165P Tissue genomic profiling of pleural mesothelioma patients treated with immunotherapy: Unraveling genetic alterations and complexity

Pleural mesothelioma (PM) is a rare disease with a poor prognosis, often diagnosed at advanced stage. Chemotherapy traditionally addresses unresectable cases; recent phase III trials emphasize the emerging role of immunotherapy (IO). Nevertheless, predictive and prognostic factors for IO remain elusive. This study aimed to assess clinical and molecular determinants that could impact the outcome of IO-treated PM patients (pts). We retrospectively analysed data from 24 unresectable PM pts treated with at least one cycle of IO based treatment in any line at Fondazione IRCCS Istituto Nazionale dei Tumori in Milan from March 2018 to December 2023. Next Generation Sequencing analysis (OncomineTM Comprehensive Assay Plus, FoundationOne®CDx or OmniSeq INSIGHT®) was performed. Tumor mutational burden (TMB) was calculated using IonReporter v5.18 software on non-synonymous mut of exonic region >1 Mb. Cox regression models and χ2 tests evaluated associations, Kaplan-Meier estimated the survival curves. Median age at diagnosis was 67 years, predominantly male (58%). Epithelioid histology was the most common (67%), followed by biphasic (29%) and sarcomatoid (4%). With a median follow up of 26,2 months (mo), median IO progression free survival was 7,85 mo (95% CI 4,4-27,85 mo). The majority of pts were referred to our centre after exhausting standard of care therapies, possibly contributing to the noteworthy median overall survival (mOS) of 27,5 mo. The most frequent somatic mutations were BAP1 (29%), NF2 (17%), FANCA (17%), SNCAIP (17%), CDNK2A (12%), PIK3CA (12%), ATR (12%) and ATM (12%). The median number of gene alterations was 9 and the median TMB was 3.9 mut/Mbp. No statistically significant associations were found among the somatic mutations, the main clinical (age, gender, smoking status, asbestos exposure) or pathological (histology, TMB) variables, and outcome. There was a trend suggesting a potential association between BAP1 loss and mOS (p= 0.13). Our study did not identify predictive or prognostic factors for IO outcomes in unresectable PM, emphasizing the complexity and heterogeneity of PM. Further research with larger cohorts is crucial to unveil biomarkers in this setting.