Pembrolizumab With or Without Maintenance Olaparib for Metastatic Squamous NSCLC That Responded to First-Line Pembrolizumab Plus Chemotherapy.

Introduction: Poly (adenosine diphosphate-ribose) polymerase inhibitors can up-regulate programmed cell death-ligand 1 expression and promote immune-mediated responses and may improve efficacy of first-line anti‒programmed cell death protein 1‒based therapies in patients with metastatic squamous NSCLC.
Methods: In this randomized, double-blind, phase 3 trial (NCT03976362), adults with previously untreated stage IV squamous NSCLC received four cycles of induction therapy (pembrolizumab 200 mg every 3 weeks plus carboplatin and paclitaxel or nab-paclitaxel). Patients with disease control were randomized to 31 cycles of pembrolizumab 200 mg every 3 weeks plus olaparib 300 mg orally twice daily or placebo. Dual primary end points were progression-free survival (PFS) and overall survival (OS). PFS was tested at interim analysis 2 (the final PFS analysis); OS was tested at final analysis.
Results: A total of 851 patients received induction treatment; 296 were randomized to pembrolizumab plus olaparib and 295 to pembrolizumab plus placebo. At interim analysis 2, with median follow-up of 27.1 months, median (95% confidence interval [CI]) PFS was 8.3 (6.7‒9.7) months in the pembrolizumab plus olaparib group and 5.4 (4.1‒5.6) months in the pembrolizumab plus placebo group (hazard ratio = 0.77, 95% CI: 0.63‒0.93, p = 0.0040 [not significant at a one-sided superiority boundary of p = 0.003]). At final analysis, with median follow-up of 33.4 months, median (95% CI) OS was 19.1 (15.9‒22.2) and 18.6 (16.0‒21.6) months, respectively (hazard ratio = 1.01, 95% CI: 0.83‒1.24, p = 0.5481). Treatment-related adverse events occurred in 76.5% and 65.1% of patients, respectively.
Conclusions: Adding olaparib to pembrolizumab as maintenance therapy for metastatic squamous NSCLC did not significantly improve PFS versus pembrolizumab plus placebo; neither PFS nor OS met the prespecified statistical significance boundary. No new safety signals were identified.
Trial Registration: ClinicalTrials.gov, NCT03976362.
Competing Interests: Disclosure Dr. Hochmair reports having financial interests, personal, other, speaker’s bureau, and consulting or advisory role from Takeda, Roche, Eli Lilly, AstraZeneca/Daiichi Sankyo, and Merck Sharp & Dohme. Dr. Schenker reports receiving research grants from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Clovis, Daiichi Sankyo, EISAI, Eli Lilly, Five Prime, Gilead, GlaxoSmithKline, Mylan, Novartis, Pfizer, PharmaMar, Samsung, and Takeda. Dr. Cobo Dols reports receiving honoraria from Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Takeda, Kyowa, Pierre Fabre, Novocure, Sanofi, and Jansen; serving on the data safety monitoring or advisory board for Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Takeda, Pfizer, Kyowa, Sanofi, and Jansen. Dr. Kim reports receiving clinical trial funding to institution from AbbVie, Amgen, AstraZeneca/Medimmune, Bayer, Black Diamond Therapeutics, Blueprint Medicines, Boryung, Bristol Myers Squibb, Celgene, Dizal, EMD Serono Inc., Enliven Therapeutics, F. Hoffmann-La Roche Ltd./Genentech, Inc., Fore Biotherapeutics, Hanmi, Genmab, Janssen, Merck & Co. Inc., Novartis, Pfizer, RAPT Therapeutics, Regeneron, Sanofi, Takeda, Taiho, and Yuhan; serving as a consultant to AstraZeneca, Daiichi Sankyo, HK inno.N, IMBDx. Inc., Janssen, Regeneron, Roche/Genentech, Samsung Bioepis, and Takeda; and serving on the data safety monitoring or advisory board for AstraZeneca, Janssen, Regeneron, Roche/Genentech, Samsung Bioepis, and Takeda. Dr. Ozyilkan reports serving as a consultant to Roche and Merck Sharp & Dohme; receiving honoraria from Merck Sharp & Dohme and Sanofi; receiving support for attending meetings from Pfizer, Merck Sharp & Dohme, AstraZeneca, and Roche; and serving on the data safety monitoring or advisory board for Merck Sharp & Dohme. Dr. Leonova reports receiving research grants from Bio-Thera Solutions, Ltd., Roche, Shanghai Henlius Biotech, Incyte Corporation, IPSEN BIOSCIENCE, Merck Serono, and Janssen Research & Development. Dr. Kato