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.

and PFS (RECIST v1.1; blinded, independent central review) were assessed by the stratified log-rank test in the ITT population. The protocol-specified first interim analysis (IA1) was planned to occur when w255 deaths occurred and w12 months after the last participant was randomized. Nonbinding futility criteria at IA1 were differences in the restricted mean survival time (RMST) between pembroeipi and pembroeplacebo of 0.2 at the maximum observation time and 0.1 at 24 months of follow-up. Results: Between 12-January-2018 and 22-August-2019, 568 participants were randomized to pembroeipi (n¼284; 282 treated) and pembroeplacebo (n¼284; 281 treated). As of 01-September-2020, median (range) study follow-up was 20.6 months (12.4-31.7), treatment was ongoing in 21.3% in the pembroe ipi arm vs 23.8% in the pembroeplacebo arm, and median number of treatment cycles was 10 vs 15. Baseline characteristics were balanced between arms. With 272 deaths, median OS was 21.4 months for pembroeipi vs 21.9 months for pembroeplacebo (HR, 1.08 [95% CI, 0.85-1.37]; P ¼ 0.74). RMST differences were e0.56 at the maximum observation time and e0.52 at 24 months, which met the futility criteria. With 372 events, median PFS was 8.2 months for pembroeipi vs 8.4 months for pembroeplacebo (HR, 1.06 [95% CI, 0.86-1.30]; P ¼ 0.72). ORR was 45.4% in both arms; median DOR was 16.1 months for pembroeipi vs 17.3 months for pembroeplacebo. Treatment-related AEs occurred in 76.2% of pembroeipi recipients vs 68.3% of pembroeplacebo recipients, were of grade 3-5 in 35.1% vs 19.6%, led to death in 2.5% vs 0%, and led to discontinuation of any treatment in 25.2% vs 10.7%. Immune-mediated AEs and infusion reactions occurred in 44.7% of pembroeipi recipients vs 32.4% of pembroe placebo recipients, were grade 3-5 in 20.2% vs 7.8%, led to death in 2.1% vs 0%, and led to discontinuation of any treatment in 14.9% vs 5.3%. Based on the observed efficacy and safety, the external data monitoring committee recommended that the study be stopped due to futility and that participants discontinue ipi/placebo. Conclusion: Adding ipilimumab to pembrolizumab does not improve efficacy and is associated with greater toxicity than pembrolizumab alone as first-line therapy for metastatic NSCLC with PD-L1 TPS 50% and no targetable EGFR or ALK aberrations. These data confirm pembrolizumab monotherapy as a standard-of-care for this population.

Owing to its physical properties, particle therapy (PT), including proton beam therapy (PBT) and carbon ion therapy (CIT), can enhance the therapeutic ratio in radiation therapy. The major factor driving PT implementation is the reduction in exit and integral dose compared to photon plans, which is expected to translate to reduced toxicity and improved quality of life. This study extends the findings from a recent systematic review by the current authors which concentrated on tumour outcomes for PT, to now examine toxicity as a separate focus. Together, these reviews provide a comprehensive collation of the evidence relating to PT outcomes in clinical practice. Three major databases were searched by two independent researchers, and evidence quality was classified according to the National Health and Medical Research Council evidence hierarchy. One hundred and seventy-nine studies were included. Most demonstrated acceptable and favourable toxicity results. Comparative evidence reported reduced morbidities and improvement in quality of life in head and neck, paediatrics, sarcomas, adult central nervous system, gastrointestinal, ocular and prostate cancers compared to photon radiotherapy. This suggestion for reduced morbidity must be counterbalanced by the overall low quality of evidence. A concerted effort in the design of appropriate comparative clinical trials is needed which takes into account integration of PT's pace of technological advancements, including evolving delivery techniques, image guidance availability and sophistication of planning algorithms.