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Introduction: In a phase 1 study, bintrafusp alfa was found to have an encouraging clinical activity in patients with previously treated advanced NSCLC. This study evaluated the safety and efficacy of bintrafusp alfa with chemotherapy in patients with stage IV NSCLC regardless of the programmed death-ligand 1 (PD-L1) expression status., Methods: In this open-label, phase 1b/2 study (NCT03840915), eligible patients were assigned to one of four cohorts. Patients with previously untreated metastatic NSCLC (cohorts A, B, and C) received bintrafusp alfa with chemotherapy as first-line treatment, whereas patients whose disease progressed on previous treatment with programmed cell death protein 1 or PD-L1 inhibitors (cohort D) received bintrafusp alfa with chemotherapy as second-line treatment. The primary objective of this study was to evaluate the safety and tolerability of bintrafusp alfa with chemotherapy., Results: Four serious and one nonserious treatment-emergent adverse events were considered dose-limiting toxicities, none of which were assessed as related to bintrafusp alfa by the investigator. Any-grade bintrafusp alfa-related adverse events occurred in 20.7% of patients in cohorts A+B+C and in 16.7% of patients in cohort D. Keratoacanthoma was the most common transforming growth factor-β inhibition-mediated skin lesion (cohorts A+B+C: 12.1% and cohort D: 8.3%). In cohorts A+B+C, the overall response rate was 48.3%, and in patients with PD-L1 tumor proportion score of more than or equal to 50.0%, it was 71.4%. On the basis of an interim analysis, the data were considered mature, and no further analysis has been planned., Conclusion: Bintrafusp alfa with chemotherapy was found to have a manageable safety profile and encouraging clinical activity in patients with stage IV NSCLC., Competing Interests: Dr. Rolfo received consulting fees from 10.13039/100004325AstraZeneca, 10.13039/501100022274Daiichi Sankyo, 10.13039/100009857Regeneron, and Novocure; received payment or honoraria from Bristol Myers Squibb (BMS), Novartis, Invitae, Guardant Health, Novocure, COR2ED, Regeneron, Bayer, Boehringer Ingelheim, AbbVie, and Thermo Fisher; is on data safety monitoring or advisory boards for Invitae, Novartis, Novocure, Janssen, EMD Serono, Bayer, and Regeneron; is a scientific advisory board member of Imagene; is a board member or has leadership roles in International Society of Liquid Biopsy, The European School of Oncology, International Association for Study of Lung Cancer, and Oncology Latin American Association; and received financial or nonfinancial interests from Lung Cancer Research Foundation, National Foundation for Cancer Research, and U54 (National Institute of Health) research grants. Dr. Greillier received consulting fees from 10.13039/100016838BMS, Merck & Co., Kenilworth, NJ, Takeda, Pfizer, Roche, Amgen, Sanofi, Janssen, Eli Lilly, and Novartis; received payment or honoraria from BMS, Merck & Co., Kenilworth, NJ, Takeda, Pfizer, Roche, Amgen, Sanofi, Janssen, Eli Lilly, and Novartis; received support for attending meetings and/or travel from Pfizer, Merck & Co., Kenilworth, NJ, AstraZeneca, Takeda, and Amgen; and is on data safety monitoring or advisory boards for InhaTarget Therapeutics. Dr. Veillon received consulting fees from 10.13039/100004334Merck & Co., Kenilworth, NJ, and Janssen; received payment or honoraria from Roche, AstraZeneca, BMS, Merck & Co., Kenilworth, NJ, Pfizer, Takeda, and Sanofi; and received support for attending meetings and/or travel from Janssen, Takeda, and Sanofi. Dr. Badin received consulting fees from 10.13039/100006775GE Health care; received payment or honoraria from BMS, Jazz Pharmaceuticals, Merck & Co., Kenilworth, NJ, Eli Lilly, Natera, Guardant, Incyte, Amgen, EMD Serono, Regeneron, and Pfizer. Dr. Chaudhary is an employee of EMD Serono. Dr. Vugmeyster is an employee of EMD Serono and has patents for work with EMD Serono. Mr. Sato is an employee of Merck Biopharma Co., Ltd., Tokyo, Japan, an affiliate of Merck KGaA, Darmstadt, Germany. Dr. Hiret received payment or honoraria from Sanofi, AstraZeneca, and BMS; and received support for attending meetings and/or travel from Roche and Novartis. The remaining authors declare no conflict of interest., (© 2024 by the International Association for the Study of Lung Cancer.)

