1842O - Mutational profile of malignant pleural mesothelioma (MPM) in the phase II RAMES study

Abstract

BackgroundMPM is an aggressive cancer with poor prognosis. Platinum/pemetrexed regimen is the standard 1°-line chemotherapy (CHT) in advanced disease. MethodsThe RAMES Study evaluated the 2°-line efficacy of gemcitabine/ramucirumab treatment vs. gemcitabine/placebo. From December 2016 to July 2018 (end of enrolment), 164 pts were admitted to this study. We evaluated by NGS the mutational profile of a panel of 34 genes (gs) (ACTB, ACTG1, ACTG2, ACTR1A, BAP1, CDH8, CDK4, CDKN2A, CDKN2B, COL3A1, COL5A2, CUL1, DHFR, GOT1, KDR, KIT, MXRA5, NF2, NFRKB, NKX6-2, NOD2, PCBD2, PDZK1IP1, PIK3CA, PIK3CB, PSMD13, RAPGEF6, RDX, SETDB1, TAOK1, TP53, TXNRD1, UQCRC1, XRCC6). We reported the results of the 103 pts (63%) of both arms with specimen available for molecular analysis. Median age was 63 years (45-81), 24.3% (n=25) were females and 75.7% (n=78) males. Histotype was 83.5% (n=86) epithelioid and 16.5% (n=17) non-epithelioid. 37.8% (n=39) were stage IV, 60.2% (n=62) were stage III, and 1.9% (n=2) were unknown. In 1°-line platinum/pemetrexed CHT treated pts, the median PFS was 5.75 months (ms) (C.I. 95% 4.75-6.76). 50 pts had PFS <6ms, while 50 pts had PFS >6ms (n=3 not available). Results260 functional somatic mutations were identified in 28 of the 34 gs analyzed. 75pts (72.8%) displayed mutations in 1 to 3 gs while 17 pts (16.5%) showed mutations in at least 4 gs. No mutated gs were detected for 11 pts (10.7%). The number of mutated gs was positively associated with higher stage and metastatic behavior (p=0.025) and increased 1°-line PFS (p=0.011). RDX (42.7%), MXRA5 (23.3%), BAP1 (13.6%), PIK3CB (10.7%) and NF2 (10.7%) were the most frequently mutated gs in our pts. Mutations in RAPGEF6 (p=0.013) and ACTG1 (p=0.01) were associated with non-epithelioid, while mutations in BAP1 (p=0.041) were associated with PFS >6 months. A positive trend of association was also observed between mutations in COL3A1 (p=0.052) and NFRKB (p=0.052) and stage IV. ConclusionsIn MPM the identification of molecular gene alterations could be an important starting point for understanding the main pathways involved in prognosis and sensitivity/resistance to therapy. In the RAMES Study, the mutation of gene BAP1 is related to a prolonged PFS at the 1°-line CHT (p=0.041). Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.