reports receiving research grants to institution from AbbVie, Amgen, Arrivent, AstraZeneca, Bayer, BeiGene, BluePrint, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Gilead, GlaxoSmithKline, Haihe, Janssen, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, and Takeda; receiving honoraria from Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Merck KGaA, Merck Sharp & Dohme, Novartis, Ono, Pfizer, Taiho, and Takeda; serving on the data safety monitoring or advisory board for AstraZeneca, BeiGene, Chugai, Daiichi Sankyo, Janssen, Merck KGaA, Merck Sharp & Dohme, Novartis, and Pfizer; and receiving other support from Eli Lilly (spouse’s employer). Dr. Aggarwal reports being an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; a shareholder of Merck & Co., Inc., Rahway, NJ, USA; and a stockholder of Eli Lilly and Company. Dr. De Angelis reports receiving honoraria for lectures, presentations, and advisory boards from Merck, Pfizer, Bristol Myers Squibb, AstraZeneca, and GlaxoSmithKline. Dr. Gray reports receiving research grants from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, EMD Serono – Merck KGaA, Genentech, Gilead Sciences, G1 Therapeutics, Ludwig Institute of Cancer Research, Merck & Co., Inc., Novartis, Panbela Therapeutics, Pfizer, and Regeneron; serving as a consultant for: AbbVie, AstraZeneca, Blueprint Medicines, Coherus, Daiichi Sankyo, EMD Serono, Gilead Sciences, Inc., IDEOlogy Health, Janssen Scientific Affairs, LLC, Jazz Pharmaceuticals, Loxo Oncology Inc., Merck & Co., Inc., Novartis, OncoCyte Biotechnology, Regeneron, Spectrum ODAC, Takeda Pharmaceuticals, Triptych Health Partners, and Zai Lab (US) LLC; receiving honoraria from AbbVie, AstraZeneca, Blueprint Medicines, Coherus, Daiichi Sankyo, EMD Serono, Gilead Sciences, Inc., IDEOlogy Health, Janssen Scientific Affairs, LLC, Jazz Pharmaceuticals, Loxo Oncology Inc., Merck & Co., Inc., Novartis, OncoCyte Biotechnology, Regeneron, Spectrum ODAC, Takeda Pharmaceuticals, Triptych Health Partners, and Zai Lab (US) LLC; and having leadership role on a committee or board for ASCO (Board of Directors Member), ASCO (Education Committee Ex-Chair), SWOG (Lung Committee Chair), and IASLC (Board of Directors Member). Dr. Greystoke reports serving as a consultant for Merck Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, Boehringer Ingelheim, Merck, Pfizer, Takeda, Roche, Janssen, and Novartis; receiving honoraria from Merck Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, Boehringer Ingelheim, Merck, Pfizer, Takeda, Roche, Janssen, and Novartis; and receiving support for attending meetings from Takeda and Roche. Mr. Huang reports being an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and a shareholder of Merck & Co., Inc., Rahway, NJ, USA. Dr. Lara-Guerra reports being an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and a shareholder of Merck & Co., Inc., Rahway, NJ, USA. Dr. Nadal reports receiving research grants from Roche, Pfizer, Bristol Myers Squibb, and Merck Serono; serving as a consultant for Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Sanofi, Pfizer, Eli Lilly, Amgen, Daiichi Sankyo, Boehringer Ingelheim, Genmab, AstraZeneca, Takeda, Johnson & Johnson, Pierre Fabre, and Qiagen; receiving honoraria from Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Sanofi, Pfizer, Eli Lilly, Amgen, Janssen, Boehringer Ingelheim, AstraZeneca, Takeda, Sanofi, Janssen, and Qiagen; receiving support for attending meetings from Takeda, Pfizer, Merck Sharp & Dohme, AstraZeneca, and Roche; and serving on the data safety monitoring or advisory board for Apollomics, Roche, Transgene, and Merck Sharp & Dohme. Dr. Rittmeyer reports serving as an advisor to AbbVie, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Gilead, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Pfizer, and Roche. Dr. Zhao reports being an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and a shareholder of Merck & Co., Inc., Rahway, NJ, USA. The remaining authors declare no conflict of interest.
(Copyright © 2024 Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, The Author(s). Published by Elsevier Inc. All rights reserved.)