Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial

Background No phase 3 trial has yet shown improved survival for patients with pleural or peritoneal malignant mesothelioma who have progressed following platinum-based chemotherapy. The aim of this study was to assess the efficacy and safety of nivolumab, an anti-PD-1 antibody, in these patients. Methods This was a multicentre, placebo-controlled, double-blind, parallel group, randomised, phase 3 trial done in 24 hospitals in the UK. Adult patients (aged >= 18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1, with histologically confirmed pleural or peritoneal mesothelioma, who had received previous first-line platinum based chemotherapy and had radiological evidence of disease progression, were randomly assigned (2:1) to receive nivolumab at a flat dose of 240 mg every 2 weeks over 30 min intravenously or placebo until disease progression or a maximum of 12 months. The randomisation sequence was generated within an interactive web response system (Alea); patients were stratified according to epithelioid versus non-epithelioid histology and were assigned in random block sizes of 3 and 6. Participants and treating clinicians were masked to group allocation. The co-primary endpoints were investigator-assessed progression-free survival and overall survival, analysed according to the treatment policy estimand (an equivalent of the intention-to-treat principle). All patients who were randomly assigned were included in the safety population, reported according to group allocation. This trial is registered with ClinicalTrials.gov, NCT03063450. Findings Between May 10, 2017, and March 30, 2020, 332 patients were recruited, of whom 221 (67%) were randomly assigned to the nivolumab group and 111 (33%) were assigned to the placebo group). Median follow-up was 11middot6 months (IQR 7middot2-16middot8). Median progression-free survival was 3middot0 months (95% CI 2middot8-4middot1) in the nivolumab group versus 1middot8 months (1middot4-2middot6) in the placebo group (adjusted hazard ratio [HR] 0middot67 [95% CI 0middot53-0middot85; p=0middot0012). Median overall survival was 10middot2 months (95% CI 8middot5-12middot1) in the nivolumab group versus 6middot9 months (5middot0-8middot0) in the placebo group (adjusted HR 0middot69 [95% CI 0middot52-0middot91]; p=0middot0090). The most frequently reported grade 3 or worse treatment-related adverse events were diarrhoea (six [3%] of 221 in the nivolumab group vs two [2%] of 111 in the placebo group) and infusion-related reaction (six [3%] vs none). Serious adverse events occurred in 90 (41%) patients in the nivolumab group and 49 (44%) patients in the placebo group. There were no treatment related deaths in either group. Interpretation Nivolumab represents a treatment that might be beneficial to patients with malignant mesothelioma who have progressed on first-line therapy. Funding Stand up to Cancer-Cancer Research UK and Bristol Myers Squibb. Copyright (c) 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

Automated summary

The study evaluated the efficacy and safety of nivolumab in patients with pleural or peritoneal malignant mesothelioma who had progressed following platinum-based chemotherapy. Nivolumab showed improved progression-free survival and overall survival compared to placebo in these patients, with manageable treatment-related adverse events. The results suggest that nivolumab might be a beneficial treatment for patients with malignant mesothelioma who have progressed on first-line therapy.