., Fu, A. n., Park, S. M., Gambhir, S. S., Fan, A. C., Neal, J. W., Padda, S. K., Das, M. n., Li, T. n., Wakelee, H. A., Wang, S. X. 2021

  Abstract

  Liquid biopsy circulating tumor DNA (ctDNA) mutational analysis holds great promises for precision medicine targeted therapy and more effective cancer management. However, its wide adoption is hampered by high cost and long turnaround time of sequencing assays, or by inadequate analytical sensitivity of existing portable nucleic acid tests to mutant allelic fraction in ctDNA.We developed a ctDNA Epidermal Growth Factor Receptor (EGFR) mutational assay using giant magnetoresistive (GMR) nanosensors. This assay was validated in 36 plasma samples of non-small cell lung cancer patients with known EGFR mutations. We assessed therapy response through follow-up blood draws, determined concordance between the GMR assay and radiographic response, and ascertained progression-free survival of patients.The GMR assay achieved analytical sensitivities of 0.01% mutant allelic fraction. In clinical samples, the assay had 87.5% sensitivity (95% CI = 64.0-97.8%) for Exon19 deletion and 90% sensitivity (95% CI = 69.9-98.2%) for L858R mutation with 100% specificity; our assay detected T790M resistance with 96.3% specificity (95% CI = 81.7-99.8%) with 100% sensitivity. After 2 weeks of therapy, 10 patients showed disappearance of ctDNA by GMR (predicted responders), whereas 3 patients did not (predicted nonresponders). These predictions were 100% concordant with radiographic response. Kaplan-Meier analysis showed responders had significantly (P < 0.0001) longer PFS compared to nonresponders (N/A vs. 12 weeks, respectively).The GMR assay has high diagnostic sensitivity and specificity and is well suited for detecting EGFR mutations at diagnosis and noninvasively monitoring treatment response at the point-of-care.

  View details for DOI 10.1093/clinchem/hvaa307

  View details for PubMedID 33393992

• Durvalumab for Patients with Stage III EGFR-Mutated Non-Small Cell Lung Cancer Receiving Definitive Chemoradiotherapy Aredo, J. V., Hellyer, J. A., Neal, J. W., Padda, S. K., McCoach, C. E., Riess, J. W., Cabebe, E. C., Loo, B. W., Diehn, M., Wakelee, H. A. ELSEVIER SCIENCE INC. 2021: S15

  View details for Web of Science ID 000610079600029

• Opportunistic Invasive Fungal Infections Mimicking Progression of Non-Small-Cell Lung Cancer. Clinical lung cancer Park, M., Ho, D. Y., Wakelee, H. A., Neal, J. W. 2020

  Abstract

  BACKGROUND: Many studies have shown that invasive pulmonary aspergillosis, cryptococcosis, and mucormycosis can mimic radiographic and clinical features of primary lung cancer. However, more research surveying the incidence and outcomes of these fungal infections among patients with a history of lung cancer is needed. The aim of this study was to describe the occurrence and clinical outcomes of opportunistic invasive fungal infections that can mimic tumors in non-small-cell lung cancer patients.PATIENTS AND METHODS: Patients seen at Stanford University Medical Center from January 1, 2007, to May 1, 2020, with pulmonary aspergillosis, cryptococcosis, or mucormycosis after non-small-cell lung cancer (NSCLC) diagnosis were reviewed. The European Organization for Research and Treatment of Cancer National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria was used to classify patients with evidence of proven or probable invasive fungal infection within our cohort.RESULTS: A total of 12 patients with proven or probable invasive mold infection (including 8 cases of aspergillosis) and 1 patient with proven cryptococcosis were identified, without any cases of mucormycosis. Of this cohort, 6 patients (46%) showed radiographic findings that were found to be most consistent with lung cancer by radiologists. Eight cases (62%) were suspected of cancer recurrence or progression by the treatment team on the basis of additional considerations of medical history and clinical symptoms. Most patients had active NSCLC or had a history of recurrence without active NSCLC at the time of fungal discovery (11 patients; 85%). Most patients died without full recovery (7 patients; 54%).CONCLUSIONS: Invasive pulmonary aspergillosis and cryptococcosis can often be mistaken as cancer recurrence or progression in patients with a history of NSCLC because of mimicking radiographic and clinical characteristics.

  View details for DOI 10.1016/j.cllc.2020.10.001

  View details for PubMedID 33168426

• Updated results from a phase I/II study of mobocertinib (TAK788) in NSCLC with EGFR exon 20 insertions (exon20ins) Riely, G. J., Neal, J. W., Camidge, D. R., Spira, A., Piotrowska, Z., Horn, L., Costa, D. B., Tsao, A., Patel, J., Gadgeel, S., Bazhenova, L., Zhu, V. W., West, H., Mekhail, T., Gentzler, R., Nguyen, D., Bunn, V., Jin, S., Feng, Z., Janne, P. A. ELSEVIER. 2020: S815–S816

  View details for DOI 10.1016/j.annonc.2020.08.1575

  View details for Web of Science ID 000573469101547

• Impact of KRAS mutations and subtypes on efficacy of immune-checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC) Mazieres, J., Tomasini, P., Lusque, A., Boucekine, M., Gautschi, O., Cortot, A. B., Couraud, S., Thai, A., Ng, T., Greillier, L., Veillon, R., Neal, J. W., Popat, S., Gounant, V., Mhanna, L., Drilon, A., Baron, J., Barlesi, F. ELSEVIER. 2020: S826–S827

  View details for DOI 10.1016/j.annonc.2020.08.1593

  View details for Web of Science ID 000573469101565

• Comparison of clinical outcomes of patients with METDex14 NSCLC treated with first-line capmatinib in the GEOMETRY mono-1 study with those of a cohort of real-world patients Wolf, J., Neal, J. W., Mansfield, A. S., Doban, V., Kanakamedala, H., Wu, W., Joshi, A., de Jong, E., Giovannini, M., Baik, C. S. ELSEVIER. 2020: S863

  View details for DOI 10.1016/j.annonc.2020.08.1660

  View details for Web of Science ID 000573469101631

• A noninvasive approach for early prediction of therapeutic benefit from immune checkpoint inhibition for lung cancer Nabet, B. Y., Esfahani, M. S., Hamilton, E. G., Chabon, J. J., Moding, E. J., Rizvi, H., Steen, C. B., Chaudhuri, A. A., Liu, C., Hui, A. B., Stehr, H., Goljenola, L., Jin, M. C., Jeon, Y., Tseng, D., Merghoub, T., Neal, J. W., Wakelee, H. A., Padda, S. K., Ramchandran, K. J., Das, M., Bonilla, R. F., Yoo, C., Chen, E. L., Ko, R. B., Newman, A. M., Hellmann, M. D., Alizadeh, A. A., Diehn, M. AMER ASSOC CANCER RESEARCH. 2020

  View details for DOI 10.1158/1538-7445.AM2020-5666

  View details for Web of Science ID 000590059306446

• Immune Profiling and Causal Antigen Discovery in Mouse and Human Models of Immune Checkpoint Inhibitor-induced Myocarditis Zhu, H., Lee, D., Sarah, W., Galdos, F. X., D'Addabbo, J., Fowler, M. B., Reddy, S., Heather, W., Neal, J. W., Witteles, R., Maecker, H. T., Davis, M., Nguyen, P. K., Wu, S. M. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for DOI 10.1161/res.127.suppl_1.350

  View details for Web of Science ID 000606541500116

• A phase II randomized study of telaglenastat, a glutaminase (GLS) inhibitor, versus placebo, in combination with pembrolizumab (Pembro) and chemotherapy as first-line treatment for KEAP1/NRF2-mutated non-squamous metastatic non-small cell lung cancer (mNSCLC). Skoulidis, F., Neal, J. W., Akerley, W. L., Paik, P. K., Papagiannakopoulos, T., Reckamp, K. L., Riess, J. W., Jenkins, Y., Holland, S., Parlati, F., Shen, Y., Whiting, S. H., Rizvi, N. A. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000560368309249

• Cabozantinib in combination with atezolizumab in non-small cell lung cancer (NSCLC) patients previously treated with an immune checkpoint inhibitor: Results from cohort 7 of the COSMIC-021 study. Neal, J. W., Lim, F., Felip, E., Gentzler, R. D., Patel, S. B., Baranda, J., Fang, B., Squillante, C., Simonelli, M., Werneke, S., Curran, D., Ponce Aix, S. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368303508

• Indirect comparison of TAK-788 vs real-world data outcomes in refractory non-small cell lung cancer (NSCLC) with EGFR exon 20 insertions. Horn, L., Lin, H., Padda, S., Aggarwal, C., McCoach, C., Zhu, Y., Yin, Y., Lin, J., Li, S., Feng, Z., Neal, J. W. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368303479

• High-dose osimertinib for CNS progression in EGFR plus non-small cell lung cancer (NSCLC): A multi-institutional experience. Piper-Vallillo, A., Rotow, J. K., Aredo, J., Shaverdashvili, K., Luo, J., Carlisle, J. W., Husain, H., Muzikansky, A., Heist, R., Rangachari, D., Ramalingam, S. S., Wakelee, H. A., Yu, H., Sequist, L., Bauml, J., Neal, J. W., Piotrowska, Z. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368303485

• Osimertinib in non-small cell lung cancer (NSCLC) with atypical EGFR activating mutations: A retrospective multicenter study. Ji, J., Aredo, J., Piper-Vallillo, A., Huppert, L., Rotow, J. K., Husain, H., Stewart, S. L., Cobb, R., Wakelee, H. A., Blakely, C., Wong, M. L., Gubens, M. A., Chen, J., Oxnard, G. R., McCoach, C., Piotrowska, Z., Neal, J. W., Riess, J. W. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368303469

• Distress screening through PROMIS at an academic cancer center and network site: Implementation of a hybrid model. Roy, M., Neal, J. W., Bugos, K., Sharp, C., Falconer, P., Rosenthal, E., Blayney, D. W., Modaressi, S., Robinson, A., Ramchandran, K. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368301136

• A mid-chemoradiation dynamic risk model integrating tumor features and ctDNA analysis for lung cancer outcome prediction. Moding, E. J., Esfahani, M., Nabet, B., Liu, Y., Chabon, J. J., He, J., Qiao, Y., Xu, T., Yao, L., Gandhi, S., Liao, Z. X., Das, M., Ramchandran, K., Padda, S., Neal, J. W., Wakelee, H. A., Loo, B. W., Lin, S. H., Alizadeh, A. A., Diehn, M. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368303378

• KEAP1/NFE2L2 mutations to predict local recurrence after radiotherapy but not surgery in localized non-small cell lung cancer. Binkley, M. S., Jeon, Y., Nesselbush, M., Moding, E. J., Nabet, B., Almanza, D. S., Yoo, C., Kurtz, D., Owen, S., Backhus, L., Berry, M. F., Shrager, J. B., Ramchandran, K., Padda, S., Das, M., Neal, J. W., Wakelee, H. A., Alizadeh, A. A., Loo, B. W., Diehn, M. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368303348

• Discovery of a novel shared tumor antigen in human lung cancer. Tseng, D., Chiou, S., Yang, X., Reuben, A., Wilhelmy, J., McSween, A., Conley, S., Sinha, R., Nabet, B., Wang, C., Shrager, J. B., Berry, M. F., Backhus, L., Lui, n., Wakelee, H. A., Neal, J. W., Zhang, J., Garcia, K., Mackall, C., Davis, M. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368301343

• Integrating genomic features for non-invasive early lung cancer detection. Nature Chabon, J. J., Hamilton, E. G., Kurtz, D. M., Esfahani, M. S., Moding, E. J., Stehr, H., Schroers-Martin, J., Nabet, B. Y., Chen, B., Chaudhuri, A. A., Liu, C. L., Hui, A. B., Jin, M. C., Azad, T. D., Almanza, D., Jeon, Y. J., Nesselbush, M. C., Co Ting Keh, L., Bonilla, R. F., Yoo, C. H., Ko, R. B., Chen, E. L., Merriott, D. J., Massion, P. P., Mansfield, A. S., Jen, J., Ren, H. Z., Lin, S. H., Costantino, C. L., Burr, R., Tibshirani, R., Gambhir, S. S., Berry, G. J., Jensen, K. C., West, R. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Kunder, C. A., Leung, A. N., Lui, N. S., Berry, M. F., Shrager, J. B., Nair, V. S., Haber, D. A., Sequist, L. V., Alizadeh, A. A., Diehn, M. 2020; 580 (7802): 245-251

  Abstract

  Radiologic screening of high-risk adults reduces lung-cancer-related mortality1,2; however, a small minority of eligible individuals undergo such screening in the United States3,4. The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)5, a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed 'lung cancer likelihood in plasma' (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.

  View details for DOI 10.1038/s41586-020-2140-0

  View details for PubMedID 32269342

• Integrating genomic features for non-invasive early lung cancer detection NATURE Chabon, J. J., Hamilton, E. G., Kurtz, D. M., Esfahani, M. S., Moding, E. J., Stehr, H., Schroers-Martin, J., Nabet, B. Y., Chen, B., Chaudhuri, A. A., Liu, C., Hui, A. B., Jin, M. C., Azad, T. D., Almanza, D., Jeon, Y., Nesselbush, M. C., Keh, L., Bonilla, R. F., Yoo, C. H., Ko, R. B., Chen, E. L., Merriott, D. J., Massion, P. P., Mansfield, A. S., Jen, J., Ren, H. Z., Lin, S. H., Costantino, C. L., Burr, R., Tibshirani, R., Gambhir, S. S., Berry, G. J., Jensen, K. C., West, R. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Kunder, C. A., Leung, A. N., Lui, N. S., Berry, M. F., Shrager, J. B., Nair, V. S., Haber, D. A., Sequist, L. V., Alizadeh, A. A., Diehn, M. 2020

  View details for DOI 10.1038/s41586-020-2140-0

  View details for Web of Science ID 000521531000011

• Circulating Tumor DNA Dynamics Predict Benefit from Consolidation Immunotherapy in Locally Advanced Non-Small Cell Lung Cancer. Nature cancer Moding, E. J., Liu, Y., Nabet, B. Y., Chabon, J. J., Chaudhuri, A. A., Hui, A. B., Bonilla, R. F., Ko, R. B., Yoo, C. H., Gojenola, L., Jones, C. D., He, J., Qiao, Y., Xu, T., Heymach, J. V., Tsao, A., Liao, Z., Gomez, D. R., Das, M., Padda, S. K., Ramchandran, K. J., Neal, J. W., Wakelee, H. A., Loo, B. W., Lin, S. H., Alizadeh, A. A., Diehn, M. 2020; 1 (2): 176-183

  Abstract

  Circulating tumor DNA (ctDNA) molecular residual disease (MRD) following curative-intent treatment strongly predicts recurrence in multiple tumor types, but whether further treatment can improve outcomes in patients with MRD remains unclear. We applied CAPP-Seq ctDNA analysis to 218 samples from 65 patients receiving chemoradiation therapy (CRT) for locally advanced NSCLC, including 28 patients receiving consolidation immune checkpoint inhibition (CICI). Patients with undetectable ctDNA after CRT had excellent outcomes whether or not they received CICI. Among such patients, one died from CICI-related pneumonitis, highlighting the potential utility of only treating patients with MRD. In contrast, patients with MRD after CRT who received CICI had significantly better outcomes than patients who did not receive CICI. Furthermore, the ctDNA response pattern early during CICI identified patients responding to consolidation therapy. Our results suggest that CICI improves outcomes for NSCLC patients with MRD and that ctDNA analysis may facilitate personalization of consolidation therapy.

  View details for DOI 10.1038/s43018-019-0011-0

  View details for PubMedID 34505064

  View details for PubMedCentralID PMC8425388

• Noninvasive Early Identification of Therapeutic Benefit from Immune Checkpoint Inhibition. Cell Nabet, B. Y., Esfahani, M. S., Moding, E. J., Hamilton, E. G., Chabon, J. J., Rizvi, H. n., Steen, C. B., Chaudhuri, A. A., Liu, C. L., Hui, A. B., Almanza, D. n., Stehr, H. n., Gojenola, L. n., Bonilla, R. F., Jin, M. C., Jeon, Y. J., Tseng, D. n., Liu, C. n., Merghoub, T. n., Neal, J. W., Wakelee, H. A., Padda, S. K., Ramchandran, K. J., Das, M. n., Plodkowski, A. J., Yoo, C. n., Chen, E. L., Ko, R. B., Newman, A. M., Hellmann, M. D., Alizadeh, A. A., Diehn, M. n. 2020

  Abstract

  Although treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs) can produce remarkably durable responses, most patients develop early disease progression. Furthermore, initial response assessment by conventional imaging is often unable to identify which patients will achieve durable clinical benefit (DCB). Here, we demonstrate that pre-treatment circulating tumor DNA (ctDNA) and peripheral CD8 T cell levels are independently associated with DCB. We further show that ctDNA dynamics after a single infusion can aid in identification of patients who will achieve DCB. Integrating these determinants, we developed and validated an entirely noninvasive multiparameter assay (DIREct-On, Durable Immunotherapy Response Estimation by immune profiling and ctDNA-On-treatment) that robustly predicts which patients will achieve DCB with higher accuracy than any individual feature. Taken together, these results demonstrate that integrated ctDNA and circulating immune cell profiling can provide accurate, noninvasive, and early forecasting of ultimate outcomes for NSCLC patients receiving ICIs.

  View details for DOI 10.1016/j.cell.2020.09.001

  View details for PubMedID 33007267

• A PHASE IIA STUDY REPOSITIONING DESIPRAMINE IN SMALL CELL LUNG CANCER AND OTHER HIGH-GRADE NEUROENDOCRINE TUMORS. Cancer treatment and research communications Riess, J. W., Jahchan, N. S., Das, M. n., Zach Koontz, M. n., Kunz, P. L., Wakelee, H. A., Schatzberg, A. n., Sage, J. n., Neal, J. W. 2020; 23: 100174

  Abstract

  A bioinformatics approach identified antitumor effects of tricyclic antidepressants (TCAs) in small cell lung cancer (SCLC) and other high-grade neuroendocrine carcinomas (grade 3 neuroendocrine carcinomas) (G3NEC) that was subsequently validated in preclinical models with a putative mechanism of action via inhibition of neuroendocrine signaling pathways. This study was undertaken to reposition the candidate TCA desipramine in a clinical trial in SCLC and G3NEC.In this prospective, phase IIa intrapatient dose escalation clinical trial, patients were required to have failed at least one prior chemotherapy for metastatic SCLC or G3NEC. Treatment with desipramine began at 75 mg nightly with escalation in increments of 75 mg weekly to a maximum of 450 mg daily.Six patients were enrolled, 3 with SCLC, and 3 with G3NEC (lung, rectal, and pancreas). Tolerability of desipramine was worse than predicted. Of the 6 patients enrolled: 1 patient achieved 300 mg daily, 2 patients reached 150 mg daily, 1 patient reached 75 mg daily, and 2 patients were unable to tolerate any stable dose. Reasons for discontinuation included drug-related grade 3 colon pseudo-obstruction, unrelated GI bleed, and grade 1-2 neurocognitive adverse events. Median clinical or radiographic progression free survival was 1.2 months (range 0.2-3.3) and median overall survival from study entry was 2.7 months (range 1.3-5.6).No clinical or radiographic benefit was observed using desipramine to treat SCLC and G3NEC, so this trial was terminated. Intolerable low and medium grade neurocognitive side effects led to intermittent treatment and early discontinuation in most patients; given this limitation, doses achieved may be inadequate compared to the preclinical studies.A bioinformatics approach previously identified a potential antitumor effect of tricyclic antidepressants (TCAs) in small cell lung cancer (SCLC) and other high-grade neuroendocrine carcinomas (grade 3 neuroendocrine carcinoma) (G3NEC), which was validated in preclinical models. In this prospective, phase IIa clinical trial, patients were required to have failed at least one prior chemotherapy for metastatic SCLC or G3NEC (Ki-67 ≥ 20% or ≥ 20 mitoses/10 HPF). Treatment with desipramine began at 75 mg nightly with escalation by 75 mg weekly to a maximum dose of 450 mg daily. Six patients were enrolled on this clinical trial, 3 with SCLC, and 3 with G3NEC (lung, rectal, and pancreatic). Tolerability of desipramine was worse than predicted. In the 6 patients enrolled: 1 patient achieved 300 mg daily, 2 patients reached 150 mg daily, 1 patient reached 75 mg daily, and 2 patients were unable to tolerate any stable dose. Reasons for discontinuation included drug-related grade 3 colon pseudo-obstruction, unrelated GI bleed, and grade 1-2 drug related dizziness, confusion, and somnolence. Though numbers are small, median clinical or radiographic progression free survival was 1.2 months (range 0.2-3.3) and median overall survival from study entry was 2.7 months (range 1.3-5.6). Although preclinical evidence was promising, no clinical or radiographic benefit was observed using desipramine to treat SCLC and G3NEC, so this trial was terminated.

