1920P - Multiomics analysis of malignant pleural mesothelioma and the effect of immune checkpoint inhibitors

Background

Malignant pleural mesothelioma (MPM) is often diagnosed in advanced stage with poor prognosis. Nivolumab+ipilimumab (Nivo+Ipi) therapy has been the standard of care as first-line treatment based on the results of CheckMate743 trial. There have been few studies evaluating the efficacy of immune checkpoint inhibitors (ICIs) on MPM from a genetic perspective.

Methods

Whole genome sequencing (WGS) and RNA sequencing were performed of patients with MPM treated at the National Cancer Center Hospital (Tokyo, Japan). We examined association between mutation status, copy number variations (CNVs), immune profiles and clinical outcomes of ICI.

Results

A total of 52 patients (median age 66 years) were evaluated. Of them, 40 (76.9%) were male, and 24 (46.2%) had a history of asbestos exposure. Regarding the histology, 35 (67.3%) were epithelioid, 16 (30.8%) were non-epithelioid, and 1 (1.9%) was unknown. Among 20 patients treated with ICIs, 9 (45%) received nivolumab and 11 (55%) received Nivo+Ipi, respectively. The overall response rate was 30%. In the gene mutation analysis of 52 patients, BAP1 mutations were found in 37%, NF2 mutations in 17%, SETD2 mutations in 12%, and TP53 mutations in 10%. CNV analysis revealed deletions at 3p21.1 (42.3%): including BAP1, 3p21.31(42.6%): including SEMA3F, 9q21.3 (46.3%): including CDKN2A, and 16p13.3 (19.2%): including RBFOX1. Gene Set Enrichment Analysis showed that epithelioid type was enriched for the T cell receptor complex (p<0.01) and had higher B cell diversity (p=0.03) in the immune environment analysis. Regarding the efficacy of ICIs, gene mutation analysis showed no predominant difference in BAP1 mutation rates between responders and non-responders to ICIs at 66.7% and 60% (p=0.81), respectively. On the other hand, the transcriptome analysis showed that responders to ICIs had higher expression of T cell-related genes such as IDO1 and IL32 compared to non-responders. Additionally, in the immune environment analysis, responders had significantly higher T cell diversity (p=0.02), CD8+Tcells (p=0.02), and M1 macrophages (p<0.01).

Conclusions

Higher T cell diversity, the infiltration of CD8 T cells, and M1 macrophages within tumor microenvironment of MPM were associated with the response of ICIs.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

T. Yoshida: Financial Interests, Personal, Advisory Board: Pfizer, MSD, Amgen; Financial Interests, Personal, Invited Speaker: AstraZeneca, Chugai pharmaceutical, Pfizer, Takeda, Lilly, Ono pharmaceutical, Novartis, Daiichi Sankyo, MSD, BMS; Financial Interests, Institutional, Local PI: AstraZeneca, Novartis, Amgen, Daiichi Sankyo, BMS, MSD, Ono pharmaceutical, BluePrint, Chugai pharmaceutical, AbbVie. Y. Shinno: Financial Interests, Personal, Invited Speaker: AstraZeneca.K.K, Bristol Myers Squibb, Chugai, Eli Lilly; Financial Interests, Personal and Institutional, Research Grant: Ono; Financial Interests, Institutional, Research Grant: Janssen and Japan Clinical Research Operations K.K. Y. Okuma: Financial Interests, Personal, Invited Speaker: AstraZeneca.K.K, AbbVie K.K., Roche, Nippon Boehringer Ingelheim, Bristol0Myers Squibb, Chugai Pharma Co. Ltd., Ely Lilly K.K., Ono Pharma, Pfizer, Taiho. Y. Goto: Financial Interests, Personal, Advisory Board: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Guardant Health Inc., Illumina, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho, Johnson and Johnson, D3bio; Financial Interests, Personal, Invited Speaker: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, MSD, Merck, Novartis, Ono Pharmaceutical, Pfizer, Taiho, Thermo Fischer; Financial Interests, Personal, Other, Travel Grant: Daiichi Sankyo; Financial Interests, Institutional, Local PI: Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Preferred Network; Financial Interests, Personal and Institutional, Coordinating PI: Chugai, Novartis, Pfizer; Financial Interests, Institutional, Research Grant: Prefered Network; Financial Interests, Institutional, Coordinating PI: Guardant Health; Non-Financial Interests, Member of Board of Directors: Cancer Net Japan, JAMT. H. Horinouchi: Financial Interests, Personal, Invited Speaker: AstraZeneca, Eli Lilly, BMS/ONO, Merck Sharp & Dohme, Roche/Chugai, Novartis, Pfizer, Boehringer Ingelheim, Kyowa-Kirin, Nihon Kayaku, AbbVie; Financial Interests, Personal, Advisory Board: AstraZeneca, Eli Lilly, BMS/ONO, Merck Sharp & Dohme, Roche/Chugai, Amgen, Nihon Kayaku; Financial Interests, Personal, Steering Committee Member: Roche/Chugai; Financial Interests, Institutional, Research Grant: Roche/Chugai, Merck Sharp & Dohme, Daiichi Sankyo, ONO pharmaceutical, AstraZeneca; Financial Interests, Institutional, Local PI: AbbVie. N. yamamoto: Financial Interests, Personal, Invited Speaker: AstraZeneca.K.K, Astellas; Financial Interests, Personal, Advisory Board: Bayer, Boehringer Ingelheim, Bristol-Myers, Squibb, Carna Biosciences, Chugai, Chime Bioscience Inc., Daiichi Sankyo, Risai, Eli Lilly, Genmab, GSK, Janssen Pharma, Kyowa-Hakko Kirin, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical Co., Otsuka, Pfizer, Quintiles, Shionogi, Sumitomo Dainipon, Takeda, Taiho. Y. Ohe: Financial Interests, Personal, Advisory Board: Amgen, AnHeart Therapeutics Inc, AstraZaneca, BMS, Celltrion, Nippon Kayaku, ONO, Pfizer, Takeda, PharmaMar, AnHeart; Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Eisai, Eli Lilly, MSD, Novartis, ONO, Takeda; Financial Interests, Institutional, Local PI: AstraZeneca, Janssen, Amgen; Financial Interests, Personal and Institutional, Coordinating PI: Takeda, ONO; Non-Financial Interests, Leadership Role: JSMO, JLCS, JCOG; Non-Financial Interests, Member: ASCO. All other authors have declared no conflicts of interest.