Immune checkpoint inhibitors (ICIs) present clinicians with the challenge of managing immune-related adverse events (irAEs), which can range from mild to severe due to immune system activation 1 . While guidelines recommend discontinuing ICIs for grade 3 partial and all grade 4 irAEs, there is growing interest in rechallenging patients based on oncological outcomes, particularly for cardiovascular and neurological irAEs where data remains scarce 1,2 . We retrospectively evaluated the safety of ICI rechallenge following grade 3-4 irAEs, specifically focusing on cardiovascular and neurological events, in patients discussed at our multidisciplinary immunotoxicity assessment board between 2019 and 2021. Fifteen patients were included, with a median time to severe irAE onset of 49 days. Among them, five patients experienced neurological adverse events (NAEs): aseptic meningitis (3), inflammatory polyradiculoneuropathy (1), and ophthalmoplegia (1), while one patient presented with myocarditis. Of the 15 patients retreated with ICIs after initial severe irAEs, 11 (73%) remained free of subsequent irAEs, two (13%) experienced recurrence of the initial irAE, and two (13%) developed new irAEs distinct from the initial event. The median time to event recurrence was 69 days, occurring no earlier than the initial severe irAE. In the subset analysis focusing on severe cardiovascular and neurological irAEs, rechallenge with ICIs was generally well tolerated. However, one patient treated with anti-PD1 experienced a relapse of grade 2 aseptic meningitis. Overall, our findings suggest that rechallenging with ICIs after severe irAEs, including those affecting the cardiovascular and neurological systems, may be safe, particularly after irAE regression and corticosteroid withdrawal., Competing Interests: EG: congress fees and investigator for BMS and MSD. RV: speakers’ bureau for BMS. SM-P: consultant on boards for BMS. AP-L: congress fees for BMS. CDu: Clinical investigation in trials, congress fees and member of boards for BMS, MSD. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Eldani, Kostine, Faure, Lazaro, Rigothier, Hiriart, Teulières, Poullenot, Haissaguerre, Zysman, Veillon, Vergnenegre, Issa, Domblides, Mary-Prey, Beylot-Barry, Pham-Ledard, Dutriaux, Sole, Duval and Gerard.)

Introduction: Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β "trap") fused to a human immunoglobulin G1 monoclonal antibody blocking programmed death-ligand 1 (PD-L1), has exhibited clinical activity in a phase 1 expansion cohort of patients with PD-L1-high advanced NSCLC., Methods: This adaptive phase 3 trial (NCT03631706) compared the efficacy and safety of bintrafusp alfa versus pembrolizumab as first-line treatment in patients with PD-L1-high advanced NSCLC. Primary end points were progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1 per independent review committee and overall survival., Results: Patients (N = 304) were randomized one-to-one to receive either bintrafusp alfa or pembrolizumab (n = 152 each). The median follow-up was 14.3 months (95% confidence interval [CI]: 13.1-16.0 mo) for bintrafusp alfa and 14.5 months (95% CI: 13.1-15.9 mo) for pembrolizumab. Progression-free survival by independent review committee was not significantly different between bintrafusp alfa and pembrolizumab arms (median = 7.0 mo [95% CI: 4.2 mo-not reached (NR)] versus 11.1 mo [95% CI: 8.1 mo-NR]; hazard ratio = 1.232 [95% CI: 0.885-1.714]). The median overall survival was 21.1 months (95% CI: 21.1 mo-NR) for bintrafusp alfa and 22.1 months (95% CI: 20.4 mo-NR) for pembrolizumab (hazard ratio = 1.201 [95% CI: 0.796-1.811]). Treatment-related adverse events were higher with bintrafusp alfa versus pembrolizumab; grade 3-4 treatment-related adverse events occurred in 42.4% versus 13.2% of patients, respectively. The study was discontinued at an interim analysis as it was unlikely to meet the primary end point., Conclusions: First-line treatment with bintrafusp alfa did not exhibit superior efficacy compared with pembrolizumab in patients with PD-L1-high, advanced NSCLC., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objective: Another course of immune checkpoint inhibitors (ICIs) is often considered in patients with cancer progression and previous immune-related adverse events, including inflammatory arthritis (ICI-IA), but there are limited data regarding safety of ICI rechallenge in this setting. We