1916P - Methylation subtypes correlate with tumor immune contextures and outcome to ICI therapy of pleural mesothelioma (PM) patients: The NIBIT EPI-MESO study

Background

Dual ICI therapy is the standard of care for first-line PM patients (pts); single agent ICI improved survival vs placebo in pretreated pts. However, ICI efficacy is comprehensively unsatisfactory in PM, and no biomarkers predict response to therapy. We aimed to identify tumor features correlated with ICI efficacy in PM pts.

Methods

The NIBIT-EPI-MESO is a multicenter study led by the NIBIT Foundation in ICI-treated PM pts. Pts with irPR or irSD were classified as responders (R), those with irPD as non-responders (NR). Tumor biopsies underwent multi-omics analyses: RNA-seq, WES, RRBS, and multiplex immunofluorescence (mIF). Results were correlated with clinical outcome.

Results

Among 73 pts studied 54 had epithelioid, 16 biphasic, and 3 sarcomatoid PM; 64 received ICI as second/third line: 27 tremelimumab plus durvalumab (Calabrò, TLRM 2018), 36 nivolumab plus ipilimumab (Italian expanded access), 10 tremelimumab monotherapy (Calabrò, TLRM 2015). IrPR, irSD, and irPD were achieved by 27%, 36% and 37% of pts. Methylation profiling clustered pts into four subtypes: Demethylated, Low, Intermediate, and CIMP (hypermethylated). The Low cluster was enriched in R pts (22/41; p=0.01) who had the highest mOS (970 days), whereas the CIMP cluster was enriched in NR pts who had the worst mOS (288 days). Also, the Low cluster was the most predictive of ICI outcome in a multivariate model including sex, age, TMB, INFg gene expression (HR=0.1, CI: 0.02-0.47; p=0.003). An enriched proliferation and mitochondrial metabolism characterized the CIMP cluster, while the Low cluster was enriched in pathways associated with innate/adaptive immune response. The Low cluster had higher densities of tumor-associated CD8⁺ T (p=0.032) and CD20⁺ B cells (p=0.01) by mIF, compared to CIMP tumors. Tumor and stroma CD20⁺ B cells associated with response (p=0.016 and p=0.043), tumor CD4⁺ (p=0.009), CD8⁺ (p=0.01), CD68⁺(p=0.017) associated with OS. The low mutational rate identified did not associate with ICI response or OS.

Conclusions

Tumor methylation drives efficacy of ICI therapy in PM pts by shaping tumor immune contextures, regardless of PM histology and TMB.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

AIRC Foundation (ID.21073); Ministry of Health, Lombardy and Tuscany regions (NET-2016-02361632).

Disclosure

L. Calabro: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Roche, Merck Sharp Dohme; Financial Interests, Personal, Financially compensated role: Bristol Myers Squibb, AstraZeneca, Sanofi. F.P. Caruso, T. Noviello: Other, Personal, Stocks/Shares: Immunomics. A. Covre, S. Coral: Other, Personal, Stocks/Shares: Epigen Therapeutics. F. Grosso: Financial Interests, Personal, Speaker, Consultant, Advisor: Bristol Myers Squibb, Novocure, Novartis, Pierre Fabre, Merck Sharp Dohme, PharmaMar. A.M. Di Giacomo: Financial Interests, Personal, Advisory Board: Pierre Fabre, GSK, Bristol Myers Squibb, Merck Sharp Dohme, Sunpharma, Immunocore, Sanofi; Financial Interests, Personal, Financially compensated role: Bristol Myers Squibb, Merck Sharp Dohme, Pierre Fabre, Sanofi. M. Ceccarelli: Other, Personal, Stocks/Shares: Immunomics; Financial Interests, Personal, Speaker, Consultant, Advisor: Moderna Therapeutics. M. Maio: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Pierre Fabre, Merck Serono, Amgen, Eli Lilly, Roche, Merck Sharp Dohme, Incyte, AstraZeneca, GSK, Sciclone, Sanofi, Alfasigma; Other, Personal, Stocks/Shares: Epigen Therapeutics, Theravance. All other authors have declared no conflicts of interest.