1921P - Molecular analysis of mesothelioma reveals mutations as prognostic biomarkers for patients treated with the combination of ipilimumab and nivolumab

Background

The immunotherapy (IT) combination of nivolumab and ipilimumab lead to a longer overall survival (OS) than chemotherapy (CHT) in patients with pleural mesothelioma (PM) in the Checkmate 743 (CM743) trial. Recently, we proposed to classify PM in four subgroups based on mutations in BAP1/CDKN2A/CDKN2B genes as follows: group 1 (G1) triple mutations in BAP1/CDKN2A/CDKN2B; group 2 (G2) double mutations in CDKN2A/CDKN2B; group 3 (G3) mutations only in BAP1; group 4 (G4) no mutations. In this study, we investigate the correlation of these four subgroups with OS and inflammatory signatures from the CM743 trial.

Methods

Whole exome sequencing was performed on 115 tumor samples from patients in the CHT and from 136 patients in the IT arms. Somatic variants were called using the union of callers (tnscope and strelka2). Subgroups association with clinical endpoints were assessed with cox proportional hazards modeling and outcome reported as Kaplan-Meier curves. Gene signatures scores were calculated by taking the median z-score from logCPM gene expression determined from RNA sequencing.

Results

Based on genetic profile, 41% of PM belonged to G1, 21% to G2, 2% to G3, and 13% to G4, respectively. With respect to OS, we observed that: 1) Patients in G1 with epithelioid histology treated with IT had a longer median OS (mOS) compared to CHT (14 vs 10.9 months), 2) Patients in G2 with PD-L1 positive (PD-L1pos= ≥1%) had longer mOS with IT than CHT irrespective of histology (15.8 vs 9.4 months), 3) Patients in G3 with epithelioid histology had the best prognosis overall, in both arms 4) Patients in G4 had no different outcome in both arms independent of PD-L1. With respect to gene expression analysis, we observed that tumors from G3 had a more inflamed signature with significantly higher levels of type-I IFN, T cell trafficking and activation as well as lower expression levels of TGF-β.

Conclusions

This exploratory analysis suggests that the four subgroups show distinct outcomes. Since this IT is currently approved to treat patients with PM, further studies including molecular analysis together with PD-L1 expression are warranted to customize treatment in these patients.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Bristol Myers Squibb.

Funding

Bristol Myers Squibb.