aimed to assess the rate and clinical features associated with ICI-IA flare/recurrence on ICI rechallenge., Methods: We conducted a multicentre observational study including cancer patients with ICI-IA who started a second course of ICI more than 3 months after ICI discontinuation in four French university hospitals. Primary outcome was the frequency of ICI flare/recurrence after ICI rechallenge., Results: Twenty-three patients were included. At the time of ICI rechallenge, 18 patients reported no symptoms of ICI-IA (78%) and 5 had grade 1 (22%), 11 patients (48%) were not receiving any ICI-IA treatment, 11 (48%) were still on prednisone, 2 (9%) were on conventional synthetic disease-modifying antirheumatic drugs and 1 (4%) on anti-IL-6. ICI-IA flare/recurrence occurred in 12 patients (52%) with a median time of 1 month after ICI rechallenge. ICI-IA phenotype, disease activity and ICI-IA treatment at the time of ICI rechallenge did not differ according to ICI-IA flare/recurrence status., Conclusion: In this first observational study of ICI-IA patients rechallenged with ICI, about half of the patients experienced ICI-IA flare/recurrence with a similar phenotype but occurring earlier than the initial ICI-IA, warranting close monitoring during the first month of retreatment. Risk of flare did not differ according to baseline immunosuppressive treatment at the time of rechallenge., Competing Interests: Competing interests: AL and TB: No conflict of interest. GM: Research support: Abbvie, BMS, Gilead, Lilly, MSD, Novartis, Roche Chugai, Sanofi; consulting fees: Abbvie, UCB, BMS, Lilly, Gilead, Novartis, Janssen; education: Abbvie, BMS, Gilead, Lilly, Novartis, Roche Chugai. AT: Consulting fees: Galapagos; speaker: Brystol-Myers Squibb; support for attending congress: Sanofi, Abbvie. SB: Co conflict of interest. SP, CD: Congress fees and investigator in clinical trials: BMS and MSD. EG: Congress fees and investigator for BMS and MSD. AP-L and MB-B: No conflict of interest. MZ: Grants from AVAD and grants from FRM. RV: Consulting fees and speaker fees: Roche; registration reimbursement: Pfizer and AstraZeneka; speaker and registration reimbursement: BMS and MSD. AD: Consulting or Advisory Role: Merck, MSD, BMS, Merus; travel, accommodations, expenses: BMS, Merck. MG-G: Consulting or Advisory Role: Astra Zeneca, Merck, Pfizer, MSD, BMS, Roche; travel, accommodations, expenses: MSD, Janssen. BS: no conflict of interest. FL: Congress fees, consulting fees, and sub investigator in trials: Astra Zeneca, BMS, MSD, Roche, Pfizer. ML, CR and M-ET: No conflict of interest. TS: Clinical research: AbbVie, Abivax, Biogen, Pfizer, Lilly, MSD, Novartis, Sandoz; advisory Boards: AbbVie, BMS, Lilly, Novartis, Pfizer, Sanofi; education: AbbVie, Biogen, BMS, Galapagos, Lilly, Janssen, Novartis, Nordic Pharma, Pfizer, Viatris; help for research: Pfizer, Lilly, Abbvie, Biogen. MK: No conflict of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

High-level MET amplification (METamp) is a primary driver in ∼1%-2% of non-small cell lung cancers (NSCLCs). Cohort B of the phase 2 VISION trial evaluates tepotinib, an oral MET inhibitor, in patients with advanced NSCLC with high-level METamp who were enrolled by liquid biopsy. While the study was halted before the enrollment of the planned 60 patients, the results of 24 enrolled patients are presented here. The objective response rate (ORR) is 41.7% (95% confidence interval [CI], 22.1-63.4), and the median duration of response is 14.3 months (95% CI, 2.8-not estimable). In exploratory biomarker analyses, focal METamp, RB1 wild-type, MYC diploidy, low circulating tumor DNA (ctDNA) burden at baseline, and early molecular response are associated with better outcomes. Adverse events include edema (composite term; any grade: 58.3%; grade 3: 12.5%) and constipation (any grade: 41.7%; grade 3: 4.2%). Tepotinib provides antitumor activity in high-level METamp NSCLC (ClinicalTrials.gov: NCT02864992)., Competing Interests: Declaration of interests X.L. reported personal/consulting fees from EMD Serono during the conduct of the study; personal or consulting fees from AstraZeneca, Spectrum Pharmaceuticals, Novartis, Eli Lilly, Boehringer Ingelheim, Janssen, Blueprint Medicines, Bayer, and Albion; grants from ArriVent, Eli Lilly, Boehringer Ingelheim, and Regeneron; and personal fees from AbbVie outside the submitted work. L.G.P.