  View details for DOI 10.1016/j.ctarc.2020.100174

  View details for PubMedID 32413603

• Relative Impact of Anticancer Therapy on Unplanned Hospital Care in Patients With Non-Small-Cell Lung Cancer. JCO oncology practice Shah, M. P., Neal, J. W. 2020: OP2000612

  Abstract

  In lung cancer, unplanned hospital care is a significant driver of costs. While toxicities of cancer therapies are well-known, there are little data on their relative contribution to unplanned care. This study aims to (1) determine the relative impact of tyrosine-kinase inhibitor (TKI) therapy, immune checkpoint inhibitor immunotherapy, and cytotoxic chemotherapy on unplanned hospital care and (2) identify potential strategies to prevent unplanned hospital encounters in patients with non-small-cell lung cancer (NSCLC).A research database search of the electronic health record was used to identify 97 patients with established NSCLC who were undergoing either TKI therapy, immunotherapy, or chemotherapy at our institution and visited our emergency department (ED) in 2018. The resulting 173 ED encounters were reviewed to determine (1) the cause (cancer, therapy, other, or rule-out) of each encounter and (2) whether the encounter was preventable.A small portion (9%) of all unplanned hospital encounters were therapy related (2% in the TKI therapy group, 12% in the immunotherapy group, and 21% in the chemotherapy group). Cancer itself was the leading cause (54%) of the encounters. Over 20% of all encounters were classified as preventable, and half of those encounters were deemed unnecessary.TKI therapy, immunotherapy, and, to a lesser extent, chemotherapy are relatively small drivers of unplanned acute hospital care for patients with NSCLC. A significant share of unplanned hospital encounters may be prevented through proactive evidence-based initiatives.

  View details for DOI 10.1200/OP.20.00612

  View details for PubMedID 33351677

• PD-1/PD-L1 Checkpoint Inhibitor Immunotherapy for Malignant Pleural Mesothelioma: Case Series and Literature Review. Clinical lung cancer Zhou, M. n., Joshi, N. n., Raj, K. P., Wakelee, H. n., Neal, J. W. 2020

  View details for DOI 10.1016/j.cllc.2020.05.012

  View details for PubMedID 32624413

• Circulating tumor DNA analysis to assess risk of progression after long-term response to PD-(L)1 blockade in NSCLC. Clinical cancer research : an official journal of the American Association for Cancer Research Hellmann, M. D., Nabet, B. Y., Rizvi, H. n., Chaudhuri, A. A., Wells, D. K., Dunphy, M. P., Chabon, J. J., Liu, C. L., Hui, A. B., Arbour, K. C., Luo, J. n., Preeshagul, I. R., Moding, E. J., Almanza, D. n., Bonilla, R. F., Sauter, J. L., Choi, H. n., Tenet, M. n., Abu-Akeel, M. n., Plodkowski, A. J., Perez-Johnston, R. n., Yoo, C. H., Ko, R. B., Stehr, H. n., Gojenola, L. n., Wakelee, H. A., Padda, S. K., Neal, J. W., Chaft, J. E., Kris, M. G., Rudin, C. M., Merghoub, T. n., Li, B. T., Alizadeh, A. A., Diehn, M. n. 2020

  Abstract

  Treatment with PD-(L)1 blockade can produce remarkably durable responses in non-small cell lung cancer (NSCLC) patients. However, a significant fraction of long-term responders ultimately progress and predictors of late progression are unknown. We hypothesized that circulating tumor DNA (ctDNA) analysis of long-term responders to PD-(L)1 blockade may differentiate those who will achieve ongoing benefit from those at risk of eventual progression.In patients with advanced NSCLC achieving long-term benefit from PD-(L)1 blockade (PFS≥12 months), plasma was collected at a surveillance timepoint late during/after treatment to interrogate ctDNA by Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq). Tumor tissue was available for 24 patients and was profiled by whole-exome sequencing (n=18) or by targeted sequencing (n=6).31 NSCLC patients with long-term benefit to PD-(L)1 blockade were identified and ctDNA was analyzed in surveillance blood samples collected at a median of 26.7 months after initiation of therapy. Nine patients also had baseline plasma samples available, and all had detectable ctDNA prior to therapy initiation. At the surveillance timepoint, 27 patients had undetectable ctDNA and 25 (93%) have remained progression-free; by contrast, all four patients with detectable ctDNA eventually progressed (Fisher's p<0.0001; PPV 1 [95% CI 0.51-1]; NPV 0.93 [95% CI 0.80-0.99]).ctDNA analysis can noninvasively identify minimal residual disease in patients with long-term responses to PD-(L)1 and predict the risk of eventual progression. If validated, ctDNA surveillance may facilitate personalization of the duration of immune checkpoint blockade and enable early intervention in patients at high risk for progression.

  View details for DOI 10.1158/1078-0432.CCR-19-3418

  View details for PubMedID 32046999

• KEAP1/NFE2L2 mutations predict lung cancer radiation resistance that can be targeted by glutaminase inhibition. Cancer discovery Binkley, M. S., Jeon, Y. J., Nesselbush, M. n., Moding, E. J., Nabet, B. Y., Almanza, D. n., Kunder, C. n., Stehr, H. n., Yoo, C. H., Rhee, S. n., Xiang, M. n., Chabon, J. J., Hamilton, E. n., Kurtz, D. M., Gojenola, L. n., Owen, S. G., Ko, R. B., Shin, J. H., Maxim, P. G., Lui, N. S., Backhus, L. M., Berry, M. F., Shrager, J. B., Ramchandran, K. J., Padda, S. K., Das, M. n., Neal, J. W., Wakelee, H. A., Alizadeh, A. A., Loo, B. W., Diehn, M. n. 2020

  Abstract

  Tumor genotyping is not routinely performed in localized non-small cell lung cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we analyze 232 consecutive patients with localized NSCLC and demonstrate that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence (LR) after radiotherapy but not surgery. Half of LRs occurred in KEAP1/NFE2L2 mutation tumors, indicating they are major molecular drivers of clinical radioresistance. Next, we functionally evaluate KEAP1/NFE2L2 mutations in our radiotherapy cohort and demonstrate that only pathogenic mutations are associated with radioresistance. Furthermore, expression of NFE2L2 target genes does not predict LR, underscoring the utility of tumor genotyping. Finally, we show that glutaminase inhibition preferentially radiosensitizes KEAP1 mutant cells via depletion of glutathione and increased radiation-induced DNA damage. Our findings suggest that genotyping for KEAP1/NFE2L2 mutations could facilitate treatment personalization and provide a potential strategy for overcoming radioresistance conferred by these mutations.

  View details for DOI 10.1158/2159-8290.CD-20-0282

  View details for PubMedID 33071215

• Immune Checkpoint Inhibitor Cardiotoxicity: Understanding Basic Mechanisms and Clinical Characteristics and Finding a Cure. Annual review of pharmacology and toxicology Waliany, S. n., Lee, D. n., Witteles, R. M., Neal, J. W., Nguyen, P. n., Davis, M. M., Salem, J. E., Wu, S. M., Moslehi, J. J., Zhu, H. n. 2020

  Abstract

  Immune checkpoint inhibitors (ICIs) attenuate mechanisms of self-tolerance in the immune system, enabling T cell responses to cancerous tissues and revolutionizing care for cancer patients. However, by lowering barriers against self-reactivity, ICIs often result in varying degrees of autoimmunity. Cardiovascular complications, particularly myocarditis but also arrhythmias, pericarditis, and vasculitis, have emerged as significant complications associated with ICIs. In this review, we examine the clinical aspects and basic science principles that underlie ICI-associated myocarditis and other cardiovascular toxicities. In addition, we discuss current therapeutic approaches. We believe a better mechanistic understanding of ICI-associated toxicities can lead to improved patient outcomes by reducing treatment-related morbidity. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 61 is January 8, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

  View details for DOI 10.1146/annurev-pharmtox-010919-023451

  View details for PubMedID 32776859

• Circulating tumor DNA dynamics predict benefit from consolidation immunotherapy in locally advanced non-small-cell lung cancer NATURE CANCER Moding, E. J., Liu, Y., Nabet, B. Y., Chabon, J. J., Chaudhuri, A. A., Hui, A. B., Bonilla, R. F., Ko, R. B., Gojenola, L., Jones, C. D., He, J., Qiao, Y., Heymach, J. V., Tsao, A., Liao, Z., Gomez, D. R., Das, M., Padda, S. K., Ramchandran, K. J., Neal, J. W., Wakelee, H. A., Loo Jr., B. W., Lin, S. H., Alizadeh, A. A., Diehn, M. 2020; 1: 176–183

  View details for DOI 10.1038/s43018-019-0011-0

• Long Term Efficacy and Safety of Ensartinib in Pre-Treated Anaplastic Lymphoma Kinase (ALK) Positive Non-Small Cell Lung Cancer (NSCLC) Patients (eXalt2) Leal, T., Wakelee, H., Reckamp, K. L., Chiappori, A., Oxnard, G. R., Waqar, S. N., Patel, S. P., Blumenschein, G. R., Neal, J. W., Harrow, K., Holzhausen, A., Selvaggi, G., Zhou, J., Horn, L. ELSEVIER SCIENCE INC. 2019: S1171–S1172

  View details for DOI 10.1016/j.jtho.2019.09.131

  View details for Web of Science ID 000494945000043

• The Real-World Risk of Brain Metastases in Stage 3 Lung Cancer Patients in the Era of PET and MRI Staging Ko, R., Therkelsen, K., Von Eyben, R., Neal, J., Loo, B., Nagpal, S. ELSEVIER SCIENCE INC. 2019: S585–S586

  View details for Web of Science ID 000492162203144

• Safety, tolerability and activity of autologous T-cells with enhanced T-cell receptors specific to NY ESO 1/LAGE 1a (GSK3377794) alone, or in combination with pembrolizumab, in advanced non-small cell lung cancer: A phase Ib/IIa randomised pilot study Reckamp, K. L., Akerley, W., Calvo, E., Clarke, J., Edelman, M. J., He, K., Moreno, V., Neal, J. W., Owonikoko, T. K., Patel, J. D., Patel, S. P., Riess, J. W., Sacher, A. G., Turcotte, S., Villaruz, L. C., Zauderer, M. G., Farsaci, B., Skoura, N., Chisamore, M., Johnson, M. L. OXFORD UNIV PRESS. 2019: 657-+

  View details for Web of Science ID 000491295504252

• Antitumor Activity of the Oral EGFR/HER2 Inhibitor TAK-788 in NSCLC with EGFR Exon 20 Insertions Riely, G., Neal, J., Camidge, D. R., Spira, A., Piotrowska, Z., Horn, L., Costa, D., Tsao, A., Patel, J., Gadgeel, S., Bazhenova, L., Zhu, V., West, H., Vincent, S., Zhu, J., Jin, S., Zhang, S., Li, S., Janne, P. ELSEVIER SCIENCE INC. 2019: S412–S413

  View details for Web of Science ID 000492162202171

• A Single-Cell Resolution Map of EMT and Drug Resistance States for Evaluating NSCLC Clinical Specimens Karacosta, L., Anchang, B., Ignatiadis, N., Kimmey, S., Benson, J., Shrager, J., Sung, A., Neal, J., Wakelee, H., Tibshirani, R., Bendall, S., Plevritis, S. ELSEVIER SCIENCE INC. 2019: S226–S227

  View details for Web of Science ID 000492162201134

• STK11/LKB1 Genomic Alterations Are Associated with Inferior Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC Skoulidis, F., Arbour, K., Hellmann, M., Patil, P., Marmarelis, M., Owen, D., Awad, M., Murray, J., Levy, B., Hellyer, J., Gainor, J., Stewart, T., Goldberg, S., Dimou, A., Bestvina, C., Cummings, A., Elamin, Y., Lam, V., Zhang, J., Shu, C., Riess, J., Blakely, C., Pecot, C., Mezquita, L., Tabbo, F., Sacher, A., Scheffler, M., Ricciuti, B., Venkatraman, D., Rizvi, H., Liu, C., Johnston, R., Ni, Y., Azok, J., Kier, M., Katz, S., Davies, K., Segal, J., Ritterhouse, L., Shaish, H., Lacroix, L., Memmott, R., Madrigal, J., Goldman, J., Lau, S., Killam, J., Walther, Z., Carter, B., Woodcock, M., Roth, J., Swisher, S., Leighl, N., Digumarthy, S., Mooradian, M., Rotow, J., Wolf, J., Scagliotti, G., Planchard, D., Besse, B., Bivona, T., Gandara, D., Garon, E., Rizvi, N., Camidge, D. R., Schalper, K., Herbst, R., Shaw, A., Neal, J., Wakelee, H., Brahmer, J., Janne, P., Carbone, D., Aggarwal, C., Pennell, N., Rudin, C., Papadimitrakopoulou, V., Heymach, J. ELSEVIER SCIENCE INC. 2019: S294–S295

  View details for Web of Science ID 000492162201276

• Rash and Efficacy in Anaplastic Lymphoma Kinase Positive (ALK plus ) Non-Small Cell Lung Cancer Patients Treated with Ensartinib Wakelee, H., Reckamp, K., Leal, T., Chiappori, A., Waqar, S., Zeman, K., Neal, J., Liang, C., Harrow, K., Holzhausen, A., Zhou, J., Selvaggi, G., Horn, L. ELSEVIER SCIENCE INC. 2019: S566

  View details for Web of Science ID 000492162203099

• Antitumor activity of TAK-788 in NSCLC With EGFR exon 20 insertions Jaenne, P., Neal, J. W., Camidge, D. R., Spira, A., Piotrowska, Z., Horn, L., Costa, D. B., Tsao, A., Patel, J., Gadgeel, S., Bazhenova, L., Zhu, V. W., West, H., Vincent, S., Zhu, J., Li, S., Riely, G. J. OXFORD UNIV PRESS. 2019

  View details for DOI 10.1093/annonc/mdz338.077

  View details for Web of Science ID 000491239300144

• Feasibility and design of a cloud-based digital platform in patients with advanced cancer. Roy, M., Hall, E., Velazquez, B., Shah, S., Fardeen, T., Cunanan, K., San Pedro-Salcedo, M., Wakelee, H. A., Neal, J. W., Padda, S., Das, M., Fan, A. C., Srinivas, S., Fisher, G. A., Haraldsdottir, S., Johnson, T., Chu, G., McMillan, A., Ramchandran, K. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.27_suppl.211

  View details for Web of Science ID 000518223100208

• Association of Antibiotic Resistance With Antibiotic Use for Epidermal Growth Factor Receptor Inhibitor-Related Papulopustular Eruption JAMA DERMATOLOGY Hirotsu, K., Dang, T. M., Li, S., Neal, J. W., Pugliese, S., Subramanian, A., Kwong, B. Y. 2019; 155 (7): 848–50

  View details for DOI 10.1001/jamadermatol.2019.0063

  View details for Web of Science ID 000482127300016

• A Phase Ib/IIa randomized pilot study to investigate the safety and tolerability of autologous T-cells with enhanced T-cell receptors specific to NY-ESO-1/LAGE-1a (GSK3377794) alone, or in combination with pembrolizumab, in advanced non-small cell lung cancer Reckamp, K. L., Akerley, W., Edelman, M. J., Halmos, B., He, K., Johnson, M., Mudad, R., Neal, J. W., Owonikoko, T. K., Patel, J. D., Patel, S. P., Riess, J. W., Sacher, A. G., Turcotte, S., Villaruz, L. C., Zauderer, M. G., Farsaci, B., Hasan, A., Patel, R., Wu, Y., Chisamore, M., Lam, V. AMER ASSOC CANCER RESEARCH. 2019

  View details for DOI 10.1158/1538-7445.AM2019-CT225

  View details for Web of Science ID 000488129900201

• Characterization of circulating tumor cells and its PD-L1 expression with high-sensitivity liquid biopsy panel in non-small cell lung cancer patients Liu, X., Ao, Z., Preiss, J. S., Neal, J., Zhou, L., Sambucetti, L., Wakelee, H. A. AMER ASSOC CANCER RESEARCH. 2019

  View details for DOI 10.1158/1538-7445.AM2019-LB-238

  View details for Web of Science ID 000488129900417

• Case series of MET exon 14 skipping mutation-positive non-small-cell lung cancers with response to crizotinib and cabozantinib ANTI-CANCER DRUGS Wang, S. Y., Zhang, B. M., Wakelee, H. A., Koontz, M. Z., Pan, M., Diehn, M., Kunder, C. A., Neal, J. W. 2019; 30 (5): 537–41

  View details for DOI 10.1097/CAD.0000000000000765

  View details for Web of Science ID 000466009600014

• Osimertinib for EGFR-Mutant Lung Cancer with Brain Metastases: Results from a Single-Center Retrospective Study ONCOLOGIST Xie, L., Nagpal, S., Wakelee, H. A., Li, G., Soltys, S. G., Neal, J. W. 2019; 24 (6): 836–43

  View details for DOI 10.1634/theoncologist.2018-0264

  View details for Web of Science ID 000471906300044

• Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Annals of oncology : official journal of the European Society for Medical Oncology Mazieres, J., Drilon, A., Lusque, A., Mhanna, L., Cortot, A. B., Mezquita, L., Thai, A. A., Mascaux, C., Couraud, S., Veillon, R., Van Den Heuvel, M., Neal, J., Peled, N., Fruh, M., Ng, T. L., Gounant, V., Popat, S., Diebold, J., Sabari, J., Zhu, V. W., Rothschild, S. I., Bironzo, P., Martinez, A., Curioni-Fontecedro, A., Rosell, R., Lattuca-Truc, M., Wiesweg, M., Besse, B., Solomon, B., Barlesi, F., Schouten, R. D., Wakelee, H., Camidge, D. R., Zalcman, G., Novello, S., Ou, S. I., Milia, J., Gautschi, O. 2019

  Abstract

  BACKGROUND: Anti-PD1/PD-L1 directed immune-checkpoint-inhibitors (ICI) are widely used to treat patients with advanced non-small cell lung cancer (NSCLC). The activity of ICI across NSCLC harboring oncogenic alterations is poorly characterized. The aim of our study was to address the efficacy of ICI in the context of oncogenic addiction.PATIENTS AND METHODS: We conducted a retrospective study for patients receiving ICI monotherapy for advanced NSCLC with at least one oncogenic driver alteration. Anonymized data were evaluated for clinicopathologic characteristics and outcomes for ICI therapy: best response (RECIST 1.1), progression-free survival (PFS) and overall survival (OS) from ICI initiation. The primary endpoint was PFS under ICI. Secondary endpoints were best response (RECIST 1.1) and overall survival (OS) from ICI initiation.RESULTS: We studied 551 patients treated in 24 centers from 10 countries. The molecular alterations involved KRAS (n=271), EGFR (n=125), BRAF (n=43), MET (n=36), HER2 (n=29), ALK (n=23), RET (n=16), ROS1 (n=7), and multiple drivers (n=1). Median age was 60 years, gender-ratio was 1:1, never/former/current smokers were 28/51/21% respectively, and the majority of tumors were adenocarcinoma. The objective response rate by driver alteration was: KRAS=26%, BRAF=24%, ROS1=17%, MET=16%, EGFR=12%, HER2=7%, RET=6%, ALK=0%. In the entire cohort, median PFS was 2.8 months, OS 13.3 months and the best response rate 19%. In a subgroup analysis, median PFS (in months) was 2.1 for EGFR, 3.2 for KRAS, 2.5 for ALK, 3.1 for BRAF, 2.5 for HER2, 2.1 for RET, and 3.4 for MET. In certain subgroups, PFS was positively associated with PD-L1 expression (KRAS, EGFR) and with smoking status (BRAF, HER2).CONCLUSIONS: ICI induced regression in some tumors with actionable driver alterations, but clinical activity was lower compared to the KRAS group and the lack of response in the ALK group was notable. Patients with actionable tumor alterations should receive targeted therapies and chemotherapy before considering immunotherapy.

