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 first-line 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, 3-week cycle (q3w) until progression] to bevacizumab (15 mg/kg, q3w until progression) and standard chemotherapy (4-6 cycles of carboplatin area under the curve with pemetrexed 500 mg/m(2), q3w; ABC versus BC) as first-line treatment for advanced DPM. The primary endpoint is OS in all randomised patients, aiming for a relative benefit of 29% [hazard ratio (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 April 2019 and 7 March 2022, 400 patients were randomised, 200 per arm. Sixty-five percent had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 and 78% had epithelioid histology. At a median follow-up of 35 months (data cut-off 1 September 2023), the median OS was 20.5 months for ABC versus 18.1 months for BC [HR 0.84, 95% confidence interval (CI) 0.66-1.06, P = 0.14]. Median PFS was significantly longer for ABC than for BC (9.2 versus 7.6 months) (HR 0.72, 95% CI 0.59-0.89, P = 0.0021). Histology showed significant treatment interaction for both PFS and OS, with an OS HR of 0.51 (95% CI 0.32-0.80) for non-epithelioid and 1.01 (95% CI 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.