-A. reported consulting roles with AstraZeneca, Lilly, EMD Serono, Spectrum Pharmaceuticals, and Daiichi Sankyo/Eli Lilly; research funding from Lilly and Boehringer Ingelheim; leadership roles from Genomica and ALTUM Sequencing; speakers bureau from Merck & Co., Kenilworth, NJ, Bristol-Myers Squibb, Roche, Pfizer, Lilly, AstraZeneca, and the healthcare business of Merck KGaA, Darmstadt, Germany; travel/accommodations/expenses from Roche, AstraZeneca, Merck & Co., Kenilworth, NJ, Bristol-Myers Squibb, Pfizer, and Takeda; and honoraria from Roche, Lilly, Pfizer, Bristol-Myers Squibb, Merck & Co., Kenilworth, NJ, AstraZeneca, the healthcare business of Merck KGaA, Darmstadt, Germany, PharmaMar, Novartis, Celgene, Amgen, Sanofi, Ipsen, Servier, Bayer, Blueprint Medicines, Mirati Therapeutics, and Takeda outside the submitted work. J.V.M. reported an advisory role with Amgen outside the submitted work. S.V. reported consulting or advisory role from the healthcare business of Merck KGaA, Darmstadt, Germany, AbbVie, Bristol-Myers Squibb, AstraZeneca, Merck & Co., Kenilworth, NJ, and Roche; non-financial support from OSE Immunotherapeutics; and personal fees from Janssen and Puma Biotechnology outside the submitted work. C.C.G. reported a consulting/advisory role with Boehringer Ingelheim and travel/accommodations/expenses from Roche and Merck & Co., Kenilworth, NJ, outside the submitted work. E.F.S. reported an advisory/consultancy role (institution) with Eli Lilly, AstraZeneca, Boehringer Ingelheim, Roche/Genentech, Bristol-Myers Squibb, the healthcare business of Merck KGaA, Darmstadt, Germany, Merck & Co., Kenilworth, NJ, Takeda, Bayer, Regeneron, Novartis, Daiichi Sankyo, and Seattle Genetics; and research funding (institution) from Boehringer Ingelheim, Bayer, Roche/Genentech, AstraZeneca, and Bristol-Myers Squibb outside the submitted work. M.G. reported personal fees from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study; grants and personal fees from AstraZeneca; and personal fees from the healthcare business of Merck KGaA, Darmstadt, Germany, Bayer, Bristol-Myers Squibb, AbbVie, Takeda, Janssen, Roche, Sanofi, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Novartis, and Blueprint outside the submitted work. R.V. reported research funding from the healthcare business of Merck KGaA, Darmstadt, Germany, during the conduct of the study; personal consulting fees from Janssen; personal speaker fees from Bristol-Myers Squibb and Takeda; personal speaker bureau fees from Amgen, Sanofi, Roche, and AstraZeneca; and travel fees from Pfizer Travel and Janssen outside the submitted work. D.V.B. reported advisory/consultancy honoraria from Roche, the healthcare business of Merck KGaA, Darmstadt, Germany, Bristol-Myers Squibb, AstraZeneca, Pfizer, Boehringer Ingelheim, and Takeda; and speaker honoraria from Roche, the healthcare business of Merck, KGaA, Darmstadt, Germany, Bristol-Myers Squibb, AstraZeneca, Pfizer, and Boehringer Ingelheim outside the submitted work. J.F.P. reported consulting/advisory roles with Roche, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck & Co., Kenilworth, NJ, and GlaxoSmithKline outside the submitted work. M.S. reported an advisory/consulting role with Roche, AstraZeneca, Bristol-Myers Squibb, and Merck & Co., Kenilworth, NJ, outside the submitted work. T.K. reported grants and personal fees from Chugai Pharmaceutical Co., AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical Co., Bristol-Myers Squibb, Merck & Co., Kenilworth, NJ, and Kyowa Hakko Kirin; personal fees from Ono Pharmaceutical, Pfizer Japan, Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis, and Daiichi-Sankyo; and grants from the healthcare business of Merck KGaA, Darmstadt, Germany, outside the submitted work. Y.-C.K. reported honoraria from AstraZeneca, Roche, Boehringer Ingelheim, Merck & Co., Kenilworth, NJ, Pfizer, Ono, Bristol-Myers Squibb, Daiichi Sankyo, and Yuhan; and research funding from AstraZeneca, Roche, and Boehringer Ingelheim outside the submitted work. S.S.Y. reported honoraria from AstraZeneca, Roche, Boehringer Ingelheim, Merck & Co., Kenilworth, NJ, Pfizer, Ono Pharmaceutical, Bristol-Myers Squibb, Daiichi Sankyo, and Yuhan; and research funding from AstraZeneca, Roche, and Boehringer Ingelheim outside the submitted work. J.-Y.H. reported research funding from Hoffmann-La Roche, Ltd., Ono Pharmaceutical, Pfizer, and Takeda outside the submitted work. J.