BEAT-meso: A randomized phase III study of bevacizumab (B) and standard chemotherapy (C) with or without atezolizumab (A), as first-line treatment (TX) for advanced pleural mesothelioma (PM)—Results from the ETOP 13-18 trial.
Authors: Sanjay Popat, Enriqueta Felip, Urania Dafni, Anthony Pope, Susana Cedres Perez, Riyaz N.H. Shah, Filippo de Marinis, Laura Cove Smith, Reyes Bernabe Caro, Martin Früh, Kristiaan Nackaerts, Laurent Greillier, Amina Scherz, Bartomeu Massuti, Saemi Schaer, Spasenija Savic Prince, Heidi Roschitzki-Voser, Barbara Ruepp, Solange Peters, Rolf A. Stahel
Journal: Journal of Clinical Oncology (2024)

LBA8002 Background: The currently approved frontline TXs for PM are the combination of ipilimumab/nivolumab or platinum plus pemetrexed. The addition of B to C has been shown to improve overall survival in a randomized clinical trial. While combined immunotherapy or single agent immunotherapy with C is superior to C alone, there is potential for a synergistic triple combination of C, B, and immunotherapy. Methods: BEAT-meso (NCT03762018) is an international open-label, 1:1 randomized phase III trial, stratified by histology and stage. The objective is to determine the efficacy and safety of adding A (1200 mg, Q3W until progression) to B (15mg/kg, Q3W until progression) and standard C (4-6 cycles of carboplatin AUC5 with pemetrexed 500 mg/m 2 , Q3W), as first-line TX for advanced PM. The trial is designed to detect an increase in the median overall survival (OS, primary endpoint) with the addition of A, aiming for a hazard ratio (HR) of 0.708, at 2.5% 1-sided alpha and 82% power (284 deaths, sample size 400 patients (pts)). In the pre-specified interim efficacy analysis (80% of the events, 01/2023), boundary was not crossed, and the trial continued to completion. Secondary endpoints include progression-free survival (PFS), objective response rate (ORR), disease control rate, duration of response (DoR), adverse events (AEs) assessed by CTCAE v5.0 and symptom-specific and global quality of life (QoL). Results: Between 04/2019 and 03/2022, a total of 400 pts was randomized, 200 per arm. The median age was 70 years, 79% were male, 50% were former smokers, 65% had ECOG performance status 1 and 78% had epithelioid histology. At a median follow-up of 35 months (m) (as of 1/09/2023), median OS was 20.5m [95% CI: 17.5-23.3] in the ABC and 18.1m [15.7-20.9] in the BC arm (deaths: 145 &amp; 150; HR ABC vs BC =0.84; [0.66 - 1.06], 2-sided stratified p=0.14, ITT final analysis). PFS was significantly longer in ABC with median 9.2m [8.1-10.9] vs 7.6m [6.9-8.3] in BC (HR=0.72; [0.59 - 0.89], 2-sided stratified p=0.0021). Histology shows a significant TX interaction for both PFS and OS. The OS HR is 0.51 [0.32-0.80] for non-epithelioid and 1.01 [0.77-1.32] for epithelioid (interaction p=0.012). In an exploratory analysis, post-progression OS was significantly different between the two arms, adjusted for post-progression TX (HR=0.76; [0.58 - 0.99]). The ORR was 55% in ABC and 49% in BC (p=0.27), while median DoR was 8.2m [6.8-9.7] in ABC and 5.6m [4.8-7.0] in BC (p=0.0041). Global QoL change was not significantly different between the two arms. Grade≥3 TX-related AEs occurred in 55% of pts in ABC and 47% of pts in BC (grade 5: 7 and 1 pt, respectively). Conclusions: The significant increase in median PFS with the addition of A did not translate into a significant increase in median OS. ABC demonstrated superiority over BC in non-epithelioid cases. Clinical trial information: NCT03762018 .