Clinical and molecular characterization of long-term survivors with extensive-stage small cell lung cancer treated with first-line atezolizumab plus carboplatin and etoposide.

Objectives: In the Phase I/III IMpower133 study, first-line atezolizumab plus carboplatin and etoposide (CP/ET) treatment for extensive-stage small cell lung cancer (ES-SCLC) significantly improved overall survival (OS) and progression-free survival versus placebo plus CP/ET. We explored patient and disease characteristics associated with long-term survival in IMpower133, and associations of differential gene expression and SCLC-A (ASCL1-driven), SCLC-N (NEUROD1-driven), SCLC-P (POU2F3-driven), and SCLC-inflamed (SCLC-I) transcriptional subtypes with long-term survival.
Materials and Methods: Patients with previously untreated ES-SCLC were randomized 1:1 to four 21-day cycles of CP/ET with atezolizumab or placebo. Long-term survivors (LTS) were defined as patients who lived ≥ 18 months post randomization. A generalized linear model was used to evaluate the odds of living ≥ 18 months. Differential gene expression was analyzed using RNA-sequencing data in LTS and non-LTS. OS was assessed by T-effector and B-cell gene signature expression. Distribution of SCLC transcriptional subtypes was assessed in LTS and non-LTS.
Results: More LTS were in the atezolizumab arm (34%) than in the placebo arm (20%). The odds ratio for living ≥ 18 months in the atezolizumab arm versus the placebo arm was 2.1 (P < 0.03). Enhanced immune-related signaling was seen in LTS in both arms. Exploratory OS analyses showed atezolizumab treatment benefit versus placebo across T-effector and B-cell gene signature expression subgroups. A higher proportion of LTS than non-LTS in both arms had the SCLC-I subtype; this difference was particularly pronounced in the atezolizumab arm.
Conclusion: These exploratory analyses suggest that long-term survival is more likely with atezolizumab than placebo in ES-SCLC, confirming the treatment benefit of the IMpower133 regimen.
Clinicaltrial: gov Identifier: NCT02763579.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S.V.L. declares grants or contracts from Alkermes, Bayer, Blueprint, Bristol Myers Squibb, Elevation Oncology, Genentech, Lilly, Merck, Merus, Pfizer, Rain Therapeutics, RAPT, Turning Point Therapeutics; consulting fees from Amgen, AstraZeneca, Bayer, BeiGene, Blueprint, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech/Roche, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Lilly, Merck/Merck Sharpe & Dohme, Novartis, Regeneron, Sanofi, Takeda, Turning Point Therapeutics; and participation on a Data Safety Monitoring or Advisory Board for Candel Therapeutics. T.S.K.M. declares consulting and advisory personal fees from AbbVie, Inc., ACEA Pharma, Alpha Biopharma Co. Ltd., Amgen, Amoy Diagnostics Co. Ltd., AstraZeneca, BeiGene, Boehringer-Ingelheim, Bristol Myers Squibb, Blueprint Medicines Corporation, CStone Pharmaceuticals, Daiichi Sankyo, Eisai, Fishawack Facilitate Ltd., geneDecode (uncompensated), Gritstone Oncology Inc., Guardant Health, Hengrui Therapeutics, Ignyta Inc., IQVIA, Incyte Corporation, Janssen, Lilly, Loxo-Oncology, Lunit USA, Inc., Merck Serono, Merck Sharp & Dohme, Mirati Therapeutics Inc., Novartis, OrigiMed, Pfizer, Inc., Puma Biotechnology Inc., Roche, Sanofi-Aventis R&D, Takeda, Yuhan Corporation, SFJ Pharmaceuticals, Curio Science, Inivata, Berry Oncology, Qiming Development (HK) Ltd., Gilead Sciences, Inc., Vertex Pharmaceuticals, and Covidien LP; lecture personal fees from ACEA Pharmaceuticals, Alpha Biopharma Co. Ltd., Amgen, Amoy Diagnostics Co. Ltd., AstraZeneca, BeiGene, Boehringer-Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Fishawack Facilitate Ltd., geneDecode, (uncompensated), InMed Medical Communication, Janssen, Lilly, Lunit USA, Inc., MD Health (Brazil), Medscape/WebMD, Merck Serono, Merck Sharpe & Dohme, Novartis, OrigiMed, PeerVoice, Physicians’ Education Resource, P. Permanyer SL, Pfizer, Inc., PrIME Oncology, Research to Practice, Roche, Sanofi-Aventis R&D, Takeda, Touch Medical Media, Daz Group, Lucence Health Inc., Merck Pharmaceuticals HK Ltd., Shanghai BeBirds Translation & Consulting Co. Ltd., Liangyihui Network Technology Co. Ltd., and Taiho; grants from AstraZeneca, Bristol Myers Squibb, Merck Serono, Merck Sharpe & Dohme, Novartis, Pfizer, Inc., Roche, Takeda, Clovis Oncology, SFJ Pharmaceuticals, XCovery, and G1 Therapeutics Inc.; personal fees for supporting an advisory board for Inivata, Berry Therapeutics Inc., and G1 Therapeutics Inc.; shareholding for Aurora, Sanomics Ltd., Hutchison ChiMed; and a role on the Board of Directors for Lunit USA, Inc., AstraZeneca PLC, Hutchison ChiMed, Sanomics Ltd., Aurora. B.Y.N declares employment by Genentech and stockholding in Roche. A.S.M declares grants or contracts from NIH/NCI, Verily, Novartis, Department of Defense, and Mark