Background: Tumour mutational burden (TMB) has been retrospectively correlated with response to immune checkpoint blockade. We prospectively explored the association of high tissue TMB (tTMB-high) with outcomes in ten tumour-type-specific cohorts from the phase 2 KEYNOTE-158 study, which assessed the anti-PD-1 monoclonal antibody pembrolizumab in patients with selected, previously treated, advanced solid tumours. Methods: In the multi-cohort, open-label, non-randomised, phase 2 KEYNOTE-158 study, patients were enrolled from 81 academic facilities and community-based institutions across 21 countries in Africa, the Americas, Asia, and Europe. Eligible patients were aged 18 years or older, had a histologically or cytologically confirmed advanced (ie, unresectable or metastatic, or both) incurable solid tumour (eligible tumour types were anal, biliary, cervical, endometrial, mesothelioma, neuroendocrine, salivary, small-cell lung, thyroid, and vulvar), progression on or intolerance to one or more lines of standard therapy, had measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) assessed by independent central radiological review, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, adequate organ function, and a tumour sample for biomarker analysis. Participants were given pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. Tissue TMB (tTMB) was assessed in formalin-fixed paraffin-embedded tumour samples using the FoundationOne CDx assay (Foundation Medicine, Cambridge, MA, USA). The prespecified definition of tTMB-high status was at least 10 mutations per megabase. The primary endpoint was the proportion of patients with an objective response (complete or partial response) as per Response Evaluation Criteria in Solid Tumours (version 1.1) by independent central review. This prespecified analysis assessed the association between antitumour activity and tTMB in treated patients with evaluable tTMB data. Efficacy was assessed in all participants who received at least one dose of pembrolizumab, had evaluable tTMB data, and were enrolled at least 26 weeks before data cutoff (June 27, 2019), and safety was assessed in all participants who received at least one dose of pembrolizumab and had tTMB-high status. KEYNOTE-158 is registered at ClinicalTrials.gov, NCT02628067, and is ongoing. Findings: Between Jan 15, 2016, and June 25, 2019, 1073 patients were enrolled. 1066 participants were treated as of data cutoff (June 27, 2019), of whom 805 (76%) were evaluable for TMB, and 105 (13%) of 805 had tTMB-high status and were assessed for safety. 1050 (98%) of 1066 patients enrolled by at least 26 weeks before data cutoff, of whom 790 (75%) were evaluable for TMB and included in efficacy analyses. 102 (13%) of these 790 patients had tTMB-high status (≥10 mutations per megabase), and 688 (87%) patients had non-tTMB-high status (<10 mutations per megabase). Median study follow-up was 37·1 months (IQR 35·0–38·3). Objective responses were observed in 30 (29%; 95% CI 21–39) of 102 patients in the tTMB-high group and 43 (6%; 5–8) of 688 in the non-tTMB-high group. 11 (10%) of 105 patients had treatment-related serious adverse events. 16 (15%) participants had a grade 3–5 treatment-related adverse event, of which colitis was the only such adverse event that occurred in more than one patient (n=2). One patient had fatal pneumonia that was assessed by the investigator to be treatment related. Interpretation: tTMB-high status identifies a subgroup of patients who could have a robust tumour response to pembrolizumab monotherapy. tTMB could be a novel and useful predictive biomarker for response to pembrolizumab monotherapy in patients with previously treated recurrent or metastatic advanced solid tumours. Funding: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.