Disclosure

S. Peters: Financial Interests, Institutional, Advisory Board: Vaccibody, Takeda, Seattle Genetics, Sanofi, Roche/Genentech, Regeneron, Phosplatin Therapeutics, PharmaMar, Pfizer, Novartis, Mirati, Merck Serono, MSD, Janssen, Incyte, Illumina, IQVIA, GSK, Gilhead, Genzyme, Foundation Medicine, F-Star, Eli Lilly, Debiopharm, Daiichi Sankyo, Boehringer Ingelheim, Blueprint Medicines, Biocartis, Bio Invent, BeiGene, Bayer, BMS, AstraZeneca, Arcus, Amgen, AbbVie, iTheos, Novocure; Financial Interests, Institutional, Invited Speaker: Takeda, Sanofi, Roche/Genentech, RTP, Pfizer, PRIME, PER, Novartis, Medscape, MSD, Imedex, Illumina, Fishawack, Eli Lilly, Ecancer, Boehringer Ingelheim, BMS, AstraZeneca, OncologyEducation, RMEI, Mirati; Financial Interests, Personal, Other, Associate Editor Annals of Oncology and Deputy Editor Lung Cancer: Elsevier; Financial Interests, Institutional, Advisory Board, Permanent independent scientific advisor: Hutchmed; Financial Interests, Institutional, Member of Board of Directors, Swiss network of pharmacies: Galenica; Financial Interests, Institutional, Coordinating PI, MERMAID-1: AstraZeneca; Financial Interests, Institutional, Steering Committee Member, MERMAID-2, POSEIDON, MYSTIC: AstraZeneca; Financial Interests, Institutional, Steering Committee Member, Clinical Trial Steering committee CheckMate 743, CheckMate 73L, CheckMate 331 and 451: BMS; Financial Interests, Institutional, Steering Committee Member, RELATIVITY 095: BMS; Financial Interests, Institutional, Steering Committee Member, BGB-A317-A1217-301/AdvanTIG-301: Beigene; Financial Interests, Institutional, Trial Chair, Clinical Trial Chair ZEAL-1: GSK; Financial Interests, Institutional, Steering Committee Member, Clinical Trial steering Committee PEARLS, MK-7684A: MSD; Financial Interests, Institutional, Steering Committee Member, Clinical Trial Steering Committee SAPPHIRE: Mirati; Financial Interests, Institutional, Steering Committee Member, LAGOON: PharmaMar; Financial Interests, Institutional, Steering Committee Member, phase 1/2 trials: Phosplatin Therapeutics; Financial Interests, Institutional, Trial Chair, Clinical Trial Chair Skyscraper-01; chair ALEX; steering committee BFAST; steering committee BEAT-Meso; steering committee ImPower-030, IMforte: Roche/Genentech; Financial Interests, Institutional, Steering Committee Member, Phase 2 Inupadenant with chemo: iTeos; Non-Financial Interests, Officer, ESMO President 2020-2022: ESMO; Non-Financial Interests, Officer, Council Member & Scientific Committee Chair: ETOP/IBCSG Partners; Non-Financial Interests, Officer, Vice-President Lung Group: SAKK; Non-Financial Interests, Other, Involved in Swiss politics: Swiss Political Activities; Non-Financial Interests, Officer, President and Council Member: Ballet Béjart Lausanne Foundation; Non-Financial Interests, Principal Investigator, Involved in academic trials: ETOP / EORTC / SAKK; Non-Financial Interests, Member: Association of Swiss Physicians FMH (CH), ASCO, AACR, IASLC; Non-Financial Interests, Leadership Role, ESMO President: ESMO; Non-Financial Interests, Member, Vice-President Lung Group: SAKK; Non-Financial Interests, Leadership Role, Vice -President: SAMO; Non-Financial Interests, Member, Association of Swiss interns and residents: ASMAC/VSAO. S. Popat: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Novartis, Amgen, Janssen, Daiichi Sankyo, AstraZeneca, Bayer, BMS, Blueprint, Merck Serono, Guardant Health, Takeda, Lilly, Roche, Turning Point Therapeutics, GSK, MSD, Pfizer, Sanofi, EQRx, AnHeart, Arcus Biosciences, Ellipses, Gilead, IO Biotech, Mirati; Financial Interests, Personal, Invited Speaker: Medscape, VJ Oncology, Novocure, PharmaMar; Financial Interests, Institutional, Other, Sub-investigator: Amgen; Financial Interests, Institutional, Coordinating PI: Ariad, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Takeda, Turning Point Therapeutics, Roche, Janssen, BMS, Lilly; Financial Interests, Institutional, Local PI: AstraZeneca, Roche, GSK, Trizel; Financial Interests, Institutional, Other, Sub-Investigator: MSD, Blueprint; Financial Interests, Institutional, Research Grant: Guardant Health; Non-Financial Interests, Leadership Role, Chair of Steering Committee, Unpaid: British Thoracic Oncology Group; Non-Financial Interests, Officer, Thoracic Faculty, Unpaid: European Society of Medical Oncology; Non-Financial Interests, Leadership Role, Foundation Council Member, Unpaid: European Thoracic Oncology Platform; Non-Financial Interests, Advisory Role, Mesothelioma Committee, Unpaid: International Association for the Study of Lung Cancer; Non-Financial Interests, Member of Board of Directors, Unpaid: Mesothelioma Applied Research Foundation; Non-Financial Interests, Advisory Role, Honorary Clinical Advisor, Unpaid: ALK Positive UK; Non-Financial Interests, Advisory Role, Research Advisory Group Member, Unpaid: Ruth Strauss Foundation; Non-Financial Interests, Advisory Role, Scientific Advisory Board Member, Unpaid: Lung Cancer Europe. A. Curioni-Fontecedro: Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Meyer Squibb, Boehringer Ingelheim, MSD, Novartis, Amgen, Roche, Takeda, Janssen; Financial Interests, Institutional, Advisory Board: Daiichi Sankyo; Non-Financial Interests, Leadership Role: Swiss Academy for Clinical Cancer Research (SAKK); Non-Financial Interests, Principal Investigator, of clinical trials: Roche; Non-Financial Interests, Principal Investigator, Clinical Trials: Takeda, MSD, Bristol Meyer Squibb, Amgen, AstraZeneca; Non-Financial Interests, Principal Investigator, Clinical trials: iTEOS therapeutics. All other authors have declared no conflicts of interest.