Foundation; payment or honoraria to institution for lecture, presentations, speakers bureaus, manuscript writing or education events from AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Genentech; support for attending meetings and/or travel from Shanghai Roche Pharmaceuticals; patents planned, issues, or pending for patents submitted unrelated to this work; and other financial or non-financial interests from non-remunerated director of the Mesothelioma Applied Research Foundation. R. De Boer declares payment of honoraria from Novartis, AstraZeneca, and Gilead; and support for attending meetings and/or travel from Amgen, Novartis, and Roche. S.S. declares payment or honoraria for lectures, presentation, speakers bureaus, manuscript writing, or educations events from Chugai Pharma, AstraZeneca, Ono Pharmaceutical, Bristol Myers Squibb, Merck Sharpe & Dohme, Nippon Boehringer-Ingelheim, Pfizer, Taiho Pharmaceutical, Eli Lilly, and Company, Novartis, Kyowa Kirin, Yakult Honsha, and Towa Pharmaceutical. R. Dziadziuszko declares consulting fees from Roche, Boehringer-Ingelheim, AstraZeneca, Takeda, Pfizer, Foundation Medicine, Novartis, and Karyopharm; and payment or honoraria from Roche, Novartis, AstraZeneca, and Pfizer. A.S. declares payment or honoraria from AstraZeneca, Bristol Myers Squibb, Roche, Merck Sharpe & Dohme, Novartis, and Pfizer; support for attending meetings and/or travel from Bristol Myers Squibb, Roche, Boehringer-Ingelheim, and AstraZeneca; and participation on data safety monitoring or advisory boards for Bristol Myers Squibb, Roche, Takeda, AstraZeneca, BIOCAD, and Boehringer-Ingelheim. M.J.H declares payment or honoraria from Boehringer-Ingelheim, AstraZeneca, Takeda, Pfizer, Merck Sharpe & Dohme, and Roche; and participation on data safety monitoring or advisory boards for Boehringer-Ingelheim, AstraZeneca, Takeda, Pfizer, Merck Sharpe & Dohme, and Roche. M.C.G. declares grants from AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Merck Serono, Merck Sharpe & Dohme, Novartis, Pfizer, Roche, Amgen, GSK, Sanofi; consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer-Ingelheim, Janssen, Lilly, Yuhan, Merck Serono, Merck Sharpe & Dohme, Novartis, Pfizer, Roche, Amgen, Libbs, and Sanofi; payment of honoraria from Boehringer-Ingelheim, Pfizer, Bayer, Roche, Merck Sharpe & Dohme, Bristol Myers Squibb, AstraZeneca, Novartis, Merck Serono, Janssen, and Amgen; support for attending meetings and/or travel from Boehringer-Ingelheim, Pfizer, Bayer, Roche, Merck Sharpe & Dohme, Bristol Myers Squibb, AstraZeneca, Novartis, and Merck Serono; participation on data safety monitoring or advisory boards for TEVA, Boehringer-Ingelheim, Bayer, Pfizer, Roche, Merck Sharpe & Dohme, Bristol Myers Squibb, AstraZeneca, Yuhan, Janssen, Merck Serono, Novartis, Amgen; and payment of honoraria for promotional activities from Boehringer-Ingelheim, Pfizer, Roche, Merck Sharpe & Dohme, Bristol Myers Squibb, AstraZeneca, Novartis, TEVA, Amgen, and Janssen. C.M.G. declares research grants/funding to self from AstraZeneca; advisory/consultancy to AstraZeneca, Kisoji Biotechnology, Jazz Pharmaceuticals, and Bristol Myers Squibb; and speaker bureau/expert testimony for AstraZeneca and BeiGene. J.V.H declares advisory/consultancy for Bristol Myers Squibb, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems Pneuma Respiratory, Kairos Venture Investments, Roche, Leads Biolabs, AstraZeneca, Boehringer-Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Guardant Health, Foundation Medicine, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum, EMD Serono, Sanofi, Takeda, and Mirati Therapeutics; research support to AstraZeneca, GlaxoSmithKline, and Spectrum; and royalties/licensing fees from Spectrum. L.A.B. declares an advisory role/consultancy for AstraZeneca, AbbVie, Bristol Myers Squibb, and Merck; and research funding from AstraZeneca and AbbVie. S.L. declares employment by Genentech and stockholding in Roche. A.C. declares employment by Roche and stockholding in Roche. S.M. declares employment by Roche and stockholding in Roche. L.A. declares employment by Roche and stockholding in Roche. D.S.S. declares employment by Genentech and stockholding in Roche. M.R. declares consulting fees from Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Lilly, Merck, Merck Sharpe & Dohme, Mirati, Novartis, Pfizer, Sanofi, and Roche; payment of honoraria from Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Lilly, Merck, Merck Sharpe & Dohme, Mirati, Novartis, Pfizer, Sanofi, and Roche; support for attending meetings and/or travel from Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Lilly, Merck, Merck Sharpe & Dohme, Mirati, Novartis, Pfizer, Sanofi, and Roche; and participation on data safety monitoring or advisory boards for DSMB Sanofi. G.L. and M.K. declare no conflicts of interest.
(Copyright © 2023. Published by Elsevier B.V.)