Bibliographical noteFunding Information:
AM reports research funding to their institution during the conduct of this study from Merck Sharp & Dohme (MSD); research grants to their institution for other clinical trials or pre-clinical studies from MSD, Bristol-Myers Squibb, AstraZeneca, Roche/Genentech, Pfizer, and Sanofi; a research grant from MSD Avenir Foundation (France); honoraria for serving as a scientific advisory board member for MSD, AstraZeneca, Roche/Genentech, and Pfizer; honoraria for serving as a symposium scientific committee member or speaker for Bristol-Myers Squibb and Roche/Genentech; travel expenses from MSD, Bristol-Myers Squibb, AstraZeneca, and Roche/Genentech; additional research funding or study drug supply from MSD, Bristol-Myers Squibb, AstraZeneca, and Roche/Genentech; and consulting fees from Sanofi. MF reports personal fees as a speaker or consultant for Amgen, Array BioPharma, Guardant Health, Pfizer, and Bayer. JL reports research grants from Roche/Genentech, Basilea, and Genmab, and personal fees from Basilea and Genmab. MS reports research grants from Loxo Oncology and Eisai, and personal fees for serving as an advisory board member for Loxo Oncology, Eisai, and Novartis. RS-F reports serving as an advisory board member for MSD, Clovis Oncology, and VBL Therapeutics, and receiving honoraria as a speaker for MSD, Bristol-Myers Squibb, Roche, Novartis, AstraZeneca, Neopharm, and Medison. KNa reports research grants from AstraZeneca KK, Astellas, MSD KK, Ono Pharmaceutical, Nippon Boehringer Ingelheim, Novartis Pharma KK, Pfizer Japan, Bristol-Myers Squibb, Eli Lilly Japan KK, Chugai Pharmaceutical, Daiichi Sankyo, Merck Serono/Merck Biopharma, Takeda, Taiho Pharma, SymBio Pharmaceuticals, AbbVie, inVentiv Health Japan, ICON Japan KK, Gritstone Oncology, Parexel, Kissei, EPS Corporation, Syneos Health, Pfizer R&D Japan GK, A2 Healthcare Corporation, Quintiles/IQVIA Services JAPAN KK, EP-CRSU, Linical, Eisai, CMIC Shift Zero KK, Kyowa Hakko Kirin, Bayer Yakuhin, EPS International, and Otsuka Pharmaceutical; personal fees from AstraZeneca KK, Astellas, MSD KK, Ono Pharmaceutical, Nippon Boehringer Ingelheim, Novartis Pharma KK, Pfizer Japan, Bristol-Myers Squibb, Eli Lilly Japan KK, Chugai Pharmaceutical, Daiichi Sankyo, Merck Serono/Merck Biopharma, Clinical Trial, MEDICUS SHUPPAN Publishers, Care Net, Reno Medical KK, KYORIN Pharmaceutical, Medical Review, Roche Diagnostics KK, Bayer Yakuhin, Medical Mobile Communications, 3H Clinical Trial, Nichi-Iko Pharmaceutical, Takeda, Taiho Pharma, SymBio Pharmaceuticals, Nanzando, YODOSHA, Nikkei Business Publications, Thermo Fisher Scientific KK, Yomiuri Telecasting, Nippon Kayaku, and AbbVie; and serving as a consultant and advisor for Ono Pharmaceutical, Pfizer Japan, Eli Lilly Japan KK, KYORIN Pharmaceutical, and Takeda. HCC reports research grants from Eli Lilly, GSK, MSD, Merck-Serono, Bristol-Myers Squibb/Ono Pharmaceutical, and Taiho Pharma; personal fees and serving as a consultant for Eli Lilly, MSD, Merck-Serono, Bristol-Myers Squibb/Ono Pharmaceutical, Amgen, BeiGene, Celltrion, Harbin Gloria, Zymeworks, and Quintiles; and non-financial support from Eli Lilly, GSK, MSD, Merck-Serono, Bristol-Myers Squibb/Ono Pharmaceutical, Taiho Pharma, Beigene, Amgen, and Incyte. HLK reports research funding to institution from Aduro Biotech, AstraZeneca, Bayer, Bristol-Myers Squibb, Deciphera, GSK, Eli Lilly, Merck, MedImmune, Polaris Pharmaceuticals, Verastem Oncology, and Blueprint Medicines; personal fees from Inventiva, Aldeyra Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, ERYTECH, Five Prime Therapeutics, Ipsen, Kyowa Kirin, MedImmune, Merck, Paredox