  View details for DOI 10.1093/annonc/mdz167

  View details for PubMedID 31125062

• ctDNA analysis for personalization of consolidation immunotherapy in localized non-small cell lung cancer. Moding, E. J., Liu, Y., Nabet, B., Chabon, J. J., Chaudhuri, A., Hui, A. B., He, J., Qiao, Y., Heymach, J., Tsao, A. S., Liao, Z. X., Gomez, D., Ramchandran, K., Neal, J. W., Wakelee, H. A., Loo, B. W., Lin, S. H., Alizadeh, A. A., Diehn, M. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.15_suppl.2547

  View details for Web of Science ID 000487345804497

• Randomized phase II study of adjuvant afatinib for three months versus two years in patients with resected stage I-III EGFR mutant NSCLC. Chaft, J. E., Costa, D., Muzikansky, A., Shrager, J. B., Lanuti, M., Huang, J., Ramchandran, K., Rangachari, D., Huberman, M., Piotrowska, Z., Kris, M. G., Azzoli, C. G., Sequist, L. V., Neal, J. W. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for Web of Science ID 000487345806385

• Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertions. Janne, P. A., Neal, J. W., Camidge, D., Spira, A. I., Piotrowska, Z., Horn, L., Costa, D., Tsao, A. S., Patel, J. D., Gadgeel, S. M., Bazhenova, L., Zhu, V., West, H., Vincent, S., Zhu, J., Li, S., Riely, G. J. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for Web of Science ID 000487345806452

• Osimertinib with chemotherapy for EGFR-mutant NSCLC at progression: Safety profile and survival analysis. Neal, J. W., Hausrath, D., Wakelee, H. A., Cunanan, K., Liu, S. V., Banwait, M., Sequist, L. V., Stirling, K., Piotrowska, Z. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for Web of Science ID 000487345806523

• Increased Galectin-1 Expression in Thymic Epithelial Tumors CLINICAL LUNG CANCER Riess, J. W., Kong, C. S., West, R. B., Padda, S. K., Neal, J. W., Wakelee, H. A., Le, Q. 2019; 20 (3): E356–E361

  View details for DOI 10.1016/j.cllc.2018.12.005

  View details for Web of Science ID 000467981200020

• Steroid-Sparing Therapy for Tyrosine Kinase Inhibitor-Induced Pneumonitis. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Sun, T. Y., Sung, A. W., Neal, J. W. 2019; 14 (4): e75-e77

  View details for DOI 10.1016/j.jtho.2018.11.030

  View details for PubMedID 30922583

• Steroid-Sparing Therapy for Tyrosine Kinase Inhibitor-Induced Pneumonitis JOURNAL OF THORACIC ONCOLOGY Sun, T., Sung, A. W., Neal, J. W. 2019; 14 (4): E75–E77

  View details for DOI 10.1016/j.jtho.2018.11.030

  View details for Web of Science ID 000462167700008

• Clinical and molecular characteristics of responders versus non-responders to immune checkpoint inhibitors (ICI) in NSCLC. Shah, A., Padda, S. K., Neal, J. W. AMER SOC CLINICAL ONCOLOGY. 2019

  View details for DOI 10.1200/JCO.2019.37.8_suppl.114

  View details for Web of Science ID 000489109600120

• Natural Disease History, Outcomes, and Co-mutations in a Series of Patients With BRAF-Mutated Non-small-cell Lung Cancer CLINICAL LUNG CANCER Myall, N. J., Henry, S., Wood, D., Neal, J. W., Han, S. S., Padda, S. K., Wakelee, H. A. 2019; 20 (2): E208–E217

  View details for DOI 10.1016/j.cllc.2018.10.003

  View details for Web of Science ID 000459793100012

• Case series of MET exon 14 skipping mutation-positive non-small-cell lung cancers with response to crizotinib and cabozantinib. Anti-cancer drugs Wang, S. X., Zhang, B. M., Wakelee, H. A., Koontz, M. Z., Pan, M., Diehn, M., Kunder, C. A., Neal, J. W. 2019

  Abstract

  The mesenchymal-to-epithelial transition (MET) gene is altered and becomes a driver mutation in up to 5% of non-small-cell lung cancer (NSCLC). We report our institutional experience treating patients with MET exon 14 skipping (METex14) mutations, including responses to the MET inhibitors crizotinib and cabozantinib. We identified cases of NSCLC with METex14 mutations using an institutionally developed or commercial next-generation sequencing assay. We assessed patient and disease characteristics by retrospective chart review. Some patients were treated off-label by the physician with crizotinib or cabozantinib, and tumor responses to these agents were assessed. A total of 15 patients with METex14-mutated NSCLC were identified, predominantly male (n=10) with a smoking history (60%) and a median age of 74.0 years. No other actionable somatic mutations were detected. Stage distribution included 26.7% stage I, 6.7% stage II, 6.7% stage III, and 60.0% stage IV. Among patients treated with crizotinib or cabozantinib (n=6), three patients showed partial response and one patient showed stable disease on the basis of RECIST criteria. Four patients experienced side effects requiring drug holiday, reduction, or cessation. Our findings highlight the diversity in presentation and histology of NSCLC with METex14 mutations, which were found in the absence of other actionable driver mutations. We observed evidence of tumor response to crizotinib and cabozantinib, supporting the previous reports that METex14 mutations in NSCLC are actionable driver events.

  View details for PubMedID 30762593

• Lengthy Progression-Free Survival and Intracranial Activity of Cabozantinib in Patients with Crizotinib and Ceritinib-Resistant ROS1-Positive Non-Small Cell Lung Cancer JOURNAL OF THORACIC ONCOLOGY Sun, T., Niu, X., Chakraborty, A., Neal, J. W., Wakelee, H. A. 2019; 14 (2): E21–E24

  View details for DOI 10.1016/j.jtho.2018.08.2030

  View details for Web of Science ID 000456410800001

• Response to comment on "Impact of KRAS mutation subtype and concurrent pathogenic mutations on non-small cell lung cancer outcomes". Lung cancer (Amsterdam, Netherlands) Aredo, J. V., Padda, S. K., Kunder, C. A., Han, S. S., Neal, J. W., Shrager, J. B., Wakelee, H. A. 2019

  View details for DOI 10.1016/j.lungcan.2019.08.020

  View details for PubMedID 31492438

• Phase II trial of single agent amrubicin in patients with previously treated advanced thymic malignancies. Lung cancer (Amsterdam, Netherlands) Hellyer, J. A., Gubens, M. A., Cunanan, K. M., Padda, S. K., Burns, M. n., Spittler, A. J., Riess, J. W., San Pedro-Salcedo, M. n., Ramchandran, K. J., Neal, J. W., Wakelee, H. A., Loehrer, P. J. 2019; 137: 71–75

  Abstract

  There are limited treatment options for patients with thymic malignancies. Here we present data supporting treatment with single agent amrubicin, a third generation anthracycline and topoisomerase II inhibitor.This was a phase 2 open-label, single arm trial of amrubicin in patients with thymoma (T) or thymic carcinoma (TC), conducted at two academic institutions. Patients were included if they had received at least one prior chemotherapy regimen. The first 18 patients received amrubicin at 40 mg/m2 IV days 1-3 repeated every 3-weeks. Due to the high incidence of febrile neutropenia, dosing was subsequently amended to 35 mg/m2 for the final 15 patients.A total of 33 patients (14 T/19 TC) were enrolled from 2011 to 2014. Median number of prior therapies was 2. Best response included 6 partial responses, 21 stable disease, and 6 progressive disease (all TC). Objective response rate was 18% (90% exact binomial CI 8.2%-32.8%; T = 4/14 (29%), TC = 2/19 (11%)). Median progression-free survival was 7.7 months (T: 8.3 months; TC: 7.3) and median overall survival was 29.7 months (T: 54.1 months; TC: 18 months). There was a high rate of febrile neutropenia (7 patients) that occurred despite a reduction in amrubicin dose and one related death. Five patients had reduction in LVEF below 50% during the course of treatment resulting in treatment discontinuation in one patient.Amrubicin shows promise as a single agent in heavily pre-treated patients with thymic malignancies. Notable side effects include febrile neutropenia and the use of growth factor support is essential. Further investigation of this agent is warranted.

  View details for DOI 10.1016/j.lungcan.2019.09.015

  View details for PubMedID 31557562

• Role of KEAP1/NFE2L2 mutations in the chemotherapeutic response of non-small cell lung cancer patients. Clinical cancer research : an official journal of the American Association for Cancer Research Jeong, Y. n., Hellyer, J. A., Stehr, H. n., Hoang, N. T., Niu, X. n., Das, M. n., Padda, S. K., Ramchandran, K. n., Neal, J. W., Wakelee, H. A., Diehn, M. n. 2019

  Abstract

  Activation of NFE2L2 has been linked to chemoresistance in cell line models. Recently, somatic mutations which activate NFE2L2, including mutations in NFE2L2,KEAP1, or CUL3,have been found to be associated with poor outcomes in patients with non-small cell lung cancer (NSCLC). However, the impact of these mutations on chemoresistance remains incompletely explored.We investigated the effect of Keap1 deletion on chemoresistance in cell lines from Trp53-based mouse models of lung squamous cell carcinoma (LSCC) and lung adenocarcinoma (LUAD). Separately, we identified 51 stage IV NSCLC patients with KEAP1, NFE2L2, or CUL3mutations and a matched cohort of 52 wildtype patients. Time to treatment failure after front line platinum doublet chemotherapy and overall survival was compared between the two groups.Deletion of Keap1 in Trp53-null murine LUAD and LSCC resulted in increased clonogenic survival upon treatment with diverse cytotoxic chemotherapies. In NSCLC patients, median time to treatment failure (TTF) after first line chemotherapy for the KEAP1/NFE2L2/CUL3-mutant cohort was 2.8 months compared to 8.3 months in the control group (p < 0.0001) Median overall survival (OS) was 11.2 months in the KEAP1/NFE2L2/CUL3-mutant group and 36.8 months in the control group (p = 0.006). Conclusions: Keap1 deletion confers chemoresistance in murine lung cancer cells. Patients with metastatic NSCLC with mutations in KEAP1, NFE2L2, or CUL3 have shorter time to treatment failure and overall survival after first line platinum doublet chemotherapy compared with matched controls. Novel approaches for improving outcomes in this subset of NSCLC patients are therefore needed.

  View details for DOI 10.1158/1078-0432.CCR-19-1237

  View details for PubMedID 31548347

• Association of Antibiotic Resistance With Antibiotic Use for Epidermal Growth Factor Receptor Inhibitor-Related Papulopustular Eruption. JAMA dermatology Hirotsu, K. n., Dang, T. M., Li, S. n., Neal, J. W., Pugliese, S. n., Subramanian, A. n., Kwong, B. Y. 2019

  View details for PubMedID 31017625

• Impact of KRAS mutation subtype and concurrent pathogenic mutations on non-small cell lung cancer outcomes. Lung cancer (Amsterdam, Netherlands) Aredo, J. V., Padda, S. K., Kunder, C. A., Han, S. S., Neal, J. W., Shrager, J. B., Wakelee, H. A. 2019; 133: 144–50

  Abstract

  Concurrent genetic mutations are prevalent in KRAS-mutant non-small cell lung cancer (NSCLC) and may differentially influence patient outcomes. We sought to characterize the effects of KRAS mutation subtypes and concurrent pathogenic mutations on overall survival (OS) and PD-L1 expression, a predictive biomarker for anti-PD-1/PD-L1 immunotherapy.We retrospectively identified patients with KRAS-mutant NSCLC at a single institution and abstracted clinical, molecular, and pathologic data from electronic health records. Cox regression and multinomial logistic regression were used to determine how KRAS mutation subtypes and concurrent pathogenic mutations are associated with OS and tumor PD-L1 expression, respectively.A total 186 patients were included. Common KRAS mutation subtypes included G12C (35%) and G12D (17%). Concurrent pathogenic mutations were identified in TP53 (39%), STK11 (12%), KEAP1 (8%), and PIK3CA (4%). On multivariable analysis, KRAS G12D mutations were significantly associated with poor OS (hazard ratio [HR] 2.43, 95% confidence interval [CI] 1.15-5.16; P = 0.021), as were STK11 co-mutations (HR 2.95, 95% CI 1.27-6.88; P = 0.012). Compared to no (<1%) PD-L1 expression, KRAS G12C mutations were significantly associated with positive yet low (1-49%) PD-L1 expression (odds ratio [OR] 4.94, 95% CI 1.07-22.85; P = 0.041), and TP53 co-mutations with high (≥50%) PD-L1 expression (OR 6.36, 95% CI 1.84-22.02; P = 0.004).KRAS G12D and STK11 mutations confer poor prognoses for patients with KRAS-mutant NSCLC. KRAS G12C and TP53 mutations correlate with a biomarker that predicts benefit from immunotherapy. Concurrent mutations may represent distinct subsets of KRAS-mutant NSCLC; further investigation is warranted to elucidate their role in guiding treatment.

  View details for DOI 10.1016/j.lungcan.2019.05.015

  View details for PubMedID 31200821

• Impact of KEAP1/NFE2L2/CUL3 mutations on duration of response to EGFR tyrosine kinase inhibitors in EGFR mutated non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) Hellyer, J. A., Stehr, H. n., Das, M. n., Padda, S. K., Ramchandran, K. n., Neal, J. W., Diehn, M. n., Wakelee, H. A. 2019; 134: 42–45

  Abstract

  For patients with Epidermal Growth Factor Receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), frontline EGFR-tyrosine kinase inhibitor (TKI) therapy compared to chemotherapy improves outcomes. However, resistance to these agents uniformly develops. Recently, mutations in the KEAP1-NFE2L2 pathway have been implicated as a potential mechanism of acquired EGFR TKI resistance.We examined all patients with metastatic NSCLC with mutations in both EGFR and KEAP1/NFE2L2/CUL3 identified on next generation sequencing from 2015 - 2018. These patients were compared to a NSCLC control cohort with mutations in EGFR and wild type in KEAP1/NFE2L2/CUL3 matched on the basis of sex, smoking status, age and race. Time to treatment failure on EGFR TKI therapy and overall survival were examined.Among 228 EGFR mutant NSCLCs, 17 (7%) also carried mutations in KEAP1, NFE2L2, or CUL3. The most common co-mutation in both the KEAP1/NFE2L2/CUL3 mutant and wild-type cohort was TP53. Patients with KEAP1/NFE2L2/CUL3 mutations had a shorter median time to treatment failure on EGFR TKI (4.7 months) compared with the wild-type matched cohort (13.0 months), p= 0.0014. There was no difference in overall survival.For NSCLC patients with mutations in EGFR, co-mutations in KEAP1/NFE2L2/CUL3 are associated with significantly decreased time to treatment failure. Our results suggest that these mutations represent a mechanism of intrinsic resistance to TKI treatment.

  View details for DOI 10.1016/j.lungcan.2019.05.002

  View details for PubMedID 31319993

• Increased Galectin-1 Expression in Thymic Epithelial Tumors. Clinical lung cancer Riess, J. W., Kong, C. S., West, R. B., Padda, S. K., Neal, J. W., Wakelee, H. A., Le, Q. 2018

  Abstract

  INTRODUCTION: Thymic epithelial tumors (TET) are rare malignancies with a paucity of data on biology and therapeutics. Galectin-1 is a member of the beta-galactoside binding protein family and has been shown to mediate tumor growth via modulation of immune cell function. This study examined galectin-1 expression in TET.PATIENTS AND METHODS: A tissue microarray of 68 patients with TET and 8 benign thymus controls were stained for galectin-1 expression and scored by a pathologist blinded to patient clinical and pathologic data. Galectin-1 expression+1 or greater staining intensity was considered positive. Clinical and pathologic data were abstracted from institutional databases. Expression of galectin-1 in thymic tumor was compared to benign thymus controls and correlated with pertinent clinical and pathologic data.RESULTS: Galectin-1 expression was higher in TET compared to benign thymus controls (65% vs. 0%). No significant association between galectin-1 expression and the development of recurrent disease, paraneoplastic syndromes, or overall survival was noted.CONCLUSION: Galectin-1 is overexpressed in the majority of TET. Detection of galectin-1 may differentiate benign from neoplastic thymic processes. Additional studies are needed to assess the role of galectin-1 in the development of TET.

  View details for PubMedID 30773448

• EGFR-Mutant Adenocarcinomas That Transform to Small-Cell Lung Cancer and Other Neuroendocrine Carcinomas: Clinical Outcomes. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Marcoux, N., Gettinger, S. N., O'Kane, G., Arbour, K. C., Neal, J. W., Husain, H., Evans, T. L., Brahmer, J. R., Muzikansky, A., Bonomi, P. D., Del Prete, S., Wurtz, A., Farago, A. F., Dias-Santagata, D., Mino-Kenudson, M., Reckamp, K. L., Yu, H. A., Wakelee, H. A., Shepherd, F. A., Piotrowska, Z., Sequist, L. V. 2018: JCO1801585

  Abstract

  PURPOSE: Approximately 3% to 10% of EGFR (epidermal growth factor receptor) -mutant non-small cell lung cancers (NSCLCs) undergo transformation to small-cell lung cancer (SCLC), but their clinical course is poorly characterized.METHODS: We retrospectively identified patients with EGFR-mutant SCLC and other high-grade neuroendocrine carcinomas seen at our eight institutions. Demographics, disease features, and outcomes were analyzed.RESULTS: We included 67 patients-38 women and 29 men; EGFR mutations included exon 19 deletion (69%), L858R (25%), and other (6%). At the initial lung cancer diagnosis, 58 patients had NSCLC and nine had de novo SCLC or mixed histology. All but these nine patients received one or more EGFR tyrosine kinase inhibitor before SCLC transformation. Median time to transformation was 17.8 months (95% CI, 14.3 to 26.2 months). After transformation, both platinum-etoposide and taxanes yielded high response rates, but none of 17 patients who received immunotherapy experienced a response. Median overall survival since diagnosis was 31.5 months (95% CI, 24.8 to 41.3 months), whereas median survival since the time of SCLC transformation was 10.9 months (95% CI, 8.0 to 13.7 months). Fifty-nine patients had tissue genotyping at first evidence of SCLC. All maintained their founder EGFR mutation, and 15 of 19 with prior EGFR T790M positivity were T790 wild-type at transformation. Other recurrent mutations included TP53, Rb1, and PIK3CA. Re-emergence of NSCLC clones was identified in some cases. CNS metastases were frequent after transformation.CONCLUSION: There is a growing appreciation that EGFR-mutant NSCLCs can undergo SCLC transformation. We demonstrate that this occurs at an average of 17.8 months after diagnosis and cases are often characterized by Rb1, TP53, and PIK3CA mutations. Responses to platinum-etoposide and taxanes are frequent, but checkpoint inhibitors yielded no responses. Additional investigation is needed to better elucidate optimal strategies for this group.

  View details for DOI 10.1200/JCO.18.01585

  View details for PubMedID 30550363

• SELECT: A Phase II Trial of Adjuvant Erlotinib in Patients With Resected Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Pennell, N. A., Neal, J. W., Chaft, J. E., Azzoli, C. G., Janne, P. A., Govindan, R., Evans, T. L., Costa, D. B., Wakelee, H. A., Heist, R. S., Shapiro, M. A., Muzikansky, A., Murthy, S., Lanuti, M., Rusch, V. W., Kris, M. G., Sequist, L. V. 2018: JCO1800131

  Abstract

  PURPOSE: Given the pivotal role of epidermal growth factor receptor (EGFR) inhibitors in advanced EGFR-mutant non-small-cell lung cancer (NSCLC), we tested adjuvant erlotinib in patients with EGFR-mutant early-stage NSCLC.MATERIALS AND METHODS: In this open-label phase II trial, patients with resected stage IA to IIIA (7th edition of the American Joint Committee on Cancer staging system) EGFR-mutant NSCLC were treated with erlotinib 150 mg per day for 2 years after standard adjuvant chemotherapy with or without radiotherapy. The study was designed for 100 patients and powered to demonstrate a primary end point of 2-year disease-free survival (DFS) greater than 85%, improving on historic data of 76%.RESULTS: Patients (N = 100) were enrolled at seven sites from January 2008 to May 2012; 13% had stage IA disease, 32% had stage IB disease, 11% had stage IIA disease, 16% had stage IIB disease, and 28% had stage IIIA disease. Toxicities were typical of erlotinib; there were no grade 4 or 5 adverse events. Forty percent of patients required erlotinib dose reduction to 100 mg per day and 16% to 50 mg per day. The intended 2-year course was achieved in 69% of patients. The median follow-up was 5.2 years, and 2-year DFS was 88% (96% stage I, 78% stage II, 91% stage III). Median DFS and overall survival have not been reached; 5-year DFS was 56% (95% CI, 45% to 66%), 5-year overall survival was 86% (95% CI, 77% to 92%). Disease recurred in 40 patients, with only four recurrences during erlotinib treatment. The median time to recurrence was 25 months after stopping erlotinib. Of patients with recurrence who underwent rebiopsy (n = 24; 60%), only one had T790M mutation detected. The majority of patients with recurrence were retreated with erlotinib (n = 26; 65%) for a median duration of 13 months.CONCLUSION: Patients with EGFR-mutant NSCLC treated with adjuvant erlotinib had an improved 2-year DFS compared with historic genotype-matched controls. Recurrences were rare for patients receiving adjuvant erlotinib, and patients rechallenged with erlotinib after recurrence experienced durable benefit.

