Author: S. Popat, A. Curioni-Fontecedro, U. Dafni, R. Shah, M. O’Brien, A. Pope, P. Fisher, J. Spicer, A. Roy, D. Gilligan, O. Gautschi, E. Nadal, W.D. Janthur, R. López Castro, R. García Campelo, S. Rusakiewicz, I. Letovanec, V. Polydoropoulou, H. Roschitzki-Voser, B. Ruepp, A. Gasca-Ruchti, S. Peters, R. Stahel,
Abstract: Background. Malignant pleural mesothelioma (MPM) is an aggressive malignancy characterized 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 (200mg/Q3W) vs 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 PD-L1 status. At progression, patients randomised to chemotherapy were allowed to crossover to pembrolizumab. The primary endpoint was progression-free survival (PFS), assessed by blinded independent central review (BICR). Secondary endpoints were overall survival (OS), investigator assessed (IA)-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 randomised, (pembrolizumab: 73; chemotherapy: 71). At data cut-off [20/02/2019, median follow-up of 11.8 months (IQR: 9.9-14.5)], 118 BICR-PFS events were observed. No difference in BICR-PFS was detected (HR=1.06, 95%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%-33%), over chemotherapy (6%,95%CI:2%-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 cross-over. 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. Keywords: Malignant pleural mesothelioma; Pembrolizumab; Immune-checkpoint inhibition; Randomized clinical trial
