Real-world outcomes and molecular correlates of incorporating immunotherapy (IO) and bevacizumab (Bev) in treating patients with peritoneal mesothelioma (PeM): A comparative analysis with pleural mesothelioma (PM).

Abstract

e23300 Background: Nivolumab/Ipilimumab (IO) and Bev/Chemo are now considered standards of care for patients (pts) with advanced PM, based on randomized (CheckMate743 and MAPS) trials. By extrapolation, they are also endorsed by guidelines and used clinically in pts with PeM. Due to lack of any prospective data, we evaluated real-world effectiveness of these agents in PeM (vs PM) and investigated molecular correlates underlying their therapeutic impact. Methods: The study cohort was composed of mesothelioma pts (N = 723) who underwent DNA (592-gene panel or whole exome)/RNA (whole transcriptome) [PeM (221/224) and PM (493/499)] sequencing at Caris Life Sciences (Phoenix, AZ). Treatment and real-world survival (OS) were obtained from insurance claims and calculated from time of tissue collection to last contact. Hazard ratio (HR) was calculated using Cox proportional hazards model. Tumor microenvironment (TME) estimates were calculated from bulk RNA sequencing using QuanTIseq method. Significance was determined using Chi-square, Mann Whitney U and log-rank tests and corrected for multiple comparisons (q-value < 0.05) when applicable. Results: PeM (vs PM) had a higher proportion of females (46% vs 29%) and younger age (62 vs 73 years; both p < 0.001). 20% and 22% of PeM were treated with IO or Bev/Chemo, with similar utilization rates in PM of 22% and 24%, respectively. OS estimates and comparisons are shown in Table. Prevalence of mutations in key mesothelioma associated genes ( BAP1, NF2, TP53 and SETD2) was not significantly different between PeM and PM. NF2 (10.1 vs 51.3 m for wild type; p < 0.001) and TP53 (10.4 vs 46.6 m for wild type; p < 0.006) mutations were associated with worse OS in PeM but not in PM. Prevalence of high tumor mutation burden (≥10 mut/Mb: 1.0% vs 3.4%; q = 0.37) and PD-L1+ (18.7% vs 28.8%; q = 0.07) tumors was slightly lower in PeM than PM. Macrophage fractions, M2 were higher (1.5-fold) and M1 were lower (0.8-fold) in PeM (both q < 0.05) compared to PM. Conclusions: In this large real-world analysis, use of IO appears to be associated with improved outcomes in PeM, despite a potentially immunosuppressive TME. Notably, addition of Bev did not appear to improve outcomes in PeM, in contrast to PM. These results highlight variances in clinical utility/value of these therapies. Molecular mechanisms underlying these outcome differences warrant further investigation. [Table: see text]