1665 - A multicentre randomized phase III trial comparing pembrolizumab (P) vs single agent chemotherapy (CT) for advanced pre-treated malignant pleural mesothelioma (MPM) – results from the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial

Background

MPM is an aggressive malignancy of increasing prevalence and poor prognosis. At relapse after platinum-based (pb) CT, single agent CT is commonly used and single arm trials of immune checkpoint inhibitors have demonstrated encouraging activity.

Methods

PROMISE-meso is an open-label 1:1 randomized phase III trial investigating the efficacy of P (200 mg/Q3W) vs institutional choice single agent CT (gemcitabine or vinorelbine) in relapsed MPM patients (pts) failing one previous line of pb CT. Pts were of PS 0-1 and unselected for PD-L1 status. P beyond progression (PD) for clinical benefit and crossover to P at PD on CT were allowed. Primary endpoint was progression-free survival (PFS, RECIST 1.1) by independent radiological review (IR). The trial was designed to detect an increase in median PFS from 3.5 months (ms) to 6ms with P (HR = 0.58, 80% power, 1-sided α = 0.025). 142 pts were needed to observe the required 110 events. Secondary endpoints were overall survival (OS), investigator assessed (IA) PFS, objective response rate (ORR), adverse events (AE), while efficacy by PD-L1 status was exploratory.

Results

Between 09/17 and 08/18, 144 pts were randomized, 73 to P and 71 to CT. At 20/02/19 data lock, 70 pts were on follow-up (median 12ms). Pts were of median age 70 years, 82% males, 77% poor EORTC prognostic score, 50% never smokers, 89% epithelioid histology and 65% (of 102 available) TPS≥1%. ORRs were 22% in P, 6% in CT (p = 0.004). 62 IR PFS events were observed in P vs 56 in CT, median PFS 2.5ms (95%CI 2.1-4.2) vs 3.4ms (2.2-4.3), HR = 1.06 (0.73–1.53), p = 0.76. Median OS was 10.7ms for P vs 11.7ms for CT, HR = 1.05 (0.66-1.67), p = 0.85. 45 CT pts crossed over to P. Accounting for crossover yielded similar OS results. Treatment-related AEs grade ≥3 were experienced by 19% P vs 24% CT pts, one fatal per arm. Most common AEs were fatigue (19%) in P vs nausea (27%) and fatigue (31%) in CT.

Conclusions

This is the first randomized trial evaluating the efficacy of P vs single agent CT in MPM pts progressing after or on previous pb CT. In unselected pts, whilst associated with an improved ORR, P does not improve PFS or OS over single agent CT.

Clinical trial identification

NCT02991482.

Editorial acknowledgement

Legal entity responsible for the study

European Thoracic Oncology Platform (ETOP).

Funding

MSD Merck Sharp & Dohme AG.

Disclosure

S. Popat: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Boehringer Ingelheim; Research grant / Funding (institution): Epizyme; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Research grant / Funding (institution): Clovis Oncology; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Research grant / Funding (institution): Lilly; Honoraria (self), Research grant / Funding (institution): Takeda; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Chugai Pharma; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Sharp & Dohme; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: AbbVie. A. Curioni-Fontecedro: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Merck Sharp and Dohme; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Takeda. R. Shah: Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Lilly. M. O’Brien: Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: BMS; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Pierre fabre; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Teaching role for Roche: Roche. P. Fisher: Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Sharp & Dohme. D. Gilligan: Honoraria (self): Merck Sharp & Dohme. E. Nadal: Advisory / Consultancy: Merck Sharp & Dohme. R. López Castro: Honoraria (self), Travel / Accommodation / Expenses: Takeda; Honoraria (self), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Boehringer Ingelheim; Honoraria (self), Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy: Aristo. R. García Campelo: Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Dohme. S. Peters: Honoraria (self): AbbVie; Honoraria (self): Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Bayer; Honoraria (self): Biocartis; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Clovis; Honoraria (self): Daiichi Sankyo; Honoraria (self): Debiopharm; Honoraria (self): Lilly; Honoraria (self): Roche; Honoraria (self): Foundation Medicine; Honoraria (self): Illumina; Honoraria (self): Janssen; Honoraria (self): Merck Sharp and Dohme; Honoraria (self): Merck Serono; Honoraria (self): Merrimack; Honoraria (self): Novartis; Honoraria (self): Pharma Mar; Honoraria (self): Pfizer; Honoraria (self): Regeneron; Honoraria (self): Sanofi; Honoraria (self): Seattle Genetics ; Honoraria (self): Takeda. R.A. Stahel: Honoraria (self): AbbVie; Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (self): Merck Sharp & Dohme; Honoraria (self), Research grant / Funding (self): Pfizer; Honoraria (self), Research grant / Funding (self): Roche; Honoraria (self): Takeda; Research grant / Funding (self): BMS; Research grant / Funding (self): Genentech. All other authors have declared no conflicts of interest.