Efficacy and safety of pembrolizumab in patients with advanced mesothelioma in the open-label, single-arm, phase 2 KEYNOTE-158 study
- PMID: 33836153
- DOI: 10.1016/S2213-2600(20)30515-4
Efficacy and safety of pembrolizumab in patients with advanced mesothelioma in the open-label, single-arm, phase 2 KEYNOTE-158 study
Abstract
Background: Malignant pleural mesothelioma (MPM) has few treatment options. Pembrolizumab showed preliminary clinical benefit in programmed death ligand 1 (PD-L1)-positive MPM. We evaluated the efficacy and safety of pembrolizumab monotherapy in patients with previously treated MPM irrespective of PD-L1 status in the KEYNOTE-158 study.
Methods: The ongoing open-label, multicohort, single-arm, phase 2 KEYNOTE-158 study enrolled eligible adults (≥18 years) with MPM who had progression on or intolerance to standard therapy, Eastern Cooperative Oncology Group performance status 0-1, and biomarker-evaluable tumour samples. Individuals were enrolled from 35 academic facilities and community-based institutions across 14 countries in Australia, North America, Europe, and Asia. Participants received pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. The primary efficacy endpoint was objective response per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, based on radiological imaging every 9 weeks for the first year of the study and every 12 weeks thereafter and assessed by independent central review. Efficacy and safety were analysed in all patients who received at least one dose of pembrolizumab. This trial is registered with ClinicalTrials.gov, NCT02628067.
Findings: Patients were enrolled in the MPM cohort between Feb 9, 2016, and Aug 16, 2016. As of June 27, 2019, 118 patients had been enrolled and received at least one dose of pembrolizumab. Ten (8% [95% CI 4-15]) patients had an objective response. Median duration of objective response was 14·3 months (range 4·0 to 33·9+), and 60% of objective responses were ongoing at 12 months. Objective responses were observed in six (8%) of 77 patients with PD-L1-positive MPM (median response duration 17·7 months [range 5·8 to 33·9+]) and four (13%) of 31 patients with PD-L1-negative MPM (10·2 months [4·0-16·6]). Median overall survival was 10·0 months (95% CI 7·6-13·4) and median progression-free survival was 2·1 months (2·1-3·9). Treatment-related adverse events occurred in 82 (69%) of 118 patients and serious adverse events that were considered to be treatment-related occurred in 14 (12%) of 118 patients. 19 (16%) patients had grade 3-4 treatment-related events, and most common of these were colitis (three patients), hyponatraemia (three), and pneumonitis (two). One patient died from treatment-related apnoea. By the end of the trial, 113 (96%) patients had discontinued pembrolizumab and progressive disease was the most common reason for discontinuation.
Interpretation: Pembrolizumab showed durable antitumour activity and manageable toxicity in patients with advanced MPM, regardless of PD-L1 status. Our data support the programmed death 1 (PD-1) and PD-L1 pathway as a potential therapeutic target in some patients with previously treated mesothelioma but biomarkers that can effectively identify such patients are yet to be elucidated.
Funding: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.
Copyright © 2021 Elsevier Ltd. All rights reserved.
Conflict of interest statement
Declaration of interests TAY reports research support (to institution) from Artios, AstraZeneca, Bayer, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech, ImmuneSensor, Ipsen, Jounce, Karyopharm, Kyowa, Merck, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, and Vertex Pharmaceuticals, and consultancy fees from Almac, Aduro, AstraZeneca, Atrin, Axiom, Bayer, Bristol-Myers Squibb, Calithera, Clovis, Cybrexa, EMD Serono, F-Star, Guidepoint, Ignyta, I-Mab, Janssen, Merck, Pfizer, Repare, Roche, Rubius, Schrodinger, Seattle Genetics, Varian and Zai Labs outside of the submitted work. KNa reports grants and personal fees from AstraZeneca KK, Astellas Pharma, 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, and consulting and advisor role for Ono Pharmaceutical, Pfizer Japan, and Eli Lilly Japan KK during the conduct of the study. KNa also reports grants from Takeda Pharmaceutical, Taiho Pharmaceutical, SymBio Pharmaceuticals, AbbVie, inVentiv Health Japan, ICON Japan KK, Gritstone Oncology, Parexel International, Kissei Pharmaceutical, EPS, Syneos Health, Pfizer R&D Japan GK, A2 Healthcare, Quintiles/IQVIA Services JAPAN KK, EP-CRSU, Linical, Eisai, CMIC Shift Zero KK, Kyowa Hakko Kirin, Bayer Yakuhin, EPS International, Otsuka Pharmaceutical, personal fees from Clinical Trial, Medicus Shuppan, Publishers Co, Care Net, Medical KK, Kyorin Pharmaceutical, Medical Review, Roche Diagnostics KK, Bayer Yakuhin, Medical Mobile Communications, 3H Clinical Trial, Nichi-Iko Pharmaceutical, Takeda Pharmaceutical, Taiho Pharmaceutical, SymBio Pharmaceuticals, Nanzando, Yodosha, Nikkei Business Publications, Thermo Fisher Scientific KK, Yomiuri Telecasting Corporation, Nippon Kayaku, AbbVie, and consulting and advisor role for Kyorin Pharmaceutical and Takeda Pharmaceutical outside the submitted work. NF reports grants from MSD during the conduct of the study and grants from ONO, Bristol-Myers Squibb, Kyorin, and Kissei, and personal fees from ONO, Bristol-Myers Squibb, Kyorin, Chugai, Daiichi Sankyo, Hisamitsu outside the submitted work. KK, TKG, and BG have nothing to disclose. LC reports consultant and advisor role for Merck Sharp Dohme during the conduct of the study, and consultant role for Bristol-Myers Squibb outside the submitted work. RSF reports honoraria for serving as a speaker for MSD, BMS, AstraZeneca, Novartis, and Roche, personal fees for acting on the advisory boards for MSD, Clovis Oncology, and VBL Therapeutics outside the submitted work. SK reports receiving personal fees paid to institution from MSD during the conduct of the study, personal fees paid to institution from BMS, Pfizer, Roche, Boerhinger, and AstraZeneca, and grants paid to institution from AstraZeneca outside the submitted work. IM reports receiving an ESMO grant sponsored by Roche, and fees from MSD for a speaker bureau outside the submitted work. DP reports personal fees for consulting, advisory role or lectures for AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche, and Samsung outside the submitted work. Clinical trials research (as Principal investigator or co-investigator): AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmune, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo during the conduct of the study. AC and KN are employees of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA and stockholders of Merck & Co Inc, Kenilworth, NJ, USA. FJ is an employee of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co Inc, Kenilworth, NJ, USA. HLK reports personal fees from Aldeyra Therapeutics, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Kyowa, Merck, Paredox Therapeutics, Deciphera, Inhibrx, and Inventiva, non-financial support from AstraZeneca, Boehringer-Ingelheim, Merck, Paredox Therapeutics, and Inventiva, funds were given to support clinical trials at her institution from Aduro, AstraZeneca, Bayer, Bristol-Myers Squibb, Deciphera, Glaxo Smith Kline, Lilly, Merck, Polaris, Verastem, Blueprint, Tesaro, and Inhibrx.
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