  View details for DOI 10.1200/JCO.18.00131

  View details for PubMedID 30444685

• Comparison of Genomic Driver Oncogenes in Vietnamese Patients With Non-Small-Cell Lung Cancer in the United States and Vietnam JOURNAL OF GLOBAL ONCOLOGY Nguyen, K. H., Stehr, H., Zhou, L., Anh-Hoa Nguyen, Pham Nhu Hiep, Nguyen Van Cau, Phan Canh Duy, Thorp, R., Wakelee, H. A., Diehn, M., Neal, J. W. 2018; 4

  View details for DOI 10.1200/JGO.18.00086

  View details for Web of Science ID 000462471900001

• EGFR Genotyping of Matched Urine, Plasma, and Tumor Tissue in Patients With Non-Small-Cell Lung Cancer Treated With Rociletinib, an EGFR Tyrosine Kinase Inhibitor. JCO precision oncology Goldman, J. W., Karlovich, C., Sequist, L. V., Melnikova, V., Franovic, A., Gadgeel, S. M., Reckamp, K. L., Camidge, D. R., Pérol, M., Ou, S. I., Liu, S. V., Yu, H. A., Soria, J. C., Socinski, M. A., Mekhail, T. M., Solomon, B. J., Natale, R. B., Otterson, G. A., Papadimitrakopoulou, V., Langer, C. J., Neal, J. W., Despain, D., Yurasov, S., Litten, J. B., Erlander, M., Raponi, M., Wakelee, H. A. 2018; 2: 1-13

  Abstract

  Liquid biopsies represent an attractive alternative to tissue biopsies, particularly rebiopsies, in determining patient eligibility for targeted therapies. Clinical utility of urine genotyping, however, has not been explored extensively. We evaluated epidermal growth factor receptor (EGFR) T790M detection in matched urine, plasma, and tissue and the clinical outcomes of patients with advanced non-small-cell lung cancer treated with rociletinib.Tissue (n = 540), plasma (n = 482), and urine (n = 213) were collected from evaluable patients enrolled in TIGER-X, a phase I/II study. Genotyping was performed by therascreen EGFR testing in tissue, BEAMing in plasma, and a quantitative short footprint assay (Trovera) in urine, which was used to further examine discordant samples.Positive percent agreement with tissue T790M results was similar for urine (82%; 142 of 173) and plasma (81%; 313 of 387) genotyping. Urine and plasma together identified more patients who were T790M positive (92%) than tissue alone (83%) among matched samples (n = 177). The ability to identify mutations in plasma was strongly associated with M stage (P < .001); rate of T790M detection for patients with M1a/M0 disease increased from 54% for plasma alone to 85% when urine and plasma were both examined. Objective response rates of patients who were T790M positive were comparable between tumor (34%), plasma (32%), and urine (37%).Clinical response to rociletinib was comparable irrespective of whether T790M status was identified by liquid or tissue biopsy. Combined, urine and plasma identified a higher percentage of patients who were T790M positive than tumor genotyping alone and improved detection of T790M, particularly in the absence of distant metastases. These findings support the noninvasive analysis of urine and plasma before tumor rebiopsy when assessing T790M status.

  View details for DOI 10.1200/PO.17.00116

  View details for PubMedID 35135111

• Natural history, treatment (tx) patterns, and outcomes in MET dysregulated non-small cell lung cancer (NSCLC) patients (pts) Wolf, J., Baik, C., Heist, R. S., Neal, J. W., Mansfield, A. S., Buettner, R., Davis, K. L., Giovannini, M., Mutebi, A., Awad, M. M. ELSEVIER SCI LTD. 2018: E131

  View details for Web of Science ID 000461258600365

• Comparison of Genomic Driver Oncogenes in Vietnamese Patients With Non-Small-Cell Lung Cancer in the United States and Vietnam. Journal of global oncology Nguyen, K. H., Stehr, H., Zhou, L., Nguyen, A., Hiep, P. N., Van Cau, N., Duy, P. C., Thorp, R., Wakelee, H. A., Diehn, M., Neal, J. W. 2018: 1–9

  Abstract

  PURPOSE: Discoveries of oncogenic driver alterations in non-small-cell lung cancer (NSCLC) have been accompanied by the development of effective targeted therapies. The frequencies of these mutations vary between populations but are less well characterized in the Vietnamese population. In this study, we analyzed the frequencies of lung cancer driver oncogenic alterations in Vietnamese patients compared with Vietnamese patients treated in the United States.METHODS: We collected data on tumor and disease characteristics of Vietnamese patients with NSCLC treated at Stanford. In addition, we collected NSCLC tumor specimens from patients with NSCLC diagnosed in Hue, Vietnam, and performed next-generation-based genotyping on these samples. The molecular and clinical characteristics of these groups were compared.RESULTS: Fifty-nine Vietnamese patients were identified at Stanford. Of the 44 patients with molecular testing results, there were 21 (47.7%) with EGFR alterations, six (13.6%) with ALK alterations, two (4.5%) with KRAS alterations, one (2.3%) with BRAF alterations, and no ROS1 or RET alterations. Across all stages, the median overall survival for patients with a tumor having a targetable genomic alteration driver mutation was 42.4 months, compared with 27.1 months for patients without such alterations. In the 45 genotyped samples from Vietnam, there were 26 (57.8%) with EGFR, 11 (24.4%) with KRAS, and one each (2.2%) with ALK, ROS1, and RET.CONCLUSION: The majority of tumors from both Stanford and Vietnam had targetable oncogenic alterations. This suggests that routine implementation of molecular testing may have a significant, positive impact on the treatment of Vietnamese patients with NSCLC, but affordability of testing and treatments remains a barrier to adoption.

  View details for PubMedID 30422746

• Natural Disease History, Outcomes, and Co-mutations in a Series of Patients With BRAF-Mutated Non-small-cell Lung Cancer. Clinical lung cancer Myall, N. J., Henry, S., Wood, D., Neal, J. W., Han, S. S., Padda, S. K., Wakelee, H. A. 2018

  Abstract

  BACKGROUND: BRAF mutations occur in 1% to 4% of non-small-cell lung cancer (NSCLC) cases. Previous retrospective studies have reported similar outcomes for BRAF-mutated NSCLC as compared with wild-type tumors without a known driver mutation or tumors harboring other mutations. However, select cases of prolonged survival have also been described, and thus, the natural history of BRAF-mutated NSCLC remains an area of ongoing study. The aim of this series was to describe the natural history, clinical outcomes, and occurrence of co-mutations in patients with BRAF-mutated NSCLC.PATIENTS AND METHODS: Patients with BRAF-mutated NSCLC seen at Stanford University Medical Center from January 1, 2006 through July 31, 2015 were reviewed. The Kaplan-Meier method was used to calculate median overall survival, and the generalized Wilcoxon test was used to compare median survivals across subgroups of patients.RESULTS: Within a cohort of 18 patients with BRAF-mutated NSCLC, V600E mutations were most common (72%; 13/18). Clinicopathologic features were similar between patients with V600E versus non-V600E mutations, although there was a trend toward more patients with non-V600E mutations being heavy smokers (80% vs. 31%; P= .12). Co-occurring mutations in TP53 were identified most commonly (28%; 5/18). The median overall survival for the entire cohort was 40.1 months, and the median survival from the onset of metastases (n= 16) was 28.1 months. Survival rates at 2 and 5 years from the onset of metastases were 56% and 13%, respectively.CONCLUSION: The clinical behavior of BRAF-mutated NSCLC is variable, but favorable outcomes can be seen in a subset of patients.

  View details for PubMedID 30442523

• Safety and anti-tumor effects of MAGE-A10c796 TCR T-cells in two clinical trials Lam, V. K., Hong, D. S., Heymach, J. V., Blumenschein, G., Butler, M. O., Johnson, M., Creelan, B., Gainor, J. F., Govindan, R., Mudad, R., Neal, J., Brophy, F., Fang, F., Hyland, N., Holdich, T., Ma, Y., Trivedi, T., Norry, E., Amado, R. G. OXFORD UNIV PRESS. 2018

  View details for Web of Science ID 000459277304397

• Safety and anti-tumor effects of MAGE-A10c796 TCR T-cells in two clinical trials. Annals of oncology : official journal of the European Society for Medical Oncology Lam, V. K., Hong, D. S., Heymach, J. V., Blumenschein, G., Butler, M. O., Johnson, M., Creelan, B., Gainor, J. F., Govindan, R., Mudad, R., Neal, J., Brophy, F., Fang, F., Hyland, N., Holdich, T., Ma, Y., Trivedi, T., Norry, E., Amado, R. G. 2018; 29 Suppl 8: viii731

  View details for DOI 10.1093/annonc/mdy424.048

  View details for PubMedID 32138012

• Safety, PK, and Preliminary Antitumor Activity of the Oral EGFR/HER2 Exon 20 Inhibitor TAK-788 in NSCLC Neal, J., Doebele, R., Riely, G., Spira, A., Horn, L., Piotrowska, Z., Costa, D., Zhang, S., Bottino, D., Zhu, J., Kerstein, D., Li, S., Janne, P. ELSEVIER SCIENCE INC. 2018: S599

  View details for DOI 10.1016/j.jtho.2018.08.901

  View details for Web of Science ID 000454014502056

• Co-Mutations, Natural History, and Outcomes of BRAF-Mutated Non-Small Cell Lung Cancer at a Single Academic Cancer Center Myall, N., Henry, S., Wood, D., Neal, J., Wakelee, H. ELSEVIER SCIENCE INC. 2018: S489–S490

  View details for DOI 10.1016/j.jtho.2018.08.627

  View details for Web of Science ID 000454014501261

• Lengthy progression-free survival and intracranial activity of cabozantinib in patients with crizotinib and ceritinib-resistant ROS1-positive non-small-cell lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer Sun, T. Y., Niu, X., Chakraborty, A., Neal, J. W., Wakelee, H. A. 2018

  View details for PubMedID 30217491

• Infiltrating the Blood-Brain Barrier in ALK-Positive Lung Cancer JOURNAL OF CLINICAL ONCOLOGY Zweig, J. R., Neal, J. W. 2018; 36 (26): 2677-+

  View details for DOI 10.1200/JCO.2018.78.8554

  View details for Web of Science ID 000445669600002

• Prognostic Value of Pretreatment FDG-PET Parameters in High-dose Image-guided Radiotherapy for Oligometastatic Non-Small-cell Lung Cancer CLINICAL LUNG CANCER Chin, A. L., Kumar, K. A., Guo, H. H., Maxim, P. G., Wakelee, H., Neal, J. W., Diehn, M., Loo, B. W., Gensheimer, M. F. 2018; 19 (5): E581–E588

  View details for DOI 10.1016/j.cllc.2018.04.003

  View details for Web of Science ID 000442538700007

• Three-dimensional organoid model for acquired drug resistance in non-small cell lung cancer Shukla, N. D., Salahudeen, A. A., Padda, S. K., Neal, J. W., Wakelee, H. A., Kuo, C. J. AMER ASSOC CANCER RESEARCH. 2018

  View details for DOI 10.1158/1557-3265.AACRIASLC18-B30

  View details for Web of Science ID 000582244900061

• Ensartinib in Anaplastic Lymphoma Kinase (ALK) Positive Non-Small Cell Lung Cancer (NSCLC) Patients: Updated Data Leal, T., Wakelee, H., Reckamp, K., Waqar, S., Patel, S., Blumenschein, G., Neal, J., Harrow, K., Holzhausen, A., Liang, C., Dukart, G., Horn, L. ELSEVIER SCIENCE INC. 2018: S156

  View details for Web of Science ID 000444519200009

• Synchronous primary lung adenocarcinomas harboring distinct MET Exon 14 splice site mutations. Lung cancer (Amsterdam, Netherlands) Wang, S. X., Lei, L., Guo, H. H., Shrager, J., Kunder, C. A., Neal, J. W. 2018; 122: 187–91

  Abstract

  When a patient is found to have multiple lung tumors, distinguishing whether they represent metastatic nodules or separate primary cancers is crucial for staging and therapy. We report the case of a 79-year-old patient with two surgically resected synchronous left upper lobe adenocarcinomas initially pathologically staged as T3 (IIB), indicating adjuvant chemotherapy should be recommended. However, the tumors appeared radiographically distinct, so next-generation sequencing was performed on each nodule. Each tumor harbored a different mesenchymal-to-epithelial transition (MET) exon 14 skipping mutation, an emerging targetable mutation, suggestive of distinct clonality. While the in frame protein deletion was the same in each tumor, the nucleotide base substitutions were different. Thus, the patient was down-staged to having two separate IA tumors, spared of adjuvant chemotherapy, and routine surveillance was recommended. This case highlights the utility of using molecular analysis in diagnosing and treating multifocal lung tumors, and the process of convergent molecular evolution toward a common oncogenic driver mutation. This is the first case of multiple synchronous lung tumors each harboring a distinct MET exon 14 splice site mutation.

  View details for PubMedID 30032829

• Synchronous primary lung adenocarcinomas harboring distinct MET Exon 14 splice site mutations LUNG CANCER Wang, S. Y., Lei, L., Guo, H. H., Shrager, J., Kunder, C. A., Neal, J. W. 2018; 122: 187–91

  View details for DOI 10.1016/j.lungcan.2018.06.019

  View details for Web of Science ID 000440769900030

• The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC) JOURNAL FOR IMMUNOTHERAPY OF CANCER Brahmer, J. R., Govindan, R., Anders, R. A., Antonia, S. J., Sagorsky, S., Davies, M. J., Dubinett, S. M., Ferris, A., Gandhi, L., Garon, E. B., Hellmann, M. D., Hirsch, F. R., Malik, S., Neal, J. W., Papadimitrakopoulou, V. A., Rimm, D. L., Schwartz, L. H., Sepesi, B., Yeap, B., Rizvi, N. A., Herbst, R. S. 2018; 6: 75

  Abstract

  Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for over 85% of all cases. Until recently, chemotherapy - characterized by some benefit but only rare durable responses - was the only treatment option for patients with NSCLC whose tumors lacked targetable mutations. By contrast, immune checkpoint inhibitors have demonstrated distinctly durable responses and represent the advent of a new treatment approach for patients with NSCLC. Three immune checkpoint inhibitors, pembrolizumab, nivolumab and atezolizumab, are now approved for use in first- and/or second-line settings for selected patients with advanced NSCLC, with promising benefit also seen in patients with stage III NSCLC. Additionally, durvalumab following chemoradiation has been approved for use in patients with locally advanced disease. Due to the distinct features of cancer immunotherapy, and rapid progress in the field, clinical guidance is needed on the use of these agents, including appropriate patient selection, sequencing of therapies, response monitoring, adverse event management, and biomarker testing. The Society for Immunotherapy of Cancer (SITC) convened an expert Task Force charged with developing consensus recommendations on these key issues. Following a systematic process as outlined by the National Academy of Medicine, a literature search and panel voting were used to rate the strength of evidence for each recommendation. This consensus statement provides evidence-based recommendations to help clinicians integrate immune checkpoint inhibitors into the treatment plan for patients with NSCLC. This guidance will be updated following relevant advances in the field.

  View details for PubMedID 30012210

• Organoid-based characterization of patient tumors and microenvironments at single cell resolution Salahudeen, A. A., Zhu, J., Ju, J., Batish, A., Sutha, K., Neal, J. T., Giangarra, V., Montesclaros, L., Sapida, J., Sharifi, O., Lee, J., Zheng, G. X., Wagh, D. A., Coller, J. A., Neal, J. W., Padda, S. K., Sabatti, C., Kuo, C. J. AMER ASSOC CANCER RESEARCH. 2018

  View details for DOI 10.1158/1538-7445.AM2018-987

  View details for Web of Science ID 000468818902486

• Infiltrating the Blood-Brain Barrier in ALK-Positive Lung Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Zweig, J. R., Neal, J. W. 2018: JCO2018788554

  View details for PubMedID 29939839

• Ensartinib (X-396) in ALK-Positive Non-Small Cell Lung Cancer: Results from a First-in-Human Phase I/II, Multicenter Study CLINICAL CANCER RESEARCH Horn, L., Infante, J. R., Reckamp, K. L., Blumenschein, G. R., Leal, T. A., Waqar, S. N., Gitlitz, B. J., Sanborn, R. E., Whisenant, J. G., Du, L., Neal, J. W., Gockerman, J. P., Dukart, G., Harrow, K., Liang, C., Gibbons, J. J., Holzhausen, A., Lovly, C. M., Wakelee, H. A. 2018; 24 (12): 2771–79

  Abstract

  Purpose: Evaluate safety and determine the recommended phase II dose (RP2D) of ensartinib (X-396), a potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), and evaluate preliminary pharmacokinetics and antitumor activity in a first-in-human, phase I/II clinical trial primarily in patients with non-small cell lung cancer (NSCLC).Patients and Methods: In dose escalation, ensartinib was administered at doses of 25 to 250 mg once daily in patients with advanced solid tumors; in dose expansion, patients with advanced ALK-positive NSCLC were administered 225 mg once daily. Patients who had received prior ALK TKI(s) and patients with brain metastases were eligible.Results: Thirty-seven patients enrolled in dose escalation, and 60 enrolled in dose expansion. The most common treatment-related toxicities were rash (56%), nausea (36%), pruritus (28%), vomiting (26%), and fatigue (22%); 23% of patients experienced a treatment-related grade 3 to 4 toxicity (primarily rash and pruritus). The maximum tolerated dose was not reached, but the RP2D was chosen as 225 mg based on the frequency of rash observed at 250 mg without improvement in activity. Among the ALK-positive efficacy evaluable patients treated at ≥200 mg, the response rate (RR) was 60%, and median progression-free survival (PFS) was 9.2 months. RR in ALK TKI-naïve patients was 80%, and median PFS was 26.2 months. In patients with prior crizotinib only, the RR was 69% and median PFS was 9.0 months. Responses were also observed in the central nervous system, with an intracranial RR of 64%.Conclusions: Ensartinib was active and generally well tolerated in patients with ALK-positive NSCLC. Clin Cancer Res; 24(12); 2771-9. ©2018 AACR.

  View details for PubMedID 29563138

  View details for PubMedCentralID PMC6004248

• Circulating Tumor DNA Quantitation for Early Response Assessment of Immune Checkpoint Inhibitors for Metastatic Non-Small Cell Lung Cancer Chaudhuri, A. A., Nabet, B. Y., Merriott, D. J., Jin, M., Chen, E. L., Chabon, J. J., Newman, A. M., Stehr, H., Say, C., Carter, J. N., Walters, S., Becker, H., Das, M., Padda, S. K., Loo, B. W., Wakelee, H. A., Neal, J. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2018: E1–E2

  View details for Web of Science ID 000432447200003

• First report of safety, PK, and preliminary antitumor activity of the oral EGFR/HER2 exon 20 inhibitor TAK-788 (AP32788) in non-small cell lung cancer (NSCLC). Doebele, R., Riely, G. J., Spira, A. I., Horn, L., Piotrowska, Z., Costa, D., Neal, J. W., Zhang, S., Reichmann, W., Kerstein, D., Li, S., Janne, P. A. AMER SOC CLINICAL ONCOLOGY. 2018

  View details for DOI 10.1200/JCO.2018.36.15_suppl.9015

  View details for Web of Science ID 000442916003189

• Facile single cell profiling and clonotype analysis of NSCLC immune microenvironments. Salahudeen, A., Zhu, J., Ju, J., Giangarra, V., Montesclaros, L., Sapida, J., Sharifi, O., Lee, J., Wagh, D., Coller, J., Neal, J. W., Padda, S., Wakelee, H. A., Sabatti, C., Kuo, C. AMER SOC CLINICAL ONCOLOGY. 2018

  View details for DOI 10.1200/JCO.2018.36.15_suppl.12014

  View details for Web of Science ID 000442916004029

• Outcomes of EGFR-mutant lung adenocarcinomas (AC) that transform to small cell lung cancer (SCLC). Marcoux, N., Gettinger, S. N., O'Kane, G. M., Arbour, K., Neal, J. W., Husain, H., Evans, T. L., Brahmer, J. R., Muzikansky, A., Bonomi, P., Del Prete, S. A., Wurtz, A., Farago, A. F., Dias-Santagata, D., Mino-Kenudson, M., Yu, H., Wakelee, H. A., Shepherd, F. A., Piotrowska, Z., Sequist, L. V. AMER SOC CLINICAL ONCOLOGY. 2018

  View details for DOI 10.1200/JCO.2018.36.15_suppl.8573

  View details for Web of Science ID 000442916003168

• Efficacy of immune-checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC) patients harboring activating molecular alterations (ImmunoTarget). Mazieres, J., Drilon, A. E., Mhanna, L., Milia, J., Lusque, A., Cortot, A. B., Mezquita, L., Thai, A., Couraud, S., Veillon, R., Mascaux, C., Schouten, R., Neal, J. W., Ng, T. L., Frueh, M., Peled, N., Gounant, V., Popat, S., Zhu, V., Gautschi, O. AMER SOC CLINICAL ONCOLOGY. 2018

  View details for DOI 10.1200/JCO.2018.36.15_suppl.9010

  View details for Web of Science ID 000442916003184

• Computed Tomography Features associated With the Eighth Edition TNM Stage Classification for Thymic Epithelial Tumors JOURNAL OF THORACIC IMAGING Padda, S. K., Terrone, D., Tian, L., Khuong, A., Neal, J. W., Riess, J. W., Berry, M. F., Hoang, C. D., Burt, B. M., Leung, A. N., Schwartz, E. J., Shrager, J. B., Wakelee, H. A. 2018; 33 (3): 176–83

  Abstract

  The eighth edition of the TNM classification of malignant tumors for the first time includes an official staging system for thymic epithelial tumors (TETs) recognized by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC). Staging is critical for the management of TETs, and determining stage accurately from imaging has the potential to improve clinical outcomes. We examine preoperative computed tomography (CT) characteristics of TETs associated with AJCC/UICC pathologic TNM stage.In this retrospective study, patients were included if they met all the following criteria: (1) diagnosis of TET, (2) had primary curative intent surgery performed at Stanford University, and (3) had available preoperative CT imaging for review. Tumor pathology was staged according to the eighth edition TNM classification. Fifteen CT scan features were examined from each patient case according to the International Thymic Malignancy Interest Group standard report terms in a blinded manner. A Lasso-regularized multivariate model was used to produce a weighted scoring system predictive of pathologic TNM stage.Examining the 54 patients included, the following CT characteristics were associated with higher pathologic TNM stage when using the following scoring system: elevated hemidiaphragm (score of 6), vascular endoluminal invasion (score of 6), pleural nodule (score of 2), lobulated contour (score of 2), and heterogeneous internal density (score of 1). Area under the receiver operating characteristic curve was 0.76.TETs with clearly invasive or metastatic features seen on CT are associated with having higher AJCC/UICC pathologic TNM stage, as expected. However, features of lobulated contour and heterogeneous internal density are also associated with higher stage disease. These findings need to be validated in an independent cohort.