-H.K. reported honoraria from Roche, Boehringer Ingelheim, Merck & Co., Kenilworth, NJ, and Bristol-Myers Squibb; consulting roles with Roche, Boehringer Ingelheim, Merck & Co., Kenilworth, NJ, AstraZeneca, and Yuhan; speakers bureau for Pfizer, Merck & Co., Kenilworth, NJ, and Roche; and research funding from Boehringer Ingelheim, AstraZeneca, Daiichi Sankyo, and Yuhan outside the submitted work. Y.J.C. reported consulting/advisory role with Astella, Yuhan, Merck & Co., Kenilworth, NJ, Roche, and Chong Kun Dang outside the submitted work. C.S. is an employee of the healthcare business of Merck KGaA, Darmstadt, Germany. D.J. is an employee of the healthcare business of Merck KGaA, Darmstadt, Germany, and holds stock in Merck KGaA, Darmstadt, Germany. H.V. is an employee of the healthcare business of Merck KGaA, Darmstadt, Germany. R.B. is an employee of the healthcare business of Merck KGaA, Darmstadt, Germany, and holds stock in Merck KGaA, Darmstadt, Germany. G.O. was an employee of the healthcare business of Merck KGaA, Darmstadt, Germany, at the time of the study and holds stock in Novartis. A.J. is an employee of the healthcare business of Merck KGaA, Darmstadt, Germany, and holds stock in Merck KGaA, Darmstadt, Germany. P.K.P. reported an advisory/consulting role from Takeda, Xencor, Janssen, CrownBio, Bicara, Mirati, and EMD Serono; and research funding (institution) from Bicara, Boehringer Ingelheim, and EMD Serono outside the submitted work., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Few real-world data are available in patients with advanced metastatic non-small cell lung cancer (NSCLC) treated with first-line immunotherapy, particularly in those with brain metastases at treatment initiation., Methods: This was a national, retrospective, multicenter study that consecutively included all patients with PD-L1-positive (tumor proportion score ≥ 50%) advanced NSCLC who initiated first-line treatment with pembrolizumab as a single agent between May 2017 (date of availability of pembrolizumab in this indication in France) to November 22, 2019 (approval of the pembrolizumab-chemotherapy combination). Data were collected from medical records with local response assessment., Results: The cohort included 845 patients and 176 (20.8%) had brain metastases at diagnosis. There were no significant differences in outcomes for patients with and without brain metastases: 9.2 (95% CI 5.6-15) and 8 (95% CI 6.7-9.2, p = 0.3) months for median progression-free survival (PFS) and, 29.5 (95% CI 17.2-NA) and 22 (95% CI 17.8-27.1, p = 0.3) months for median overall survival (OS), respectively. Overall response rates were 47% and 45% in patients with and without cerebral metastases. In multivariate analysis, performance status 2-4 vs. 0-1 and neutrophil-to-lymphocyte ratio ≥ 4 vs. < 4 were the main independent negative factors for OS; brain metastasis was not an independent factor for OS., Conclusion: In this large multicenter cohort, nearly 20% of patients initiating pembrolizumab therapy for advanced NSCLC had cerebral metastases. There was no significant difference in response rates, PFS and OS between patients with and without brain metastases., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Few strategies exist for treatment of patients with small-cell lung cancer (SCLC) extended-stage after failure of first-line platinum-based chemotherapy. Lurbinectedin is a novel RNA-polymerase-II inhibitor investigated as a second-line therapy for SCLC. However, its efficacy and safety profile in real clinical practice remain to be determined., Objective: To determine the efficacy and safety of lurbinectedin in real-life among patients with SCLC previously treated with first-line platinum-based chemotherapy., Methods: We retrospectively evaluated patients who received at least one dose of lurbinectedin (3.2 mg/m 2 ) between March 2020 and November 2021, in the pulmonary department of Bordeaux University Hospital. Endpoints were time to treatment discontinuation, progression-free survival, overall survival, and safety profile., Results: Thirteen patients were included. The median age was 60 years (range: 42-77), seven (54%) were females, nine (69%) having a performance status of 0-1. Lurbinectedin was given as second-line treatment before platinum rechallenge in four (31%) patients. After a mean follow-up of 4.1 months, the objective response rate (ORR) was 17%. The median time to treatment discontinuation (TTD) was 