A multicentre randomised phase III trial comparing pembrolizumab versus single-agent chemotherapy for advanced pre-treated malignant pleural mesothelioma: the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial.

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy characterised by limited treatment options and a poor prognosis. At relapse after platinum-based chemotherapy, single-agent chemotherapy is commonly used and single-arm trials of immune-checkpoint inhibitors have demonstrated encouraging activity.
Patients and Methods: PROMISE-meso is an open-label 1:1 randomised phase III trial investigating the efficacy of pembrolizumab (200 mg/Q3W) versus institutional choice single-agent chemotherapy (gemcitabine or vinorelbine) in relapsed MPM patients with progression after/on previous platinum-based chemotherapy. Patients were performance status 0-1 and unselected for programmed cell death ligand 1 (PD-L1) status. At progression, patients randomly assigned to receive chemotherapy were allowed to crossover to pembrolizumab. The primary end point was progression-free survival (PFS), assessed by blinded independent central review (BICR). Secondary end points were overall survival (OS), investigator-assessed PFS, objective response rate (ORR), and safety. Efficacy by PD-L1 status was investigated in exploratory analyses.
Results: Between September 2017 and August 2018, 144 patients were randomly allocated (pembrolizumab: 73; chemotherapy: 71). At data cut-off [20 February 2019, median follow-up of 11.8 months (interquartile range: 9.9-14.5)], 118 BICR-PFS events were observed. No difference in BICR-PFS was detected [hazard ratio = 1.06, 95% confidence interval (CI): 0.73-1.53; P = 0.76], and median BICR-PFS (95% CI) for pembrolizumab was 2.5 (2.1-4.2), compared with 3.4 (2.2-4.3) months for chemotherapy. A difference in ORR for pembrolizumab was identified (22%, 95% CI: 13% to 33%), over chemotherapy (6%, 95% CI: 2% to 14%; P = 0.004). Forty-five patients (63%) assigned to chemotherapy received pembrolizumab at progression. With follow-up to 21 August 2019 [17.5 months: (14.8-19.7)], no difference in OS was detected between groups (HR = 1.12, 95% CI: 0.74-1.69; P = 0.59), even after adjusting for crossover. Pembrolizumab safety was consistent with previous observations. Exploratory efficacy analyses by PD-L1 status demonstrated no improvements in ORR/PFS/OS.
Conclusion: This is the first randomised trial evaluating the efficacy of pembrolizumab in MPM patients progressing after/on previous platinum-based chemotherapy. In biologically unselected patients, although associated with an improved ORR, pembrolizumab improves neither PFS nor OS over single-agent chemotherapy.
Competing Interests: Disclosure SP reports personal fees from Bristol-Myers Squibb, personal fees from Roche, personal fees from Takeda, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Merck Sharp & Dohme, personal fees from EMD Serono, personal fees from Guardant Health, personal fees from Abbvie, personal fees from Boehringer Ingelheim, personal fees from OncLive, personal fees from Medscape, personal fees from Incyte, personal fees from Paradox Pharmaceuticals, personal fees from Eli Lilly, outside the submitted work. AC-F reports the receipt of honoraria or consultation fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, F. Hoffmann-La Roche, Merck Sharp & Dohme, and Takeda, and honoraria for talks in a company's organised public event from F. Hoffmann-La Roche and Merck Sharp & Dohme. UD reports consultancy services for Roche Tumour Agnostic Evidence Working Group 2020. RS has attended advisory boards for Merck Sharp & Dohme. MO'B is a co-investigator in the Merck Sharp & Dohme Pearls study (Keynote 091) and has attended advisory boards for Merck Sharp & Dohme. DG received honoraria from Merck Sharp & Dohme for chairing a meeting. EN participated in advisory boards from Bristol-Myers Squibb, Merck Sharpe & Dohme, Lilly, Roche, Pfizer, Takeda, Boehringer Ingelheim, Amgen, and AstraZeneca. WDJ reports honoraria and travel grants from Roche, Merck Sharp & Dohme, Pfizer, Takeda, and Novartis. RLC received honoraria or travel expenses from Takeda, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Novartis, Roche, Merck Serono, Pfizer, had consulting or advisory role from Roche, Boehringer Ingelheim, Aristo and received research funding from Roche, Bristol-Myers Squibb, Boehringer Ingelheim. RGC reports advisory board and speaker invitations from Merck Sharp & Dohme. SP received honoraria from Abbvie, Amgen, AstraZeneca, Bayer, Biocartis, Boehringer-Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp & Dohme, Merck Serono, Merrimack, Novartis, Pharma Mar, Pfizer, Regeneron, Sanofi, Seattle Genetics, and Takeda. RS received grants for ETOP during the conduct of the study, personal fees from: Abbvie, AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Roche, Takeda and grants from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Genentech, Merck Sharp & Dohme, Roche, and Pfizer outside the submitted work. All other authors declare no conflicts of interest.
(Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)