  View details for PubMedID 29219888

• Antimicrobial resistance due to antibiotic use for EGFR inhibitor related papulopustular skin reaction Hirotsu, K., Subramanian, A., Neal, J., Li, S., Pugliese, S., Kwong, B. ELSEVIER SCIENCE INC. 2018: S176

  View details for Web of Science ID 000431498600302

• EGFR Genotyping of Matched Urine, Plasma , and Tumor Tissue in Patients With Non-Small-Cell Lung Cancer Treated With Rociletinib, an EGFR Tyrosine Kinase Inhibitor JCO PRECISION ONCOLOGY Goldman, J. W., Karlovich, C., Sequist, L., Melnikova, V., Franovic, A., Gadgeel, S. M., Reckamp, K. L., Camidge, D., Perol, M., Ou, S., Liu, S., Yu, H. A., Soria, J., Socinski, M. A., Mekhail, T. M., Solomon, B. J., Natale, R. B., Otterson, G. A., Papadimitrakopoulou, V., Langer, C. J., Neal, J. W., Despain, D., Yurasov, S., Litten, J. B., Erlander, M., Raponi, M., Wakelee, H. A. 2018; 2: 1–13

  Abstract

  OBJECTIVECerebral cavernous malformations (CCMs) are frequently diagnosed vascular malformations of the brain. Although most CCMs are asymptomatic, some can be responsible for intracerebral hemorrhage or seizures. In selected cases, microsurgical resection is the preferred treatment option. Treatment with the unselective β-blocker propranolol has been presumed to stabilize and eventually lead to CCM size regression in a limited number of published case series; however, the underlying mechanism and evidence for this effect remain unclear. The aim of this study was to investigate the risk for CCM-related hemorrhage in patients on long-term β-blocker medication.METHODSA single-center database containing data on patients harboring CCMs was retrospectively interrogated for a time period of 35 years. The database included information about hemorrhage and antihypertensive medication. Descriptive and survival analyses were performed, focusing on the risk of hemorrhage at presentation and during follow-up (first or subsequent hemorrhage) in patients on long-term β-blocker medication versus those who were not. Follow-up was censored at the first occurrence of new hemorrhage, surgery, or the last clinical review. For purposes of this analysis, the β-blocker group was divided into the following main subgroups: any β-blocker, β1-selective β-blocker, and any unselective β-blocker.RESULTSOf 542 CCMs among 408 patients, 81 (14.9%) were under treatment with any β-blocker; 65 (12%) received β1-selective β-blocker, and 16 (3%) received any unselective β-blocker. One hundred thirty-six (25.1%) CCMs presented with hemorrhage at diagnosis. None of the β-blocker groups was associated with a lower risk of hemorrhage at the time of diagnosis in a univariate descriptive analysis (any β-blocker: p = 0.64, β1-selective: p = 0.93, any unselective β-blocker: p = 0.25). Four hundred ninety-six CCMs were followed up after diagnosis and included in the survival analysis, for a total of 1800 lesion-years. Follow-up hemorrhage occurred in 36 (7.3%) CCMs. Neither univariate descriptive nor univariate Cox proportional-hazards regression analysis showed a decreased risk for follow-up hemorrhage under treatment with β-blocker medication (any β-blocker: p = 0.70, HR 1.19, 95% CI 0.49-2.90; β1-selective: p = 0.78, HR 1.15, 95% CI 0.44-3.00; any unselective β-blocker: p = 0.76, HR 1.37, 95% CI 0.19-10.08). Multivariate Cox proportional-hazards regression analysis including brainstem location, hemorrhage at diagnosis, age, and any β-blocker treatment showed no reduced risk for follow-up hemorrhage under any β-blocker treatment (p = 0.53, HR 1.36, 95% CI 0.52-3.56).CONCLUSIONSIn this retrospective cohort study, β-blocker medication does not seem to be associated with a decreased risk of CCM-related hemorrhage at presentation or during follow-up.

  View details for DOI 10.1200/PO.17.00116

  View details for Web of Science ID 000462068300001

  View details for PubMedID 29905510

• Randomized phase 2 study of tivantinib plus erlotinib versus single-agent chemotherapy in previously treated KRAS mutant advanced non-small cell lung cancer LUNG CANCER Gerber, D. E., Socinski, M. A., Neal, J. W., Wakelee, H. A., Shirai, K., Sequist, L. V., Rosovsky, R. P., Lilenbaum, R. C., Bastos, B. R., Huang, C., Johnson, M. L., Hesketh, P. J., Subramaniam, D. S., Dietrich, M. F., Chai, F., Wang, Y., Kazakin, J., Schwartz, B., Schiller, J. H., Brahmer, J. R., Kelly, R. J. 2018; 117: 44–49

  Abstract

  KRAS mutations are identified in approximately 25% of non-small cell lung cancer (NSCLC) cases and are associated with resistance to currently available targeted therapies. The MET oncogene may be implicated in malignant progression of KRAS-mutant tumors. In a pre-specified subset analysis of KRAS mutant cancers in an earlier phase 2 study of erlotinib plus the oral MET inhibitor tivantinib, combination therapy was associated with substantial clinical benefit compared to erlotinib alone (progression-free survival [PFS] HR 0.18; P < 0.01). The current study was conducted to evaluate this combination further in KRAS mutant non-small cell lung cancer (NSCLC).Previously treated patients with advanced KRAS mutant NSCLC were randomized to receive either oral tivantinib (360 mg twice daily) plus erlotinib (150 mg daily) (ET) or single-agent chemotherapy (investigator's choice of pemetrexed, docetaxel, or gemcitabine) (C). The primary endpoint was PFS. At progression, crossover from C to ET was permitted.Ninety-six patients were randomly assigned to ET (n = 51) or to C (n = 45). Median PFS was 1.7 months (mos) for ET and 4.3 mos for C (HR 1.19; 95% CI, 0.71-1.97; P = 0.50). There was no difference in overall survival (HR 1.20; 95% CI, 0.76-1.88; P = 0.44). There were 4 partial responses in the C arm, and none in the ET arm. Overall, adverse events occurred more frequently in the C arm, with more cytopenias, nausea, fatigue, and alopecia. Dermatologic toxicities were more common in the ET arm.In previously treated patients with advanced KRAS mutant NSCLC, the combination of the MET inhibitor tivantinib and erlotinib is not superior to conventional single-agent chemotherapy.

  View details for PubMedID 29496255

• Prognostic Value of Pretreatment FDG-PET Parameters in High-dose Image-guided Radiotherapy for Oligometastatic Non-Small-cell Lung Cancer. Clinical lung cancer Chin, A. L., Kumar, K. A., Guo, H. H., Maxim, P. G., Wakelee, H. n., Neal, J. W., Diehn, M. n., Loo, B. W., Gensheimer, M. F. 2018

  Abstract

  Emerging data support aggressive local treatment of oligometastatic non-small-cell lung cancer (NSCLC) patients. We sought to determine whether the metabolic burden of disease found by fluorodeoxyglucose positron emission tomography at the time of high-dose radiotherapy (RT) for oligometastatic NSCLC can serve as a prognostic biomarker.We conducted a retrospective cohort study of 67 RT treatment courses in 55 patients with oligometastatic NSCLC who had undergone high-dose RT to all sites of active disease at our institution. The metabolic tumor volume, total lesion glycolysis (TLG), and maximum standardized uptake value of all lesions were measured on the pretreatment fluorodeoxyglucose positron emission tomography scans. Cox regression analysis was used to assess the influence of imaging and clinical factors on overall survival (OS).On univariate analysis, a greater metabolic tumor volume and TLG were predictive of shorter OS (hazard ratio of death, 2.42 and 2.14, respectively; P = .009 and P = .004, respectively). The effects remained significant on multivariate analysis. Neither the maximum standardized uptake value nor the number of lesions was significantly associated with OS. Patients within the highest quartile of TLG values (> 86.8 units) had a shorter median OS than those within the lower 3 quartiles (12.4 vs. 30.1 months; log-rank P = .014).The metabolic tumor burden was prognostic of OS and might help to better select oligometastatic NSCLC patients for locally ablative therapy.

  View details for PubMedID 29759331

• Commentary: Treatment Considerations for Patients With Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer Brain Metastases in the Era of Tyrosine Kinase Inhibitors NEUROSURGERY Vaca, S., Connolly, I., Ho, C., Neal, J., Gephart, M. 2018; 82 (1): E6–E14

  View details for DOI 10.1093/neuros/nyx429

  View details for Web of Science ID 000424223500003

• Osimertinib for EGFR-Mutant Lung Cancer with Brain Metastases: Results from a Single-Center Retrospective Study. The oncologist Xie, L. n., Nagpal, S. n., Wakelee, H. A., Li, G. n., Soltys, S. G., Neal, J. W. 2018

  Abstract

  Osimertinib is a third-generation tyrosine kinase inhibitor, initially approved for epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) with T790M acquired resistance, and now approved in the first-line setting. However, data supporting the use of osimertinib in untreated brain metastases are limited, although it has established central nervous system (CNS) activity. Our study compares the clinical outcomes of patients experiencing progressing brain metastases treated with cranial irradiation and osimertinib with those treated with osimertinib alone.Forty patients who were treated with osimertinib at the Stanford Cancer Center from November 2015 to December 2016 were identified by searching an electronic medical record database. Eleven patients had progressing brain metastases and did not receive radiation (group A), 9 patients had progressing brain metastases and received radiation when starting osimertinib (group B), and 20 patients had stable brain metastases at the time of initiating osimertinib (group C). Patient and disease characteristics, radiographic responses, and survival outcomes were evaluated retrospectively for the three groups.The CNS response rate was 32.3%. Median time to treatment failure (TTF), overall progression-free survival (PFS), and overall survival (OS) were 10.0 months (95% confidence interval [CI], 4.5-11.8), 8.8 months (95% CI, 6.2-12.1), and 16.2 months, respectively. Median TTF was 15.1 months for group A (95% CI, 1.7-28.5), 7.7 months for group B (95% CI, 0-15.5), and 10.7 months for group C (95% CI, 9.0-12.5). The median PFS was 8.8 months for group A (95% CI, 4.3-13.4), not reached for group B, and 8.4 months for group C (95% CI, 5.6-11.1). The median OS was not reached for group A and C, and was 16.2 months for group B. There was no apparent difference in TTF, PFS, or OS between the three groups.Receiving radiation prior to starting osimertinib for patients with progressing brain metastases did not prolong TTF, PFS, or OS in our series. To minimize the risks of radiation-related toxicity, delaying radiation could be considered for some patients with EGFR-mutant NSCLC with brain metastases who initially respond to osimertinib in the second-line setting.Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor recently approved for the first-line treatment of EGFR-mutant non-small cell lung cancer. Although it appears to have central nervous system (CNS) activity, most clinical trials have excluded patients with untreated, progressing brain metastases. This study included patients with stable and progressing CNS metastases treated with osimertinib and found no apparent differences in median time to treatment failure, time to progression, and overall survival in patients who received osimertinib alone compared with those who received osimertinib and radiosurgery. This may support a clinician's decision to defer radiation for selected patients with untreated brain metastases who are candidates for osimertinib therapy.

  View details for PubMedID 30126856

• Survival and risk factors for progression after resection of the dominant tumor in multifocal, lepidic-type pulmonary adenocarcinoma Gao, R. W., Berry, M. F., Kunder, C. A., Khuong, A. A., Wakelee, H., Neal, J. W., Backhus, L. M., Shrager, J. B. MOSBY-ELSEVIER. 2017: 2092-+

  Abstract

  It remains unclear whether a dominant lung adenocarcinoma that presents with multifocal ground glass opacities (GGOs) should be treated by local therapy. We sought to address survival in this setting and to identify risk factors for progression of unresected GGOs.Retrospective review of 70 patients who underwent resection of a pN0, lepidic adenocarcinoma, who harbored at least 1 additional GGO. Features associated with GGO progression were determined using logistic regression and survival was evaluated using the Kaplan-Meier method.Subjects harbored 1 to 7 GGOs beyond their dominant tumor (DT). Mean follow-up was 4.1 ± 2.8 years. At least 1 GGO progressed after DT resection in 21 patients (30%). In 11 patients (15.7%), this progression prompted resection (n = 5) or stereotactic radiotherapy (n = 6) at mean 2.8 ± 2.3 years. Several measures of the overall tumor burden were associated with GGO progression (all P values < .03) and with progression prompting intervention (all P values < .01). In logistic regression, greater DT size (odds ratio, 1.07; 95% confidence interval, 1.01-1.14) and an initial GGO > 1 cm (odds ratio, 4.98; 95% confidence interval, 1.15-21.28) were the only factors independently associated with GGO progression. Survival was not negatively influenced by GGO progression (100% with vs 80.7% without; P = .1) or by progression-prompting intervention (P = .4).At 4.1-year mean follow-up, 15.7% of patients with unresected GGOs after resection of a pN0 DT underwent subsequent intervention for a progressing GGO. Some features correlated with GGO growth, but neither growth, nor need for an intervention, negatively influenced survival. Thus, even those at highest risk for GGO progression should not be denied resection of a DT.

  View details for PubMedID 28863952

• Clinical and Pathological Variables Influencing Noninvasive Detection of Early Stage Lung Cancer Using Circulating Tumor DNA Chabon, J., Chaudhuri, A., Azad, T., Kurtz, D., Stehr, H., Liu, C. L., Martin, J., Merriott, D., Carter, J., Ayers, K., Mansfield, A., Jen, J., Ren, H., West, R., Nair, V., Shrager, J., Neal, J., Wakelee, H., Loo, B., Alizadeh, A., Diehn, M. ELSEVIER SCIENCE INC. 2017: S1851

  View details for DOI 10.1016/j.jtho.2017.09.560

  View details for Web of Science ID 000463860800456

• Response to Ensartinib in TKI Naive ALK plus NSCLC Patients Wakelee, H., Sanborn, R., Nieva, J., Waqar, S., Brzezniak, C., Bauman, J., Neal, J., Dukart, G., Tan, F., Harrow, K., Liang, C., Horn, L. ELSEVIER SCIENCE INC. 2017: S1826

  View details for DOI 10.1016/j.jtho.2017.09.504

  View details for Web of Science ID 000463860800400

• A Phase 1b Study of Erlotinib and Momelotinib for TKI-Naive EGFR-Mutated Metastatic Non-Small Cell Lung Padda, S., Reckamp, K., Koczywas, M., Neal, J., Kawashima, J., Kong, S., Xin, Y., Huang, D., Wakelee, H. ELSEVIER SCIENCE INC. 2017: S2142–S2143

  View details for Web of Science ID 000463860801716

• Molecular and Clinicopathologic Features Associated with PD-L1 Expression in Lung Adenocarcinoma Yang, S., Steiner, D., Berry, G. J., Neal, J. W., Zehnder, J. L., Kunder, C. A. ELSEVIER SCIENCE INC. 2017: 1009–10

  View details for Web of Science ID 000414275900290

• Mid-radiotherapy PET/CT for prognostication and detection of early progression in patients with stage III non-small cell lung cancer RADIOTHERAPY AND ONCOLOGY Gensheimer, M. F., Hong, J. C., Chang-Halpenny, C., Zhu, H., Eclov, N. W., To, J., Murphy, J. D., Wakelee, H. A., Neal, J. W., Le, Q., Hara, W. Y., Quon, A., Maxim, P. G., Graves, E. E., Olson, M. R., Diehn, M., Loo, B. W. 2017; 125 (2): 338–43

  Abstract

  Pre- and mid-radiotherapy FDG-PET metrics have been proposed as biomarkers of recurrence and survival in patients treated for stage III non-small cell lung cancer. We evaluated these metrics in patients treated with definitive radiation therapy (RT). We also evaluated outcomes after progression on mid-radiotherapy PET/CT.Seventy-seven patients treated with RT with or without chemotherapy were included in this retrospective study. Primary tumor and involved nodes were delineated. PET metrics included metabolic tumor volume (MTV), total lesion glycolysis (TLG), and SUVmax. For mid-radiotherapy PET, both absolute value of these metrics and percentage decrease were analyzed. The influence of PET metrics on time to death, local recurrence, and regional/distant recurrence was assessed using Cox regression.91% of patients had concurrent chemotherapy. Median follow-up was 14months. None of the PET metrics were associated with overall survival. Several were positively associated with local recurrence: pre-radiotherapy MTV, and mid-radiotherapy MTV and TLG (p=0.03-0.05). Ratio of mid- to pre-treatment SUVmax was associated with regional/distant recurrence (p=0.02). 5/77 mid-radiotherapy scans showed early out-of-field progression. All of these patients died.Several PET metrics were associated with risk of recurrence. Progression on mid-radiotherapy PET/CT was a poor prognostic factor.

  View details for PubMedID 28830717

• Outcomes of Moderately Hypofractionated Intensity-Modulated Thoracic Radiotherapy with Concurrent Chemotherapy for Treatment of Non-Small Cell Lung Cancer Xiang, M., Gensheimer, M. F., Maxim, P. G., Wakelee, H. A., Neal, J. W., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2017: E504

  View details for DOI 10.1016/j.ijrobp.2017.06.1806

  View details for Web of Science ID 000411559104073

• Mid-radiation Therapy PET/CT for Prognostication and Detection of Early Progression in Patients With Stage III Non-small Cell Lung Cancer Gensheimer, M. F., Hong, J. C., Chang-Halpenny, C. N., Eclov, N., To, J., Murphy, J. D., Wakelee, H. A., Neal, J. W., Le, Q. T., Hara, W., Quon, A., Maxim, P. G., Graves, E. E., Olson, M. R., Diehn, M., Loo, B. W. ELSEVIER SCIENCE INC. 2017: E456

  View details for DOI 10.1016/j.ijrobp.2017.06.1695

  View details for Web of Science ID 000411559103253

• Circulating Tumor DNA Quantitation for Early Response Assessment of Immune Checkpoint Inhibitors for Lung Cancer Merriott, D. J., Chaudhuri, A. A., Jin, M., Chabon, J. J., Newman, A., Stehr, H., Say, C., Carter, J. N., Walters, S., Becker, H. R., Das, M., Padda, S., Loo, B. W., Wakelee, H. A., Neal, J. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2017: S20–S21

  View details for DOI 10.1016/j.ijrobp.2017.06.061

  View details for Web of Science ID 000411559106127

• Circulating Tumor DNA Analysis during Radiation Therapy for Localized Lung Cancer Predicts Treatment Outcome Chaudhuri, A. A., Lovejoy, A. F., Chabon, J. J., Newman, A., Stehr, H., Merriott, D. J., Carter, J. N., Azad, T. D., Padda, S., Gensheimer, M. F., Wakelee, H. A., Neal, J. W., Loo, B. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2017: S1–S2

  View details for DOI 10.1016/j.ijrobp.2017.06.021

  View details for Web of Science ID 000411559106087

• Comparison of Circulating Tumor DNA Analysis and Surveillance Imaging After Treatment for Localized Lung Cancer Chaudhuri, A. A., Chabon, J. J., Lovejoy, A. F., Newman, A., Stehr, H., Azad, T. D., Carter, J. N., Merriott, D. J., Liu, C. L., Kurtz, D. M., Gensheimer, M. F., Shrager, J. B., Wakelee, H. A., Neal, J. W., Loo, B. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2017: S114

  View details for DOI 10.1016/j.ijrobp.2017.06.269

  View details for Web of Science ID 000411559107060

• Commentary: Treatment Considerations for Patients With Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer Brain Metastases in the Era of Tyrosine Kinase Inhibitors. Neurosurgery Vaca, S. D., Connolly, I. D., Ho, C., Neal, J., Hayden Gephart, M. 2017

  Abstract

  Brain metastasis is a serious complication of non-small cell lung cancer (NSCLC) affecting up to 40% of NSCLC patients. A subset of NSCLC tumors has mutations in the epidermal growth factor receptor (EGFR) gene, and determination of tumor EGFR mutation status is essential in guiding treatment decisions, as it directly affects the treatment approach. Patients with EGFR-mutated NSCLC have a higher cumulative incidence of brain metastases, and are especially sensitive to EGFR tyrosine kinase inhibitors (TKIs). Patients with newly diagnosed EGFR-mutated lung cancer presenting to a neurosurgeon with a new diagnosis of brain metastases now have a variety of treatment options available, including whole brain radiation therapy, stereotactic radiosurgery, surgical resection, chemotherapy, and targeted therapeutics such as the EGFR TKIs. In this review, we discuss the impact of EGFR mutation status on brain and leptomeningeal metastasis treatment considerations. Additionally, we present clinical cases of patients treated with EGFR TKIs alone and in combination with other therapies to highlight treatment alternatives.