2.3 months (interquartile range [IQR], 1.2-3.6). The median progression-free survival (PFS) and overall survival (OS) were, respectively, 1.9 (IQR, 0.1.8) and 4.1 (IQR, 2.0-3.5) months. No significant difference regarding TTD, PFS or OS was found in the two groups according to treatment history or according to chemotherapy-free intervall (CMI) 〈1 or 〉1 month. The most common adverse events (AEs) were asthenia, nausea, and anemia in nine (70%) patients. Grade 3 AEs were reported, fatigue, vomiting, nausea, anorexia, and neutropenia., Conclusions: Lurbinectedin in real clinical practice could have had a lower efficacy than in phase II trial, but a better hematological and bioclinical tolerance than previously reported. Early relapse after platinum-based chemotherapy seems to have a lower response to lurbinectedin., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Immune checkpoint inhibitors (ICIs) are widely used in lung cancer management. However, myocarditis, which is a rare, yet potentially severe adverse-related event associated with ICIs, could be under-reported., Objectives: This study is aimed to prospectively evaluate the cumulative incidence rate of myocarditis, through systematic screening, among patients receiving ICIs for lung cancer., Methods: All patients who received the first administration of ICIs for non-small cell (NSCLC) and small cell lung cancer (SCLC), between May and November 2020, in the pulmonary department of Bordeaux University Hospital, were included. Echocardiography (ECG), troponin-I, and natriuretic peptide dosages before ICIs' first administration and before each infusion were recorded. ECG and magnetic resonance imaging (MRI) were done additionally, in case of at least three times increase in troponin levels, ECG modifications, and the onset of cardiovascular symptoms. Second, if possible, coronarography than endomyocardial biopsy was assessed. The primary outcome was defined as ICIs related to myocarditis onset, while secondary outcomes included other cardiovascular events, disease-free, and overall survival., Results: During the period of interest, 99 patients received their first infusion of ICIs for lung cancer (mean age 64 ± 9 years; 52 men, 67% with adenocarcinoma). Three cases of myocarditis without major adverse cardiac events (MACEs) occurred (two definite and one possible), and the mean duration between the first ICIs' administration and myocarditis onset was 144 ± 3 days. Median disease-free survival and overall survival were 169 [102; 233] days and 209 [147; 249] days, respectively., Conclusion: In our study, systematic screening of myocarditis associated with ICIs leads to a more frequent incidence and a later onset than previously reported. None of them were severe. Additional prospective evidence is needed before we could adopt routine cardiac screening in unselected patients starting ICIs; however, these data shed new light on the risk of myocarditis associated with ICIs administration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Faubry, Faure, Toublanc, Veillon, Lemaître, Vergnenègre, Cochet, Khan, Raherison, Dos Santos and Zysman.)

Background: The effect of the sequential combination of chemotherapy and immune checkpoint inhibitors (ICIs) remains unclear. Here, we evaluated the efficacy of different chemotherapy regimens administered after ICIs in advanced non-small cell lung cancer (NSCLC), compared to the same regimens administered without previous ICIs., Methods: We retrospectively included all patients treated between 2015 and 2019 for an advanced NSCLC, receiving a salvage chemotherapy just after ICI (CAI group) comparing them to ICI naive patients (CWPI group) undergoing the same chemotherapy at Bordeaux University Hospital. The primary outcome was the time to treatment discontinuation (TTD), and secondary endpoints were overall survival (OS) and overall response rate (ORR)., Results: A total of 152 patients were included, with 34/23 (CAI/CWPI) receiving paclitaxel/bevacizumab (PB), 24/11 paclitaxel (P), 27/12 gemcitabine (G) and 6/15 pemetrexed (PE). Characteristics were comparable, except for CAI treated with PB (more patients with an ECOG PS ≤1 [p <0.001]). Median number of lines received was higher in CAI for all groups. There was no difference between CAI and CWPI for TTD, OS and ORR. However, PB was associated with a nonsignificant increase in OS in the CAI group (HR = 0.65; 95% CI: 0.38-1.2, p = 