A randomised phase III study of bevacizumab and carboplatin-pemetrexed chemotherapy with or without atezolizumab, as first-line treatment for advanced pleural mesothelioma: results of the ETOP 13 18 BEAT-meso trial.

Background
The currently approved frontline treatments for diffuse pleural mesothelioma (DPM) are ipilimumab-nivolumab or platinum-pemetrexed. The addition of bevacizumab to chemotherapy improves overall survival (OS). While single-agent immunotherapy or chemotherapy-immunotherapy combinations are superior to chemotherapy monotherapy, there is a potential for synergistic triple combination of chemotherapy, bevacizumab, and immunotherapy.Patients And Methods
BEAT-meso is an international open-label, 1:1 randomised phase III trial, with stratification factors histology and stage aiming to determine the efficacy and safety of adding atezolizumab (1200 mg, Q3W until progression) to bevacizumab (15 mg/kg, Q3W until progression) and standard chemotherapy (4-6 cycles of carboplatin AUC5 with pemetrexed 500 mg/m2, Q3W; ABC versus BC) as first-line treatment for advanced DPM. The primary endpoint is OS in all randomised patients, aiming to a relative benefit of 29% (HR=0.708). Secondary endpoints include progression-free survival (PFS), adverse events (AEs) and symptom-specific and global quality of life (QoL).Results
Between 30/04/2019 and 7/03/2022, 400 patients were randomised, 200 per arm. 65% had ECOG performance status 1 and 78% had epithelioid histology. At a median follow-up of 35 months (data cut-off 1/09/2023), the median OS was 20.5 months for ABC versus 18.1 months for BC (HR(95%CI): 0.84(0.66-1.06); p=0.14). Median PFS was significantly longer for ABC than BC (9.2 vs 7.6 months); HR: 0.72(0.59-0.89); p=0.0021). Histology showed significant treatment interaction for both PFS and OS, with OS HR: 0.51(0.32-0.80) for non-epithelioid and 1.01(0.77-1.32) for epithelioid (interaction p=0.012). Grade≥3 treatment-related AEs were reported in 55% of patients in ABC and 47% in BC, QoL was maintained with ABC with no clinically meaningful differences from BC.Conclusions
The significant benefit in median PFS for ABC found in this study translated into a numerical but not significant increase in median OS. Thus, the primary endpoint was not met. In the pre-specified analysis by histology, superior OS and PFS were found for ABC in non-epithelioid cases.