  View details for PubMedID 28945866

• The Persistent Promise of Combining HGF/MET and EGFR Inhibition in Non-Small Cell Lung Cancer CANCER Chuang, J. C., Neal, J. W. 2017; 123 (15): 2798–2801

  View details for PubMedID 28472534

• Circulating Tumor DNA Detects Residual Disease and Anticipates Tumor Progression Earlier Than CT Imaging Chaudhuri, A. A., Chabon, J. J., Lovejoy, A. F., Newman, A. M., Stehr, H., Azad, T. D., Zhou, L., Liu, C., Scherer, F., Kurtz, D. M., Esfahani, M. S., Say, C., Carter, J. N., Merriott, D., Dudley, J., Binkley, M. S., Modlin, L., Padda, S. K., Gensheimer, M., West, R. B., Shrager, J. B., Neal, J. W., Wakelee, H. A., Billy, W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2017: E4

  View details for DOI 10.1016/j.ijrobp.2017.02.048

  View details for Web of Science ID 000403079100013

• Novel systemic therapy against malignant pleural mesothelioma TRANSLATIONAL LUNG CANCER RESEARCH Mancuso, M. R., Neal, J. W. 2017; 6 (3): 295–314

  Abstract

  Malignant pleural mesothelioma is an aggressive tumor of the pleura with an overall poor prognosis. Even with surgical resection, for which only a subset of patients are eligible, long term disease free survival is rare. Standard first-line systemic treatment consists of a platinum analog, an anti-metabolite, and sometimes anti-angiogenic therapy, but there is currently no well-established standard therapy for refractory or relapsed disease. This review focuses on efforts to develop improved systemic therapy for the treatment of malignant pleural mesothelioma (MPM) including cytotoxic systemic therapy, a variety of tyrosine kinase inhibitors and their downstream effector pathways, pharmacologic targeting of the epigenome, novel approaches to target proteins expressed on mesothelioma cells (such as mesothelin), arginine depletion therapy, and the emerging role of immunotherapy. Overall, these studies demonstrate the challenges of improving systemic therapy for MPM and highlight the need to develop therapeutic strategies to control this disease.

  View details for PubMedID 28713675

  View details for PubMedCentralID PMC5504105

• 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

• Tumor Evolution, Heterogeneity, and Therapy for Our Patients With Advanced Cancer: How Far Have We Come? American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting El-Deiry, W. S., Taylor, B., Neal, J. W. 2017: e8–e15

  Abstract

  The clinical and molecular heterogeneity of various cancer types is well documented. In the era of precision oncology whereby molecular profiling of tumors is incorporated into clinical care, both intra- and intertumoral molecular and genetic heterogeneity have been described. Together, they impact patient treatment and outcomes. Host genetics and the tumor microenvironment impact on tumor evolution and heterogeneity through variations in immune cell infiltration, stromal variations, and selection pressures from hypoxia or nutrient stress, among others. Tumor progression and exposure to therapeutic agents lead to further molecular evolution and heterogeneity that is clinically relevant. Moreover, tumors that evolve after diagnosis and as a function of therapy generally become more aggressive and refractory to available therapeutics, including targeted agents and immunotherapy. The evolving clinical and molecular heterogeneity of patient tumors can be explored with various clinical and research-based specimens and testing such as pre- and post-treatment biopsies; serial liquid biopsies; single cell analysis; PDX and organoid models; anatomic, functional, and molecular imaging; and rapid postmortem studies. Other factors that influence tumor heterogeneity include immune checkpoints, cancer stem cells, therapy-acquired resistance mechanisms that may occur through secondary mutations, and adaptive responses. Modern technologic advances for tumor characterization provide opportunities to understand tumor evolution and its impact on clinical outcomes to improve therapeutic regimens. Characterization of novel targets and development of effective therapeutics are needed to target heterogeneity and the evolution of resistance mechanisms.

  View details for DOI 10.1200/EDBK_175524

  View details for PubMedID 30372200

• 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 PubMedID 28447912

• CNS activity of ensartinib in ALK1 non-small cell lung cancer (NSCLC) patients (pts) Reckamp, K. L., Wakelee, H. A., Patel, S., Blumenschein, G., Neal, J. W., Gitlitz, B., Waqar, S. N., Tan, F., Harrow, K., Horn, L. OXFORD UNIV PRESS. 2017

  View details for Web of Science ID 000405512800076

• 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

• Elusive Target of Angiogenesis in Small-Cell Lung Cancer. Journal of clinical oncology Neal, J. W., Wakelee, H. A. 2017: JCO2016716084-?

  View details for DOI 10.1200/JCO.2016.71.6084

  View details for PubMedID 28165898

• ERBB2-Mutated Metastatic Non-Small Cell Lung Cancer: Response and Resistance to Targeted Therapies. Journal of thoracic oncology Chuang, J. C., Stehr, H., Liang, Y., Das, M., Huang, J., Diehn, M., Wakelee, H. A., Neal, J. W. 2017

  Abstract

  Erb-b2 receptor tyrosine kinase 2 gene (ERBB2) (also called HER2) has long been recognized as an oncogenic driver in some breast and gastroesophageal cancers in which amplification of this gene confers sensitivity to treatment with Erb-b2 receptor tyrosine kinase 2 (ERBB2)-directed agents. More recently, somatic mutations in ERBB2 have been reported in 1% to 2% of patients with lung adenocarcinoma. Previous case series have suggested clinical tumor responses using anti-ERBB2 small molecules and antibody therapies.Here we report the outcomes of nine patients with metastatic lung adenocarcinoma with ERBB2 mutations being treated with ERBB2-targeted therapies.Four of the nine patients had response to targeted therapies, with durations of response ranging from 3 to 10 months. We identified a de novo phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation and ERBB2 copy number gain as potential resistance mechanisms.We showed patients with ERBB2-mutated lung adenocarcinoma can respond to targeted therapies, and we identified potential resistance mechanisms upon progression to targeted therapies.

  View details for DOI 10.1016/j.jtho.2017.01.023

  View details for PubMedID 28167203

• Response and Plasma Genotyping from Phase I/II Trial of Ensartinib (X-396) in Patients (Pts) with ALK plus NSCLC Horn, L., Wakelee, H., Reckamp, K., Blumenschein, G., Infante, J., Carter, C., Waqar, S., Neal, J., Gockerman, J., Harrow, K., Dukart, G., Liang, C., Gibbons, J., Hernandez, J., Newman-Eerkes, T., Lim, L., Lovly, C. ELSEVIER SCIENCE INC. 2017: S1159

  View details for Web of Science ID 000413055802442

• Chart Review Versus an Automated Bioinformatic Approach to Assess Real-World Crizotinib Effectiveness in Anaplastic Lymphoma Kinase–Positive Non–Small-Cell Lung Cancer JCO: Clinical Cancer Informatics Bui, N., Henry, S., Wood, D., Wakelee, H. A., Neal, J. W. 2017

  View details for DOI 10.1200/CCI.16.00055

• Relationship between anti-depressant use and lung cancer survival. Cancer treatment and research communications Zingone, A., Brown, D., Bowman, E. D., Vidal, O., Sage, J., Neal, J., Ryan, B. M. 2017; 10: 33–39

  Abstract

  OBJECTIVES: In recent years, the anti-cancer properties of several commonly used drugs have been explored, with drugs such as aspirin and beta-blockers associated with improved cancer outcomes. Previous preclinical work demonstrated that tricyclic anti-depressants have antitumor efficacy in lung cancer. Our goal was to examine the association between anti-depressant use and survival in lung cancer.MATERIALS AND METHODS: We examined the association between use of common anti-depressants and survival in 1,097 lung cancer patients from the NCI-Maryland lung cancer study. The types of anti-depressants included in the study were norepinephrine and dopamine reuptake inhibitors, serotonin reuptake inhibitors, selective serotonin reuptake inhibitors, non-selective serotonin reuptake inhibitors, and tricyclic anti-depressants. Anti-depressant use was extracted from the medical history section of a detailed interviewer-administered questionnaire. Specific use in the three months before a lung cancer diagnosis was determined. Cox portioned hazards modeling was used to estimate the association between anti-depressant use with lung cancer-specific death with adjustment for potential confounding co-factors.RESULTS: Anti-depressant use was associated with extended lung cancer-specific survival. In an analysis of specific classes of anti-depressant use, NDRIs and TCAs were associated with improved survival. Importantly, the extended survival associated with anti-depressants was maintained after adjustment for the clinical indications for these drugs, suggestive of a direct effect on lung cancer biology.CONCLUSIONS: Considering the manageable and largely tolerable side effects of anti-depressants, and the low cost of these drugs, these results indicate that evaluation of anti-depressants as adjunct therapeutics with chemotherapy may have a translational effect for lung cancer patients.

  View details for PubMedID 28944316

• Phase 1/2 Trial of the Oral EGFR/HER2 Inhibitor AP32788 in Non-Small Cell Lung Cancer (NSCLC) Doebele, R., Horn, L., Spira, A., Piotrowska, Z., Costa, D., Neal, J., Reichmann, W., Kerstein, D., Li, S., Janne, P. ELSEVIER SCIENCE INC. 2017: S1072–S1073

  View details for Web of Science ID 000413055802315

• A Phase lb Study of Erlotinib and Momelotinib for EGFR TKI Naive EGFR Mutated Metastatic Non-Small Cell Lung Cancer Padda, S., Reckamp, K., Koczywas, M., Neal, J., Brachmann, C., Kawashima, J., Kong, S., Xin, Y., Huang, D., Wakelee, H. ELSEVIER SCIENCE INC. 2017: S1070–S1071

  View details for Web of Science ID 000413055802312

• A Phase II Study of Etirinotecan Pegol (NKTR-102) in Patients with Refractory Brain Metastases and Advanced Lung Cancer Nagpal, S., Wakelee, H., Padda, S., Bertrand, S., Acevedo, B., Tisch, A., Pagtama, J., Soltys, S., Neal, J. ELSEVIER SCIENCE INC. 2017: S940

  View details for Web of Science ID 000413055802110

• Tumor Evolution, Heterogeneity, and Therapy for Our Patients With Advanced Cancer: How Far Have We Come? American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Meeting El-Deiry, W. S., Taylor, B., Neal, J. W. 2017; 37: e8–e15

  Abstract

  The clinical and molecular heterogeneity of various cancer types is well documented. In the era of precision oncology whereby molecular profiling of tumors is incorporated into clinical care, both intra- and intertumoral molecular and genetic heterogeneity have been described. Together, they impact patient treatment and outcomes. Host genetics and the tumor microenvironment impact on tumor evolution and heterogeneity through variations in immune cell infiltration, stromal variations, and selection pressures from hypoxia or nutrient stress, among others. Tumor progression and exposure to therapeutic agents lead to further molecular evolution and heterogeneity that is clinically relevant. Moreover, tumors that evolve after diagnosis and as a function of therapy generally become more aggressive and refractory to available therapeutics, including targeted agents and immunotherapy. The evolving clinical and molecular heterogeneity of patient tumors can be explored with various clinical and research-based specimens and testing such as pre- and post-treatment biopsies; serial liquid biopsies; single cell analysis; PDX and organoid models; anatomic, functional, and molecular imaging; and rapid postmortem studies. Other factors that influence tumor heterogeneity include immune checkpoints, cancer stem cells, therapy-acquired resistance mechanisms that may occur through secondary mutations, and adaptive responses. Modern technologic advances for tumor characterization provide opportunities to understand tumor evolution and its impact on clinical outcomes to improve therapeutic regimens. Characterization of novel targets and development of effective therapeutics are needed to target heterogeneity and the evolution of resistance mechanisms.

  View details for PubMedID 28746017

• Vorinostat and Concurrent Stereotactic Radiosurgery for Non-Small Cell Lung Cancer Brain Metastases: A Phase 1 Dose Escalation Trial. International journal of radiation oncology, biology, physics Choi, C. Y., Wakelee, H. A., Neal, J. W., Pinder-Schenck, M. C., Yu, H. M., Chang, S. D., Adler, J. R., Modlin, L. A., Harsh, G. R., Soltys, S. G. 2017; 99 (1): 16–21

  Abstract

  To determine the maximum tolerated dose (MTD) of vorinostat, a histone deacetylase inhibitor, given concurrently with stereotactic radiosurgery (SRS) to treat non-small cell lung cancer (NSCLC) brain metastases. Secondary objectives were to determine toxicity, local failure, distant intracranial failure, and overall survival rates.In this multicenter study, patients with 1 to 4 NSCLC brain metastases, each ≤2 cm, were enrolled in a phase 1, 3 + 3 dose escalation trial. Vorinostat dose levels were 200, 300, and 400 mg orally once daily for 14 days. Single-fraction SRS was delivered on day 3. A dose-limiting toxicity (DLT) was defined as any Common Terminology Criteria for Adverse Events version 3.0 grade 3 to 5 acute nonhematologic adverse event related to vorinostat or SRS occurring within 30 days.From 2009 to 2014, 17 patients were enrolled and 12 patients completed study treatment. Because no DLTs were observed, the MTD was established as 400 mg. Acute adverse events were reported by 10 patients (59%). Five patients discontinued vorinostat early and withdrew from the study. The most common reasons for withdrawal were dyspnea (n=2), nausea (n=1), and fatigue (n=2). With a median follow-up of 12 months (range, 1-64 months), Kaplan-Meier overall survival was 13 months. There were no local failures. One patient (8%) at the 400-mg dose level with a 2.0-cm metastasis developed histologically confirmed grade 4 radiation necrosis 2 months after SRS.The MTD of vorinostat with concurrent SRS was established as 400 mg. Although no DLTs were observed, 5 patients withdrew before completing the treatment course, a result that emphasizes the need for supportive care during vorinostat administration. There were no local failures. A larger, randomized trial may evaluate both the tolerability and potential local control benefit of vorinostat concurrent with SRS for brain metastases.

  View details for PubMedID 28816142

• Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling. Cancer discovery Chaudhuri, A. A., Chabon, J. J., Lovejoy, A. F., Newman, A. M., Stehr, H. n., Azad, T. D., Khodadoust, M. S., Esfahani, M. S., Liu, C. L., Zhou, L. n., Scherer, F. n., Kurtz, D. M., Say, C. n., Carter, J. N., Merriott, D. J., Dudley, J. C., Binkley, M. S., Modlin, L. n., Padda, S. K., Gensheimer, M. F., West, R. B., Shrager, J. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Alizadeh, A. A., Diehn, M. n. 2017

  Abstract

  Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here we apply Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I-III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first post-treatment blood sample, indicating reliable identification of MRD. Post-treatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in lung cancer patients can be accurately detected using CAPP-Seq and may allow personalized adjuvant treatment while disease burden is lowest.

  View details for PubMedID 28899864

• Circulating Tumor DNA Detects Minimal Residual Disease and Predicts Outcome in Localized Lung Cancer Chaudhuri, A., Lovejoy, A., Chabon, J., Newman, A., Stehr, H., Say, C., Carter, J., Zhou, L., West, R., Shrager, J., Neal, J., Wakelee, H., Loo, B., Alizadeh, A., Diehn, M. ELSEVIER SCIENCE INC. 2017: S445

  View details for Web of Science ID 000413055801024

• A Highly Sensitive Next-Generation Sequencing Platform for Detection of NSCLC EGFR T790M Mutation in Urine and Plasma Wakelee, H., Melnikova, V., Karlovich, C., Gadgeel, S., Reckamp, K., Goldman, J. W., Camidge, D., Perol, M., Ou, S., Liu, S., Yu, H., Socinski, M., Mekhai, T., Solomon, B., Natale, R., Otterson, G., Papadimitrakopoulou, V., Soria, J., Langer, C., Neal, J., Despain, D., Yurasov, S., Litten, J., Raponi, M., Erlander, M., Sequist, L. ELSEVIER SCIENCE INC. 2017: S384–S385

  View details for Web of Science ID 000413055800415

• 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 PubMedID 27956614

• 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

• Corrigendum: 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., Thomas Purcell, W., Ross Camidge, D., Goldman, J. W., Sequist, L. V., Piotrowska, Z., Wakelee, H. A., Neal, J. W., Alizadeh, A. A., Diehn, M. 2016; 7: 13513-?

  View details for DOI 10.1038/ncomms13513

  View details for PubMedID 27841271

  View details for PubMedCentralID PMC5114547

• PS01.67: Case Series of MET Exon 14 Skipping Mutation-Positive Non-Small Cell Lung Cancers and Response to Crizotinib: Topic: Medical Oncology. Journal of thoracic oncology Wang, S. X., Zhang, B. M., Wakelee, H., Diehn, M., Kunder, C. A., Neal, J. W. 2016; 11 (11S): S312-S313

  View details for DOI 10.1016/j.jtho.2016.09.102

  View details for PubMedID 27969534

• PS01.22: Novel 3-Dimensional Preclinical Models: Topic: Medical Oncology. Journal of thoracic oncology Salahudeen, A., De La O, S., Padda, S. K., Neal, J. W., Wakelee, H., Kuo, C. 2016; 11 (11S): S282-?