0.17]., Conclusion: Our data showed no difference in TTD, OS and ORR regardless of chemotherapy, but a trend towards an increased OS with PB when given after an ICI, while patients received chemotherapy later in the CAI group. This suggests that a sequential combination of ICI followed by chemotherapy could be an interesting strategy in advanced NSCLC for selected patients., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Purpose: Primary analysis of VISION showed tepotinib had durable clinical activity in patients with MET exon 14 (METex14) skipping non-small cell lung cancer (NSCLC). We present updated outcomes for clinically relevant subgroups., Patients and Methods: This phase II, open-label, multi-cohort study of 500 mg (450 mg active moiety) tepotinib in patients with METex14 skipping NSCLC assessed efficacy and safety in predefined subgroups according to age, prior therapies (chemotherapy and immune checkpoint inhibitors), and brain metastases. An ad hoc retrospective analysis using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria assessed intracranial activity., Results: 152 patients were evaluable for efficacy (median age: 73.1). Overall, objective response rate (ORR) was 44.7% [95% confidence interval (CI): 36.7-53.0]. Patients aged <75 (n = 84) and ≥75 (n = 68) had ORRs of 48.8% (95% CI: 37.7-60.0) and 39.7% (95% CI: 28.0-52.3), respectively. Treatment-naïve (n = 69) versus previously treated (n = 83) patients showed consistent efficacy [ORR (95% CI): 44.9% (32.9-57.4) vs. 44.6% (33.7-55.9); median duration of response (95% CI): 10.8 (6.9-not estimable) vs. 11.1 (9.5-18.5) months]. Of 15 patients analyzed by RANO-BM (12 received prior radiotherapy), 13 achieved intracranial disease control; 5 of 7 patients with measurable brain metastases had partial intracranial responses. Of 255 patients evaluable for safety, 64 (25.1%) experienced grade ≥3 treatment-related adverse events (TRAE), leading to discontinuation in 27 patients (10.6%). Rates of adverse events (AE) were broadly consistent irrespective of prior therapies., Conclusions: Tepotinib showed meaningful activity across subgroups by age, prior therapies, and brain metastases, with a manageable safety profile and few treatment discontinuations. See related commentary by Rosner and Spira, p. 1055., (©2021 The Authors; Published by the American Association for Cancer Research.)

Objective: Immune checkpoint inhibitors (ICIs) for cancer therapy frequently induce immune-related adverse effects (IRAEs). Therefore, most patients with preexisting autoimmune diseases have been excluded from clinical trials of ICIs. This study was undertaken to evaluate the safety and efficacy of ICIs in patients with preexisting autoimmune disease and cancer., Methods: A retrospective cohort study was conducted from January 2017 to January 2018 via 3 French national networks of experts in oncology and autoimmunity. Adults with preexisting autoimmune disease who were receiving ICIs were assessed for the occurrence of flare of preexisting autoimmune disease, other IRAEs, and cancer response., Results: The study included 112 patients who were followed up for a median of 8 months. The most frequent preexisting autoimmune diseases were psoriasis (n = 31), rheumatoid arthritis (n = 20), and inflammatory bowel disease (n = 14). Twenty-four patients (22%) were receiving immunosuppressive therapy at ICI initiation. Autoimmune disease flare and/or other IRAE(s) occurred in 79 patients (71%), including flare of preexisting autoimmune disease in 53 patients (47%) and/or other IRAE(s) in 47 patients (42%), with a need for immunosuppressive therapy in 48 patients (43%) and permanent discontinuation of ICI in 24 patients (21%). The median progression-free survival was shorter in patients receiving immunosuppressive therapy at ICI initiation (3.8 months versus 12 months; P = 0.006), confirmed by multivariable analysis. The median progression-free survival was shorter in patients who experienced a flare of preexisting autoimmune disease or other IRAE, with a trend toward better survival in the subgroup without immunosuppressant use or ICI discontinuation., Conclusion: Our findings indicate that flares or IRAEs occur frequently but are mostly manageable without ICI discontinuation in patients with a preexisting autoimmune disease. Immunosuppressive therapy at baseline is associated with poorer outcomes., (© 2019, American College of Rheumatology.)