Therapeutics, and Deciphera; and non-financial support from Inventiva, AstraZeneca, Boehringer Ingelheim, Merck, and Paredox Therapeutics. JAL-M reports research funding during the conduct of this study from MSD; and research funding from Bristol-Myers Squibb, Merck-Serono, Pfizer, Eli Lilly, Pharma Mar, Roche, and Novartis; personal fees from Bristol-Myers Squibb, Pfizer, Bayer, Eli Lilly, Pharma Mar, Roche, Novartis, and Pierre Fabre; and non-financial support from Bristol-Myers Squibb, Pharma Mar, and Roche. WHM Jr reports personal fees for serving as a consultant for Bristol-Myers Squibb, Merck, Roche, Novartis, Amgen, and GSK. AI reports research grants from MSD, Bristol-Myers Squibb, Bayer, AstraZeneca, Roche, Ipsen, and Pharma Mar; and personal fees from Bayer, SpringWorks Therapeutics, and Roche. SK reports personal fees during the conduct of this study from MSD, and personal fees paid to their institution from Roche, AstraZeneca, Pfizer, Boehringer Ingelheim, Bristol-Myers Squibb, and Takeda. SAP-P reports research support to their institution from AbbVie, Alkermes, Aminex Therapeutics, Amphivena Therapeutics, BioMarin, Boehringer Ingelheim, Bristol-Myers Squibb, Cerulean Pharma, Chugai Pharmaceutical, Curis, Daichi Sanko, Eli Lilly, Five Prime Therapeutics, Genmab A/S, GSK, Helix BioPharma, Incyte, Jacobio Pharmaceuticals, Medimmune, Medivation, Merck Sharp & Dohme (a subsidiary of Merck & Co, Kenilworth, NJ, USA), NewLink Genetics Corporation/Blue Link Pharmaceuticals, Novartis, Pieris Pharmaceuticals, Pfizer, Principia Biopharma, Puma Biotechnology, Rapt Therapeutics, Seattle Genetics, Taiho Oncology, Tesaro, TransThera Biosciences, and XuanZhu Biopharmaceutical; and a National Cancer Institute, National Institutes of Health Cancer Center Support Grant, Shared Resources Grant (#P30Ca016672) to their institution. RRM reports research funding during the conduct of this study from Merck; and research funding outside of this study from Merck. DAF is an employee of Foundation Medicine, and has a pending patent for methods and systems for evaluating tumour mutational burden (WO/2017/151524). DA-G, LX, FJ, and KNo are employees of Merck Sharp & Dohme (a subsidiary of Merck & Co., Kenilworth, NJ, USA). Y-JB reports research grants paid to their institution from AstraZeneca, Novartis, Genentech/Roche, MSD, Merck Serono, Bayer, Bristol-Myers Squibb, GSK, Pfizer, Eli Lilly, Boehringer Ingelheim, MacroGenics, Boston Biomedical, Five Prime Therapeutics, Curis, Taiho Pharma, Takeda, Ono Pharmaceutical, Daiichi Sankyo, Astellas Pharma, BeiGene, Green Cross, CKD Pharmaceuticals, and Genexine; and serving in a consulting or advisory role for AstraZeneca, Novartis, Genentech/Roche, MSD, Merck Serono, Bayer, Bristol-Myers Squibb, Eli Lilly, Taiho Pharma, Daiichi Sankyo, Astellas Pharma, BeiGene, Green Cross, Samyang Biopharmaceuticals, Hanmi Pharmaceutical, and Genexine. J-PD declares no competing interests.
Funding for this research was provided by Merck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA). We thank the patients and their families and caregivers for participating in this study, along with all investigators and site personnel, and Foundation Medicine for contributions to validation of the tumour mutational burden cutpoint. Additional study support was provided by Eric H Rubin, Jared Lunceford, Razvan Cristescu, Alex Snyder, Nageatte Ibrahim, Scot W Ebbinghaus, Alissa Moore, Jennifer Smedberg, Tammy Winser, Sara Sadowski, and Melanie Leiby of Merck & Co. Medical writing assistance was provided by Sheri Arndt of ICON (North Wales, PA, USA), funded by Merck Sharp & Dohme.
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