  View details for DOI 10.1016/j.jtho.2016.09.057

  View details for PubMedID 27969489

• PS01.04: A Phase II Study of Etirinotecan Pegol (NKTR-102) in Patients with Refractory Brain Metastases and Advanced Lung Cancer: Topic: Medical Oncology. Journal of thoracic oncology Neal, J. W., Wakelee, H., Padda, S. K., Bertrand, S., Acevedo, B., Holmes Tisch, A., Pagtama, J. Y., Soltys, S. G., Nagpal, S. 2016; 11 (11S): S271-S272

  View details for DOI 10.1016/j.jtho.2016.09.040

  View details for PubMedID 27969472

• MINI01.02: Response and Plasma Genotyping from Phase I/II Trial of Ensartinib (X-396) in Patients (pts) with ALK+ NSCLC: Topic: Medical Oncology. Journal of thoracic oncology Horn, L., Wakelee, H., Reckamp, K. L., Blumenschein, G., Infante, J. R., Carter, C. A., Waqar, S. N., Neal, J. W., Harrow, K., Gockerman, J. P., Dukart, G., Liang, C., Gibbons, J. L., Hernandez, J., Newman-Eerkes, T., Lim, L., Lovly, C. M. 2016; 11 (11S): S256-S257

  View details for DOI 10.1016/j.jtho.2016.09.017

  View details for PubMedID 27969449

• CAPP-Seq Circulating Tumor DNA Analysis for Early Detection of Tumor Progression After Definitive Radiation Therapy for Lung Cancer Chaudhuri, A. A., Lovejoy, A. F., Chabon, J. J., Newman, A., Stehr, H., Say, C., Aggarwal, S., Carter, J. N., West, R. B., Neal, J. W., Wakelee, H. A., Loo, B. W., Alizadeh, A., Diehn, M. ELSEVIER SCIENCE INC. 2016: S41–S42

  View details for DOI 10.1016/j.ijrobp.2016.06.112

  View details for Web of Science ID 000387655804429

• Phase I/II trial of X-396 in patients (pts) with ALK plus non-small cell lung cancer (NSCLC): Correlation with plasma and tissue genotyping and response to therapy (tx) Horn, L., Wakelee, H., Blumenschein, G., Reckamp, K., Waqar, S., Carter, C. A., Gitlitz, B. J., Infante, J. R., Sanborn, R. E., Neal, J., Gockerman, J. P., Dukart, G., Harrow, K., Liang, C., Gibbons, J. J., Hernandez, J., Newman-Eerkes, T., Lim, L., Lovly, C. OXFORD UNIV PRESS. 2016

  View details for Web of Science ID 000393913000302

• Rociletinib-associated cataracts in EGFR-mutant NSCLC Piotrowska, Z., Liu, E., Varga, A., Thakur, M., Narayanan, V., Liu, S. V., Neal, J., Spiegel, M., Solomon, B., Yu, H., Ou, S. I., Papadimitrakopoulou, V. A., Gadgeel, S., Camidge, D. R., Soria, J., Wakelee, H., Goldman, J., Kopani, K., Rolfe, L., Sequist, L. V. OXFORD UNIV PRESS. 2016

  View details for DOI 10.1093/annonc/mdw383.39

  View details for Web of Science ID 000393913000331

• 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

• 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

• 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 PubMedID 27283993

• Inter- and intra-patient heterogeneity of resistance mechanisms to the mutant EGFR selective inhibitor rociletinib. Chabon, J., Simmons, A., Newman, A. M., Lovejoy, A. F., Esfahani, M. S., Haringsma, H., Kurtz, D., Stehr, H., Scherer, F., Durkin, K. A., Otterson, G., Purcell, W. T., Camidge, D., Goldman, J., Sequist, L. V., Piotrowska, Z., Wakelee, H. A., Neal, J. W., Alizadeh, A. A., Diehn, M. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.9000

  View details for Web of Science ID 000404711506148

• Integrated digital error suppression for noninvasive detection of circulating tumor DNA in NSCLC. Newman, A. M., Lovejoy, A. F., Klass, D. M., Kurtz, D., Chabon, J. J., Scherer, F., Stehr, H., Liu, C., Bratman, S., 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., Alizadeh, A. A., Diehn, M. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.e20500

  View details for Web of Science ID 000404711506257

• Plasma genotyping of patients enrolled on the expansion phase VII trial of X-396 in patients (pts) with ALK plus non-small cell lung cancer (NSCLC). Horn, L., Wakelee, H. A., Reckamp, K. L., Blumenschein, G. R., Infante, J. R., Carter, C., Waciar, S., Neal, J. W., Gockerman, J. P., Harrow, K., Dukart, G., Liang, C., Gibbons, J. J., Hernandez, J., Newman-Eerkes, T., Lim, L., Lovly, C. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.9056

  View details for Web of Science ID 000404711506202

• Epidermal growth factor receptor (EGFR) genotyping of matched urine, plasma and tumor tissue from non-small cell lung cancer (NSCLC) patients (pts) treated with rociletinib. Wakelee, H. A., Gadgeel, S. M., Goldman, J., Reckamp, K. L., Karlovich, C., Melnikova, V., Soria, J., Yu, H., Solomon, B. J., Perol, M., Neal, J. W., Liu, S. V., Raponi, M., Despain, D., Erlander, M. G., Matheny, S. L., Yurasov, S., Camidge, D., Sequist, L. V. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.9001

  View details for Web of Science ID 000404711506149

• 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 PubMedID 27018799

• 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 PubMedID 26536199

• Vorinostat and Concurrent Stereotactic Radiosurgery for Non-Small Cell Lung Cancer Brain Metastases: A Phase 1 Dose-Escalation Trial Modlin, L. A., Choi, C. H., Gibbs, I. C., Wakelee, H. A., Neal, J., Pinder-Schenck, M. C., Chang, S. D., Adler, J. R., Harsh, G. R., Soltys, S. G. ELSEVIER SCIENCE INC. 2015: S178

  View details for DOI 10.1016/j.ijrobp.2015.07.425

  View details for Web of Science ID 000373215302104

• 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

• 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): 50-?

  Abstract

  In recent years, oncogene-directed targeted agents and immunotherapies have expanded the treatment armamentarium for advanced lung cancer and, in particular, non-small cell lung cancer (NSCLC). Along with extended survival, these agents are accompanied by a host of cutaneous complications that affect the skin, hair, and nails. These skin complications range from the well-characterized papulopustular (acneiform) eruption of the epidermal growth factor receptor (EGFR) inhibitors to the emerging characterization of lichenoid skin eruptions seen during treatment with antibodies targeting the programmed cell death protein 1 (PD-1) and programmed cell death protein 1 ligand (PD-L1). When promptly recognized and accurately diagnosed, most cutaneous adverse events can be managed with supportive treatments, avoiding the need to interrupt antitumor therapy. Furthermore, preemptive management of skin problems can lead to significantly decreased severity of many cutaneous complications of these therapies. We encourage close collaboration between dermatologists and oncologists to better characterize cutaneous toxicity, select appropriate management, and avoid unnecessary dose reduction or discontinuation while simultaneously improving patient quality of life.

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

  View details for PubMedID 26338208

• 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

  Abstract

  To report rapid onset of retinal toxicity in a series of patients followed on high-dose (1000 mg daily) hydroxychloroquine during an oncologic clinical trial studying hydroxychloroquine with erlotinib for non-small cell lung cancer.Retrospective observational case series.Ophthalmic surveillance was performed on patients in a multicenter clinical trial testing high-dose (1000 mg daily) hydroxychloroquine for advanced non-small cell lung cancer. The US Food & Drug Administration-recommended screening protocol included only visual acuity testing, dilated fundus examination, Amsler grid testing, and color vision testing. In patients seen at Stanford, additional sensitive screening procedures were added at the discretion of the retinal physician: high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence (FAF) imaging, Humphrey visual field (HVF) testing, and multifocal electroretinography (mfERG).Out of the 7 patients having exposure of at least 6 months, 2 developed retinal toxicity (at 11 and 17 months of exposure). Damage was identified by OCT imaging, mfERG testing, and, in 1 case, visual field testing. Fundus autofluorescence imaging remained normal. Neither patient had symptomatic visual acuity loss.These cases show that high doses of hydroxychloroquine can initiate the development of retinal toxicity within 1-2 years. Although synergy with erlotinib is theoretically possible, there are no prior reports of erlotinib-associated retinal toxicity despite over a decade of use in oncology. These results also suggest that sensitive retinal screening tests should be added to ongoing and future clinical trials involving high-dose hydroxychloroquine to improve safety monitoring and preservation of vision.

  View details for DOI 10.1016/j.ajo.2015.07.012

  View details for PubMedID 26189086

• 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

• 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

• 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-?

  Abstract

  In recent years, oncogene-directed targeted agents and immunotherapies have expanded the treatment armamentarium for advanced lung cancer and, in particular, non-small cell lung cancer (NSCLC). Along with extended survival, these agents are accompanied by a host of cutaneous complications that affect the skin, hair, and nails. These skin complications range from the well-characterized papulopustular (acneiform) eruption of the epidermal growth factor receptor (EGFR) inhibitors to the emerging characterization of lichenoid skin eruptions seen during treatment with antibodies targeting the programmed cell death protein 1 (PD-1) and programmed cell death protein 1 ligand (PD-L1). When promptly recognized and accurately diagnosed, most cutaneous adverse events can be managed with supportive treatments, avoiding the need to interrupt antitumor therapy. Furthermore, preemptive management of skin problems can lead to significantly decreased severity of many cutaneous complications of these therapies. We encourage close collaboration between dermatologists and oncologists to better characterize cutaneous toxicity, select appropriate management, and avoid unnecessary dose reduction or discontinuation while simultaneously improving patient quality of life.

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

  View details for PubMedID 26338208

• Computed Tomography (CT) Characteristics Associated with the Proposed IASLC/ITMIG TNM Pathologic Staging System for Thymoma Padda, S. K., Terrone, D., Khuong, A., Tian, L., Neal, J. W., Riess, J. W., Berry, M., Leung, A. N., Schwartz, E. J., Shrager, J. B., Wakelee, H. A. ELSEVIER SCIENCE INC. 2015: S196

  View details for Web of Science ID 000370365100273

• 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): 366-73

  Abstract

  Pemetrexed is approved in the treatment of advanced stage nonsquamous non-small-cell lung cancer (NSCLC). The length of response is variable, and we thus sought to identify which clinicopathologic characteristics are associated with long-term disease control with pemetrexed.Patients with metastatic NSCLC received pemetrexed (with or without bevacizumab) for 12 months or longer, either as maintenance treatment after first-line platinum-based chemotherapy or as subsequent treatment. Clinical and pathologic characteristics were collected.Of a total of 196 patients who received pemetrexed starting in 2007, 25 patients were identified who received pemetrexed for over 1 year. Of these, 15 patients received pemetrexed with or without bevacizumab as maintenance treatment and 10 patients received pemetrexed as subsequent treatment. Fifteen (60%) of 25 patients had an oncogenic driver mutation as follows: 5 (20%) had ROS1 gene rearrangements, 4 (16%) had ALK gene rearrangements, 3 (12%) had KRAS mutations, 2 (8%) had epidermal growth factor receptor (EGFR) mutations, and 1 (4%) had an NRAS mutation. The median overall survival was 42.2 months (95% confidence interval, 37.4-61.3) and median progression-free survival was 22.1 months (95% confidence interval, 15.1-29.1). Patients with an oncogenic driver mutation had significantly better progression-free survival (P = .006) and overall survival (P = .001).Among patients with NSCLC who received pemetrexed for an extended time, those with ALK and ROS1 gene rearrangements were proportionally overrepresented compared with that anticipated in a general nonsquamous NSCLC population, and patients with oncogenic driver mutations had improved outcomes.

  View details for DOI 10.1016/j.cllc.2014.12.009

  View details for PubMedID 25665893

  View details for PubMedCentralID PMC4490141

• Dovitinib and erlotinib in patients with metastatic non-small cell lung cancer: A drug-drug interaction. Lung cancer (Amsterdam, Netherlands) Das, M., Padda, S. K., Frymoyer, A., Zhou, L., Riess, J. W., Neal, J. W., Wakelee, H. A. 2015; 89 (3): 280-6

  Abstract

  Erlotinib is a FDA approved small molecule inhibitor of epidermal growth factor receptor and dovitinib is a novel small molecule inhibitor of fibroblast growth factor and vascular endothelial growth factor receptor. This phase 1 trial was conducted to characterize the safety and determine the maximum tolerated dose of erlotinib plus dovitinib in patients with previously treated metastatic non-small cell lung cancer.Escalating dose cohorts of daily erlotinib and dovitinib dosed 5 days on/2 days off, starting after a 2-week lead-in of erlotinib alone, were planned. A potential pharmacokinetic interaction was hypothesized as dovitinib induces CYP1A1/1A2. Only cohort 1 (150mg erlotinib+300mg dovitinib) and cohort -1 (150mg erlotinib+200mg dovitinib) enrolled. Plasma concentrations of erlotinib were measured pre- and post-dovitinib exposure.Two of three patients in cohort 1 had a DLT (grade 3 transaminitis and grade 3 syncope). Two of 6 patients in cohort -1 had a DLT (grade 3 pulmonary embolism and grade 3 fatigue); thus, the study was terminated. Erlotinib exposure (average Cmax 2308±698ng/ml and AUC 0-24 41,030±15,577 ng×h/ml) approximated previous reports in the six patients with pharmacokinetic analysis. However, erlotinib Cmax and AUC0-24 decreased significantly by 93% (p=0.02) and 97% (p<0.01), respectively, during dovitinib co-administration.This small study demonstrated considerable toxicity and a significant pharmacokinetic interaction with a marked decrease in erlotinib exposure in the presence of dovitinib, likely mediated through CYP1A1/1A2 induction. Given the toxicity and the pharmacokinetic interaction, further investigation with this drug combination will not be pursued.

  View details for DOI 10.1016/j.lungcan.2015.06.011

  View details for PubMedID 26149476

• A Randomized Phase 2 Trial of Cabozantinib, Erlotinib or the Combination as 2nd or 3rd Line Therapy in EGFR Wild-Type NSCLC: ECOG-ACRIN E1512 Neal, J. W., Dahlberg, S. E., Wakelee, H. A., Aisner, S. C., Bowden, M., Carbone, D. P., Ramalingam, S. S. ELSEVIER SCIENCE INC. 2015: S373

  View details for Web of Science ID 000370365101334

• Phase II Trial of Single Agent Amrubicin in Patients with Previously Treated Advanced Thymic Malignancies Wakelee, H. A., Padda, S. K., Burns, M., Spittler, A. J., Riess, J. W., San Pedro-Salcedo, M., Ramchandran, K. J., Gubens, M. A., Neal, J. W., Loehrer, P. J. ELSEVIER SCIENCE INC. 2015: S195

  View details for Web of Science ID 000370365100271

• VeriStrat (R) and Epidermal Growth Factor Receptor Mutation Status in a Phase 1b/2 Study of Cabozantinib plus /- Erlotinib in Non-Small Cell Lung Cancer Padda, S. K., Lara, P., Gettinger, S. N., Engelman, J. A., Jaenne, P. A., West, H., Zhou, L. Y., Subramaniam, D. S., Leach, J. W., Wax, M. B., Neal, J. W., Clary, D. O., Goodman, L. J., Wakelee, H. A. ELSEVIER SCIENCE INC. 2015: S291

  View details for Web of Science ID 000370365101080

• 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

  Abstract

  Pemetrexed is approved in the treatment of advanced stage nonsquamous non-small-cell lung cancer (NSCLC). The length of response is variable, and we thus sought to identify which clinicopathologic characteristics are associated with long-term disease control with pemetrexed.Patients with metastatic NSCLC received pemetrexed (with or without bevacizumab) for 12 months or longer, either as maintenance treatment after first-line platinum-based chemotherapy or as subsequent treatment. Clinical and pathologic characteristics were collected.Of a total of 196 patients who received pemetrexed starting in 2007, 25 patients were identified who received pemetrexed for over 1 year. Of these, 15 patients received pemetrexed with or without bevacizumab as maintenance treatment and 10 patients received pemetrexed as subsequent treatment. Fifteen (60%) of 25 patients had an oncogenic driver mutation as follows: 5 (20%) had ROS1 gene rearrangements, 4 (16%) had ALK gene rearrangements, 3 (12%) had KRAS mutations, 2 (8%) had epidermal growth factor receptor (EGFR) mutations, and 1 (4%) had an NRAS mutation. The median overall survival was 42.2 months (95% confidence interval, 37.4-61.3) and median progression-free survival was 22.1 months (95% confidence interval, 15.1-29.1). Patients with an oncogenic driver mutation had significantly better progression-free survival (P = .006) and overall survival (P = .001).Among patients with NSCLC who received pemetrexed for an extended time, those with ALK and ROS1 gene rearrangements were proportionally overrepresented compared with that anticipated in a general nonsquamous NSCLC population, and patients with oncogenic driver mutations had improved outcomes.

  View details for DOI 10.1016/j.cllc.2014.12.009

  View details for Web of Science ID 000360182100017

  View details for PubMedCentralID PMC4490141

• 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

• Case Series of HER2 Mutated Metastatic Lung Adenocarcinoma and Response to HER2 Targeted Therapies Chuang, J., Neal, J. W., Wakelee, H. A. ELSEVIER SCIENCE INC. 2015: S549

  View details for Web of Science ID 000370365102479

• Improved survival among lung cancer patients taking antidepressants Zingone, A., Brown, D., Bowman, E., Vidal, O., Neal, J., Sage, J., Ryan, B. M. AMER ASSOC CANCER RESEARCH. 2015

  View details for DOI 10.1158/1538-7445.AM2015-LB-182

  View details for Web of Science ID 000371597100282

• 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

• Cabozantinib (C), erlotinib (E) or the combination (E plus C) as second-or third-line therapy in patients with EGFR wild-type (wt) non-small cell lung cancer (NSCLC): A randomized phase 2 trial of the ECOG-ACRIN Cancer Research Group (E1512). Neal, J. W., Dahlberg, S., Wakelee, H. A., Aisner, S. C., Bowden, M., Carbone, D., Ramalingam, S. S. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for Web of Science ID 000358036901716

• Phase II trial of single agent amrubicin (A) in patients (pts) with previously treated advanced thymic malignancies (TM). Wakelee, H. A., Padda, S., Burns, M., Spittler, A., Riess, J., San Pedro-Salcedo, M., Ramchandran, K., Gubens, M. A., Neal, J. W., Loehrer, P. J. AMER SOC CLINICAL ONCOLOGY. 2015

  View details for Web of Science ID 000358036901710

• Rociletinib in EGFR-Mutated Non-Small-Cell Lung Cancer NEW ENGLAND JOURNAL OF MEDICINE Sequist, L. V., Soria, J., Goldman, J. W., Wakelee, H. A., Gadgeel, S. M., Varga, A., Papadimitrakopoulou, V., SOLOMON, B. J., Oxnard, G. R., Dziadziuszko, R., Aisner, D. L., Doebele, R. C., Galasso, C., Garon, E. B., Heist, R. S., Logan, J., Neal, J. W., Mendenhall, M. A., Nichols, S., Piotrowska, Z., Wozniak, A. J., Raponi, M., Karlovich, C. A., Jaw-Tsai, S., Isaacson, J., Despain, D., Matheny, S. L., Rolfe, L., Allen, A. R., Camidge, D. R. 2015; 372 (18): 1700-1709

  Abstract

  Non-small-cell lung cancer (NSCLC) with a mutation in the gene encoding epidermal growth factor receptor (EGFR) is sensitive to approved EGFR inhibitors, but resistance develops, mediated by the T790M EGFR mutation in most cases. Rociletinib (CO-1686) is an EGFR inhibitor active in preclinical models of EGFR-mutated NSCLC with or without T790M.In this phase 1-2 study, we administered rociletinib to patients with EGFR-mutated NSCLC who had disease progression during previous treatment with an existing EGFR inhibitor. In the expansion (phase 2) part of the study, patients with T790M-positive disease received rociletinib at a dose of 500 mg twice daily, 625 mg twice daily, or 750 mg twice daily. Key objectives were assessment of safety, side-effect profile, pharmacokinetics, and preliminary antitumor activity of rociletinib. Tumor biopsies to identify T790M were performed during screening. Treatment was administered in continuous 21-day cycles.A total of 130 patients were enrolled. The first 57 patients to be enrolled received the free-base form of rociletinib (150 mg once daily to 900 mg twice daily). The remaining patients received the hydrogen bromide salt (HBr) form (500 mg twice daily to 1000 mg twice daily). A maximum tolerated dose (the highest dose associated with a rate of dose-limiting toxic effects of less than 33%) was not identified. The only common dose-limiting adverse event was hyperglycemia. In an efficacy analysis that included patients who received free-base rociletinib at a dose of 900 mg twice daily or the HBr form at any dose, the objective response rate among the 46 patients with T790M-positive disease who could be evaluated was 59% (95% confidence interval [CI], 45 to 73), and the rate among the 17 patients with T790M-negative disease who could be evaluated was 29% (95% CI, 8 to 51).Rociletinib was active in patients with EGFR-mutated NSCLC associated with the T790M resistance mutation. (Funded by Clovis Oncology; ClinicalTrials.gov number, NCT01526928.).

  View details for DOI 10.1056/NEJMoa1413654

  View details for PubMedID 25923550

• 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

• 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

• 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

  Abstract

  Thymic epithelial tumors (TET) are rare. Wingless and INT (WNT), NOTCH and sonic hedgehog pathway interactions between thymocytes and thymic stroma are important to thymus and T-cell development. We analyzed a thymoma tissue microarray (TMA) for glioma associated oncogene homolog 1 (GLI1), NOTCH1 and catenin (cadherin-associated protein, beta 1) (CTNNB1) expression as surrogate markers of sonic hedgehog, NOTCH and WNT pathway activity.GLI1, NOTCH1 and CTNNB1 expression were assayed in a tissue microarray of 68 TET and eight benign thymus by fluorescent immunohistochemistry (AQUA) as surrogates for activity of the sonic hedgehog, NOTCH and WNT pathways respectively.No difference in tumor GLI1 (mean 201 vs. 211, p=0.31), CTNNB1 (mean 222 vs. 306, p=0.66) or NOTCH1 expression (mean 317 vs. 325, p=0.82) was noted between thymic tumor and benign thymus.No evidence for preferential expression of GLI1, NOTCH1 or CTNNB1 was noted. High-throughput immunofluorescence using AQUA technology can help overcome limitations of small sample size and tissue heterogeneity when analyzing protein expression in thymic tumors.

  View details for PubMedID 25667444

• Pemetrexed in patients with thymic malignancies previously treated with chemotherapy. Lung cancer 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

• Unicentric, multifocal castleman disease of the mediastinum associated with cerebellitis. Annals of thoracic surgery Hamaji, M., Neal, J. W., Burt, B. M. 2015; 99 (1): e7-9

  Abstract

  A 30-year-old man presented with rapidly progressive cerebellar symptoms. Brain magnetic resonance imaging was consistent with cerebellitis. A subsequent chest computed tomography revealed a multilobulated anterior mediastinal mass, which was diagnosed on the surgical biopsy specimen as hyaline vascular Castleman disease. After resection of the mediastinal mass and multiple involved adjacent mediastinal lymph nodes, the cerebellitis resolved. To the best of our knowledge, this is the first report of Castleman disease associated with cerebellitis. This rare case of suspected paraneoplastic cerebellitis related to a multifocal unicentric Castleman disease confined to the mediastinum is discussed.