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 end point was PFS under ICI. Secondary end points were best response (RECIST 1.1) and 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%, and 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 with 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 as a single agent., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Although second-line immunotherapy obtained better outcomes than chemotherapy for patients with advanced non-small-cell lung cancers (NSCLCs), it is expensive and only a minority of patients seem to benefit, based on early tumor progression post-immunotherapy. Notable host inflammation, characterized by biomarkers (e.g. neutrophil-to-lymphocyte ratio (NLR])), prolongs overall survival (OS) of surgery-, chemotherapy- and immunotherapy-treated patients. To our knowledge, no previous studies used biomarker evolution to analyze the immunotherapy impact on host inflammation. Immunotherapy mainly exerts its activity by lymphocyte reactivation., Methods: This retrospective study was conducted on patients, selected by their progression status just before their 4th nivolumab injection, and treated at Bordeaux and Limoges University Hospitals. A comparative group of at least 1-year responders was also selected. Clinical parameters and hematological data just before the 1st (baseline) and 4th nivolumab infusions were collected to calculate the NLR change (ΔNLR) between those two infusions. The combined impact of the different known prognostic factors was also analyzed with multivariable analyses., Results: Fifty-nine patients were included. The 29 early progressors had significantly more frequent ΔNLR > 1 (p = 0.0007), OR 18.08 [95% CI 2.96-246.24] with progressive disease as best response to prior treatment line (p = 0.0014). ΔNLR < 1 prolonged OS (HR 0.001 [0.0007-0.18], p = 0.001); as did a partial response to prior line of systemic treatment (HR 0.14 [0.03--0.56], p = 0.005)., Conclusion: Based on selected early progressors given second-line immunotherapy for advanced NSCLC, progression as best response to prior treatment and ΔNLR > 1 characterized the early progressors and shortened OS after starting nivolumab. This phenomenon questions nivolumab utility in patients with a major host neutrophil inflammation., Competing Interests: The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: TE is a paid advisory board member for Bristol-Myers Squibb, Merck-Sharp and Dohme, and Hoffmann-La Roche. RV is a paid expert for Bristol-Myers Squibb and Merck-Sharp and Dohme. He received honoraria from Bristol-Myers Squibb, and Merck-Sharp and Dohme for consultancy and board membership, and received reimbursement for congress registration from Bristol-Myers Squibb and Merck-Sharp and Dohme outside the present study. AV is a paid expert board member for Bristol-Myers Squibb, Merck-Sharp and Dohme, and Hoffmann-La Roche. He received honoraria from Bristol-Myers Squibb, Merck-Sharp and Dohme, Hoffmann-La Roche, Pierre Fabre Oncologie, and AstraZeneca for consultancy and board membership. AV also received reimbursement for congress registration from Pierre Fabre Oncologie and AstraZeneca outside the present study. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Overall survival (OS) with the anaplastic lymphoma kinase (ALK) inhibitor (ALKi) crizotinib in a large population of unselected patients with ALK-positive non-small-cell lung cancer (NSCLC) is not documented. We sought to assess OS with crizotinib in unselected ALK-positive NSCLC patients and whether post-progression systemic treatments affect survival outcomes.ALK-positive NSCLC patients receiving crizotinib in French expanded access programs or as approved drug were enrolled. We collected clinical and survival data, RECIST-defined progressive disease (PD) and post-PD systemic treatment efficacy. We performed multivariable analysis of OS from crizotinib initiation and PD under crizotinib.At time of analysis, 209 (65.7%) of the 318 included patients had died. Median OS with crizotinib was 16.6 months. The line of crizotinib therapy did not impact survival outcomes. Of the 263 patients with PD, 105 received best supportive care, 74 subsequent drugs other than next-generation ALKi and 84 next-generation ALKi. Next-generation ALKi treatment correlated with better survival outcomes in multivariate analysis. These patients had a median post-PD survival of 25.0 months and median OS from metastatic disease diagnosis of 89.6 months.Unselected ALK-positive NSCLC patients achieve good survival outcomes with crizotinib therapy. Next-generation ALKi may provide survival improvement after PD under crizotinib.

Introduction: Approximately 2% of lung adenocarcinomas have BRAF (v-Raf murine sarcoma viral oncogene homolog B) mutations, including V600E and other types. Vemurafenib, dabrafenib, and sorafenib as BRAF inhibitors are currently tested in clinical trials, but access for patients is limited. The aim of this study was to document the clinical course of patients treated outside of clinical trials., Methods: We conducted a retrospective multicenter cohort study in Europe of patients with advanced BRAF-mutant lung cancer treated with known BRAF inhibitors. Data were anonymized and centrally assessed for age, gender, smoking, histology, stage, local molecular diagnostic results, systemic therapies, and survival. Best response was assessed locally by RECIST1.1., Results: We documented 35 patients treated in 17 centers with vemurafenib, dabrafenib, or sorafenib. Median age was 63 years (range 42-85); gender was balanced; 14 (40%) were never smokers; all (100%) had adenocarcinoma; 29 (83%) had V600E; 6 (17%) had other mutations; one of them had a concomitant KRAS mutation. Thirty (86%) patients had chemotherapy in the first line. Overall survival with first-line therapy was 25.3 months for V600E and 11.8 months for non-V600E. Thirty-one patients received one BRAF inhibitor, and four received a second inhibitor. Overall response rate with BRAF therapy was 53%, and disease control rate was 85%. Median progression-free survival with BRAF therapy was 5.0 months, and overall survival was 10.8 months., Conclusions: These results confirm the activity of targeted therapy in patients with BRAF-mutant lung adenocarcinoma. Further trials are warranted to study combination therapies and drug resistance mechanisms.