  View details for DOI 10.1016/j.athoracsur.2014.10.028

  View details for PubMedID 25555986

• Ultrasensitive Detection of Circulating Tumor DNA in Non-Small Cell Lung Cancer by Deep Sequencing Diehn, M., Bratman, S. V., Newman, A. M., Neal, J. W., Wakelee, H. A., Merritt, R. E., Shrager, J. B., Loo, B. W., Alizadeh, A. ELSEVIER SCIENCE INC. 2014: S75

  View details for DOI 10.1016/j.ijrobp.2014.08.315

  View details for Web of Science ID 000346413500167

• Randomized Phase 2 Study of Tivantinib (ARQ 197) Plus Erlotinib Versus Single-Agent Chemotherapy in Previously Treated KRAS Mutant Advanced Non-Small Cell Lung Cancer (NSCLC) Gerber, D. E., Socinski, M. A., Neal, J. W., Wakelee, H. A., Shirai, K., Sequist, L. V., Rosovsky, R., Lilenbaum, R., Bastos, B. R., Huang, C., Johnson, M. L., Hasketh, P. J., Subramaniam, D. S., Chai, F., Kazakin, J., Schwartz, B. E., Schiller, J. H., Brahmer, J. R. ELSEVIER SCIENCE INC. 2014: S36

  View details for Web of Science ID 000346413500076

• 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

• 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): 576–87

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

  View details for Web of Science ID 000439080800003

• A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer and other neuroendocrine tumors Jahchan, N. S., Dudley, J. T., Mazur, P. K., Flores, N., Yang, D., Palmerton, A., Zmoos, A., Vaka, D., Tran, K. T., Zhou, M., Krasinska, K., Riess, J. W., Neal, J. W., Khatri, P., Park, K. S., Butte, A. J., Sage, J. AMER ASSOC CANCER RESEARCH. 2014

  View details for DOI 10.1158/1538-7445.AM2014-4610

  View details for Web of Science ID 000349910203084

• PRURITUS AS A PARANEOPLASTIC SYMPTOM OF THYMOMA Padda, S., Pagtama, J. Y., Tisch, A. H., Neal, J. W., Riess, J. W., Loo, B. W., Hardy, R., Shrager, J. B., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2014: S240–S241

  View details for Web of Science ID 000344627500044

• COMPUTED TOMOGRAPHY (CT) CHARACTERISTICS ASSOCIATED WITH MASAOKA-KOGA PATHOLOGIC STAGE IN THYMOMA Padda, S., Terrone, D., Khuong, A., Tian, L., Neal, J. W., Riess, J. W., Hoang, C. D., Burt, B. M., Leung, A. N., Shrager, J. B., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2014: S222

  View details for Web of Science ID 000344627500014

• PROGRAMMED DEATH RECEPTOR LIGAND-1 (PD-L1) EXPRESSION IN A THYMOMA TISSUE MICROARRAY (TMA) Padda, S., Riess, J. W., Schwartz, E., Tian, L., Kohrt, H., Neal, J. W., West, R., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2014: S212

  View details for Web of Science ID 000344627500002

• PEMETREXED IN PATIENTS WITH THYMIC MALIGNANCIES PREVIOUSLY TREATED WITH CHEMOTHERAPY Liang, Y., Padda, S., Riess, J. W., West, R., Neal, J. W., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2014: S226

  View details for Web of Science ID 000344627500020

• Circulating Tumor DNA Concentrations Reflect Metabolic Tumor Volume in NSCLC Modlin, L. A., Bratman, S. V., Newman, A. M., Eclov, N. W., Neal, J. W., Wakelee, H. A., Shrager, J. B., Loo, B. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2014: S812

  View details for DOI 10.1016/j.ijrobp.2014.05.2342

  View details for Web of Science ID 000342331403138

• Programmed death receptor ligand-1 (PD-L1) expression in a thymoma (T) tissue microarray (TMA) Padda, S., Riess, J., Schwartz, E., Tian, L., Kohrt, H., Neal, J. W., Natkunam, Y., West, R. B., Wakelee, H. A. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for Web of Science ID 000358613204064

• A multicenter randomized phase II trial of erlotinib with and without hydroxychloroquine (HCQ) in TKI-naive patients (pts) with epidermal growth factor receptor (EGFR) mutant advanced non-small cell lung cancer (NSCLC) Neal, J. W., Wakelee, H. A., Feliciano, J., Goldberg, S. B., Morgensztern, D., Das, M., Heist, R., Lennes, I., Muzikansky, A., Edelman, M. J., Gettinger, S. N., Sequist, L. V. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for Web of Science ID 000358613204150

• SELECT: A multicenter phase II trial of adjuvant erlotinib in resected early-stage EGFR mutation-positive NSCLC. Pennell, N. A., Neal, J. W., Chaft, J. E., Azzoli, C. G., Janne, P. A., Govindan, R., Evans, T. L., Costa, D., Rosovsky, R., Wakelee, H. A., Heist, R., Shaw, A., Temel, J. S., Shapiro, M. A., Muzikansky, A., Lanuti, M., Lynch, T., Kris, M. G., Sequist, L. V. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for Web of Science ID 000358613203950

• Noninvasive and ultrasensitive quantitation of circulating tumor DNA by hybrid capture and deep sequencing. Bratman, S., Newman, A. M., To, J., Wynne, J. F., Neal, J. W., Wakelee, H. A., Shrager, J. B., Loo, B. W., Diehn, M., Alizadeh, A. A. AMER SOC CLINICAL ONCOLOGY. 2014

  View details for Web of Science ID 000358613204749

• 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

  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 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

• A phase II multicentre study of ziv-aflibercept in combination with cisplatin and pemetrexed in patients with previously untreated advanced/metastatic non-squamous non-small cell lung cancer. British journal of cancer Chen, H., Modiano, M. R., Neal, J. W., Brahmer, J. R., Rigas, J. R., Jotte, R. M., Leighl, N. B., Riess, J. W., Kuo, C. J., Liu, L., Gao, B., DiCioccio, A. T., Adjei, A. A., Wakelee, H. A. 2014; 110 (3): 602-608

  Abstract

  Background:This study evaluated the efficacy and safety of ziv-aflibercept in combination with cisplatin and pemetrexed in non-small cell lung cancer (NSCLC).Methods:This single arm, multicentre phase II trial enrolled patients with previously untreated, locally advanced or metastatic non-squamous NSCLC. Patients received intravenous ziv-aflibercept 6 mg kg(-1), pemetrexed 500 mg m(-2), and cisplatin 75 mg m(-2), every 21 days for up to six cycles. Maintenance administration of ziv-aflibercept was to continue until disease progression, intolerable toxicity or other cause for withdrawal. The co-primary end points were objective response rate (ORR) and progression-free survival (PFS). Planned sample size was 72 patients.Results:The study was closed prematurely because of three confirmed and two suspected cases of reversible posterior leukoencephalopathy syndrome (RPLS). A total of 42 patients were enrolled. Median age was 61.5 years; 55% were male, 86% Caucasian and 50% had Eastern Cooperative Oncology Group performance status (ECOG PS)=0. A median of four cycles of ziv-aflibercept was administered. The most common treatment-emergent adverse events (TEAEs) of any grade were nausea (69%) and fatigue (67%), with hypertension (36%) as the most common grade 3/4 TEAE. Of the 38 evaluable patients, ORR was 26% and median PFS was 5 months.Conclusion:Cases of RPLS had been observed in other studies in the ziv-aflibercept clinical development programme but the rate observed in this study was higher than previously observed. This might be related to declining renal function and/or hypertension. Although ORR and PFS were in accordance with most historical first-line NSCLC studies, this combination of ziv-aflibercept/cisplatin/pemetrexed will not be further explored in NSCLC.

  View details for DOI 10.1038/bjc.2013.735

  View details for PubMedID 24292447

• 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

• A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell lung cancer. Jahchan, N., Joel, D., Mazur, P., Neal, J., Khatri, P., Butte, A., Sage, J. AMER ASSOC CANCER RESEARCH. 2014

  View details for DOI 10.1158/1078-0432.14AACRIASLC-IA02

  View details for Web of Science ID 000361385000055

• 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

• FIRST-IN-HUMAN EVALUATION OF CO-1686, AN IRREVERSIBLE, HIGHLY, SELECTIVE TYROSINE KINASE INHIBITOR OF MUTATIONS OF EGFR (ACTIVATING AND T790M) Soria, J., Sequist, L. V., Gadgeel, S., Goldman, J., Wakelee, H., Varga, A., Fidias, P., Wozniak, A. J., Neal, J. W., Doebele, R. C., Garon, E. B., Jaw-Tsai, S., Caunt, L., Kaur, P., Rolfe, L., Camidge, D., Allen, A. LIPPINCOTT WILLIAMS & WILKINS. 2013: S141–S142

  View details for Web of Science ID 000339624900168

• PALLIATIVE CARE AND ANTI-CANCER CARE INTEGRATION: DESCRIPTION OF THREE MODELS OF CARE DELIVERY AT A TERTIARY MEDICAL CENTER Ramchandran, K. J., Fronk, J., Trieu, S., Wakelee, H. A., Das, M., Neal, J. W., Harman, S., Dwyer, P., Bosch, J., Shaw, H., Safari, S., Oden, R., Morrison, T., Blayney, D. LIPPINCOTT WILLIAMS & WILKINS. 2013: S1324

  View details for Web of Science ID 000339624906208

• VIETNAMESE NON-SMALL CELL LUNG CANCER PATIENTS IN CALIFORNIA: MOLECULAR PROFILES AND CLINICAL CHARACTERISTICS Nguyen, K. H., Das, M., Ramchandran, K., Shrager, J., Merritt, R. E., Hoang, C., Burt, B., Tisch, A., Pagtama, J., Zehnder, J., Berry, G., Wakelee, H. A., Anh-Hoa Nguyen, Neal, J. W. LIPPINCOTT WILLIAMS & WILKINS. 2013: S208–S209

  View details for Web of Science ID 000339624901009

• STAGE 1 RESULTS OF A 2-STAGE PHASE II TRIAL OF SINGLE AGENT AMRUBICIN IN PATIENTS WITH PREVIOUSLY TREATED THYMIC MALIGNANCIES Wakelee, H. A., Riess, J. W., San Pedro-Salcedo, M., Padda, S. K., Ramchandran, K., Gubens, M. A., Neal, J. W. LIPPINCOTT WILLIAMS & WILKINS. 2013: S731

  View details for Web of Science ID 000339624903218

• GLI1, NOTCH1 AND CTNNB1 EXPRESSION BY AUTOMATED QUANTITATIVE IMMUNOFLUORESCENCE (AQUA) IN A THYMIC MALIGNANCY TISSUE MICROARRAY (TMA) Riess, J. W., West, R., Padda, S. K., Dean, M., Klimowicz, A., Huong, C., Neal, J. W., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2013: S944

  View details for Web of Science ID 000339624904251

• CORRELATIVE ANALYSIS OF CIRCULATING BIOMARKERS FROM A PHASE 1B/2 TRIAL OF CABOZANTINIB (C) WITH OR WITHOUT ERLOTINIB (E) IN PATIENTS (PTS) WITH ADVANCED OR METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) Padda, S. K., Rosenberg-Hasson, Y., Neal, J. W., Gettinger, S. N., Engelman, J. A., Jaenne, P. A., West, H. L., Subramaniam, D., Leach, J. W., Lara, P. N., Wax, M. B., Wakelee, H. A., Clary, D. O., Zhou, L. LIPPINCOTT WILLIAMS & WILKINS. 2013: S1072–S1073

  View details for Web of Science ID 000339624905131

• ENERGY METABOLISM IN LUNG ADENOCARCINOMA Hoang, C., Xu, Y., Shi, Z., Lin, Y., Merritt, R. E., Shrager, J., Das, M., Neal, J. W., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2013: S1036–S1037

  View details for Web of Science ID 000339624905063

• ERLOTINIB (E) AND DOVITINIB (TKI258) (D) IN PATIENTS (PTS) WITH METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC): A SIGNIFICANT PHARMACOKINETIC (PK) INTERACTION Das, M., Padda, S. K., Zhou, L., Frymoyer, A., Neal, J. W., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2013: S1185–S1186

  View details for Web of Science ID 000339624905335

• Noninvasive and Ultrasensitive Quantitation of Circulating Tumor DNA by Hybrid Capture and Deep Sequencing Bratman, S. V., Newman, A. M., To, J., Wynne, J. F., Neal, J. W., Wakelee, H., Shrager, J., Loo, B. W., Alizadeh, A. A., Diehn, M. ELSEVIER SCIENCE INC. 2013: S92

  View details for DOI 10.1016/j.ijrobp.2013.06.237

  View details for Web of Science ID 000324503600224

• 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): 411–14

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

  View details for Web of Science ID 000218799300011

• 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

• STAGE 1 RESULTS OF A 2-STAGE PHASE II TRIAL OF SINGLE AGENT AMRUBICIN IN PATIENTS WITH PREVIOUSLY TREATED THYMIC MALIGNANCIES Wakelee, H., Riess, J., Pedro-Salcedo, M., Padda, S., Ramchandran, K., Gubens, M., Neal, J. LIPPINCOTT WILLIAMS & WILKINS. 2013: 22–23

  View details for Web of Science ID 000339623500024

• GLI1, NOTCH1 AND CTNNB1 EXPRESSION BY AUTOMATED QUANTITATIVE IMMUNOFLUORESCENCE (AQUA) IN A THYMIC MALIGNANCY TISSUE MICROARRAY (TMA) Riess, J., West, R., Padda, S., Dean, M., Klimowicz, A., Huong, C., Neal, J., Wakelee, H. LIPPINCOTT WILLIAMS & WILKINS. 2013: 25

  View details for Web of Science ID 000339623500027

• 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

• First-in-human evaluation of CO-1686, an irreversible, selective, and potent tyrosine kinase inhibitor of EGFR T790M. Sequist, L. V., Soria, J., Gadgeel, S. M., Wakelee, H. A., Camidge, D., Varga, A., Fidias, P., Wozniak, A. J., Neal, J. W., Doebele, R., Garon, E. B., Jaw-Tsai, S. S., Stern, J. C., Allen, A. R., Goldman, J. AMER SOC CLINICAL ONCOLOGY. 2013

  View details for Web of Science ID 000335419601042

• 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 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): e17-8

  View details for DOI 10.1097/JTO.0b013e31827690da

  View details for PubMedID 23328555

  View details for PubMedCentralID PMC3552378

• 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

  View details for PubMedCentralID PMC3552378

• 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 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): 238–53

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

  View details for Web of Science ID 000218783300003

• 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

• Cell-free DNA as a Biomarker of Residual Disease Following Radiation Therapy for Non-small Cell Lung Cancer 54th Annual Meeting of the American-Society-for-Radiation-Oncology (ASTRO) Bratman, S. V., Eclov, N. C., Modlin, L. A., Neal, J., Loo, B. W., Wu, G., Richardson, K., Newman, A. M., Alizadeh, A., Diehn, M. ELSEVIER SCIENCE INC. 2012: S713–S713

  View details for Web of Science ID 000310542902315

• 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

• Prolonged Survival in Non-Small Cell Lung Cancer (NSCLC) Patients with Leptomeningeal Metastases (LM) in the Modern Treatment Era Riess, J. W., Nagpal, S., Iv, M., Zeineh, M., Gubens, M. A., Neal, J. W., Wakelee, H. A. LIPPINCOTT WILLIAMS & WILKINS. 2012: S243–S243

  View details for Web of Science ID 000317035000106

• The Select Study: A Multicenter Phase II Trial Of Adjuvant Erlotinib In Resected Epidermal Growth Factor Receptor (EGFR) Mutation-positive Non-small Cell Lung Cancer (NSCLC) Neal, J. W., Pennell, N. A., Govindan, R., Heist, R. S., Shaw, A. T., Muzikansky, A., Janne, P. A., Lynch, T. J., Azzoli, C. G., Sequist, L. V. LIPPINCOTT WILLIAMS & WILKINS. 2012: S209–S209

  View details for Web of Science ID 000317035000018

• A phase I dose-escalation study of aflibercept administered in combination with pemetrexed and cisplatin in patients with advanced solid tumours BRITISH JOURNAL OF CANCER Diaz-Padilla, I., Siu, L. L., San Pedro-Salcedo, M., Razak, A. R., Colevas, A. D., Shepherd, F. A., Leighl, N. B., Neal, J. W., Thibault, A., Liu, L., Lisano, J., Gao, B., Lawson, E. B., Wakelee, H. A. 2012; 107 (4): 604-611

  Abstract

  To evaluate the safety, pharmacokinetics (PKs), and pharmacodynamics of aflibercept, and to identify the recommended phase II dose (RP2D) of aflibercept in combination with pemetrexed and cisplatin.Aflibercept was administered at escalating doses of 2, 4, or 6 mg kg(-1) in combination with fixed doses of pemetrexed (500 mg m(-2)) plus cisplatin (75 mg m(-2)) every 3 weeks. Blood samples were collected for PK analyses. Serum antiaflibercept antibodies were quantified to assess their impact on systemic aflibercept concentrations.Eighteen patients were enrolled. One patient dosed at 4 mg kg(-1) experienced grade 3 hypophosphatemia (dose-limiting toxicity; DLT), which prompted a cohort expansion. No further DLTs were observed in the 4 mg kg(-1) cohort or the 6 mg kg(-1) dose cohort. Most common adverse events (AEs) of all grades included (%): fatigue (89), anaemia (89), nausea (83), hyponatremia (78), and neutropenia (72). Grade ≥ 3 AEs consistent with anti-vascular endothelial growth factor therapy included (%): hypertension (22), pulmonary embolism (11), and deep vein thrombosis (6). Five patients (28%) experienced mild neurocognitive disturbance. No episodes of reversible posterior leukoencephalopathy syndrome (RPLS) were noted.The results of this phase I study allowed further evaluation of the combination of aflibercept with pemetrexed and cisplatin in a phase II study. The RP2D of aflibercept was 6 mg kg(-1), to be administered intravenously every 3 weeks in combination with pemetrexed and cisplatin.

  View details for DOI 10.1038/bjc.2012.319

  View details for Web of Science ID 000307770300005

  View details for PubMedID 22805331

  View details for PubMedCentralID PMC3419963

• 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

• A phase II multicenter study of aflibercept (AFL) in combination with cisplatin (C) and pemetrexed (P) in patients with previously untreated advanced/metastatic nonsquamous non-small cell lung cancer (NSCLC). 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Chen, H., Modiano, M. R., Neal, J. W., Brahmer, J. R., Rigas, J. R., Jotte, R. M., Leighl, N. B., Liu, L., Lisano, J. M., Adjei, A. A., Wakelee, H. A. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for Web of Science ID 000318009804215

• The SELECT study: A multicenter phase II trial of adjuvant erlotinib in resected epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Neal, J. W., Pennell, N. A., Govindan, R., Lanuti, M., Rosovsky, R. P., Heist, R. S., Shaw, A. T., Temel, J. S., Muzikansky, A., Janne, P. A., Lynch, T. J., Azzoli, C. G., Sequist, L. V. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for Web of Science ID 000318009801374

• Utility of 18F FDG PET/CT in patients with advanced thymic neoplasms Davidzon, G., Wakelee, H., Neal, J., Mittra, E., Quon, A., Iagaru, A. SOC NUCLEAR MEDICINE INC. 2012

  View details for Web of Science ID 000443680202308

• 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

  View details for PubMedCentralID PMC3459550

• 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: 337–45

  View details for DOI 10.2147/BTT.S26558

  View details for Web of Science ID 000214920000035

• 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 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

  View details for DOI 10.1097/01.JTO.0000407562.07029.52

  View details for Web of Science ID 000296705500007

  View details for PubMedID 22005534

• Phase II trial of carboplatin, abraxane, and bevacizumab in NSCLC Heist, R. S., Duda, G. D., Sahani, D., Ancukiewicz, M., Fidias, P., Sequist, L. V., Shaw, A. T., Temel, J. S., Lennes, I. T., Neal, J. W., Pennell, N. A., Lynch, T. J., Engelman, J. A., Jain, R. K. AMER SOC CLINICAL ONCOLOGY. 2011

  View details for DOI 10.1200/jco.2011.29.15_suppl.e18016

  View details for Web of Science ID 000208880304394

• 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

  View details for PubMedCentralID PMC3045701

• 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

  View details for PubMedCentralID PMC3042878

• 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 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