Peripheral blood (PB) T cell phenotype and tumor microenvironment (TME) subtype are independently associated with immune checkpoint blockade (ICB) outcomes in sarcomas

BackgroundICB can be an effective treatment option for a subset of sarcoma patients (pts). Identifying biomarkers of response and resistance is essential to determining pts most likely to benefit.MethodsWe conducted a retrospective analysis of PB and tumor samples from sarcoma pts enrolled in 5 distinct ICB-based clinical trials. Pre-treatment PB samples from 185 pts were analyzed using 11-color flow cytometry. RNA sequencing of 58 baseline tumor samples was used to classify the TME into 4 subtypes by consensus clustering of single-sample functional gene expression signature enrichment scores. We investigated associations between PB and tumor characteristics and clinical outcomes.ResultsIn a multivariable analysis accounting for study treatment and histology, higher proportion of TIM-3+/CD8+PD-1- T cells in the PB was associated with shorter PFS and OS (hazard ratio [HR] 1.44, 95% confidence interval [CI] 1.17-1.77, p < 0.001, false discovery rate [FDR] q = 0.0376 and HR 1.70, 95% CI 1.35-2.13, p < 0.001, FDR q < 0.001, respectively). TME subtype was associated with overall response rate (ORR) and PFS (Table). In a multivariable analysis accounting for TME subtype, higher proportion of these TIM-3+ T cells remained associated with shorter PFS and OS (HR 1.9, CI 1.22-2.96, p = 0.006 and HR 1.84, CI 1.12-3.02, p = 0.022, respectively). Table: 1775P TME Subtype N ORR (CI)1 Median PFS in months (CI)2 Median OS in months (CI)3 Immune-enriched, non-fibrotic 9 78% (40-97) NR NR Immune-enriched, fibrotic 23 14% (2.9-35) 2.1 (1.8-5.4) 11 (9.4-22) Depleted 8 13% (0.32-53) 1.7 (1.6-NR) 7.8 (6.2-NR) Fibrotic 18 0% (0-19) 1.8 (1.6-5.5) 12 (4.8-NR) 1Fisher’s exact p < 0.0012Log-rank p = 0.0023Log-rank p = 0.2 ConclusionsSarcoma pts with a lower proportion of PB TIM-3+/CD8+PD-1- T cells and a baseline immune-enriched non-fibrotic TME are more likely to benefit from ICB. These factors are independently associated with outcomes and could serve as complementary biomarkers for predicting response to ICB.Legal entity responsible for the studyE. Rosenbaum.FundingHas not received any funding.DisclosureE. Rosenbaum: Financial Interests, Personal, Stocks/Shares: Iovance Biotherapeutics, PMV Pharmaceuticals; Financial Interests, Institutional, Local PI: Incyte Corporation, Arcus Biosciences, GSK. C.M. Kelly: Financial Interests, Personal, Other, Employment, Stock, or other Ownership Interest: Daiichi Sankyo; Financial Interests, Personal, Advisory Role: Exicure, Immunicum; Financial Interests, Institutional, Research Funding: Agios, Amgen, Merck, Incyte, Kartos, Epicure, Xencor. S. Movva: Financial Interests, Institutional, Coordinating PI: Tracon, Pfizer, Merck, BMS, Clovis, Ascentage; Financial Interests, Institutional, Local PI: PTC therapeutics, Hutchinson Medipharma. J. Chan: Financial Interests, Institutional, Other, Received antibodies in part of a collaboration for a grant.: Cytek; Financial Interests, Institutional, Other, My research work in lung cancer was funded as part of a sponsored research agreement between my PI and the company.: Ono Pharmaceutical. P. Chi: Financial Interests, Personal, Other, Advisor and Consultant: Ningbo NewBay Medical Technology; Financial Interests, Institutional, Funding, Clinical trial funding: Ningbo NewBay Medical Technology; Financial Interests, Personal and Institutional, Steering Committee Member, Clinical Trial: Ningbo NewBay Medical Technology, Deciphera; Financial Interests, Institutional, Funding, clinical trial: Deciphera; Financial Interests, Institutional, Funding, Trial: Pfizer. M. Dickson: Financial Interests, Institutional, Other: Sumitomo Dainippon Pharma Oncology, Aadi; Financial Interests, Institutional, Principal Investigator: Lilly. R.G. Maki: Financial Interests, Personal, Other, DSMB participation: Deciphera; Financial Interests, Personal, Other, Consultant to serve as Medical Monitor: Peel Therapeutics; Financial Interests, Personal, Invited Speaker, Sarcoma content for web site: Physician's Education Resource; Financial Interests, Personal, Writing Engagement, Sarcoma content editor: UptoDate; Financial Interests, Personal, Advisory Board, Advisory board: GSK; Financial Interests, Personal, Advisory Board: Medtronic; Financial Interests, Personal, Other, Associate Editor, JCO: American Society of Clinical Oncology; Financial Interests, Personal and Institutional, Coordinating PI, Clinical trial support and steering committee - brigimadlin studies: Boehringer Ingelheim; Financial Interests, Personal and Institutional, Coordinating PI, Investigator initiated trial with pembrolizumab: GSK. P. Wong: Financial Interests, Personal, Other, Professional services and activities: Leap Therapeutics Inc.; Non-Financial Interests, Personal, Other, Professional services and activities: Sellas Life Science Group. K. Panageas: Financial Interests, Personal, Stocks/Shares: 23andMe. W.D. Tap: Financial Interests, Personal, Leadership Role: Certis Oncology Solutions, Atropos, Innova Therapeutics; Financial Interests, Personal, Advisory Role: EMD Serono, Lilly, Daiichi, Deciphera, C4, Mundipharma, Ascendo, Ayala Pharma, Kowa Pharma, Servier, Bayer, Epizyme, Cogent, Medpacto, Foghorn, Amgen; Financial Interests, Institutional, Research Funding: Novartis, Lilly, Plexxikon, Daiichi Sankyo, Tracon, Blueprint, Immune Design, Bioatla, Deciphera. S.P. D'Angelo: Financial Interests, Personal, Advisory Role: EMD Serono, Amgen, Nektar, Immune design, GSK, Incyte, Merck, Adaptimmiune, Immunocore; Financial Interests, Institutional, Research Funding: EMD Serono, Amgen, Merck, Incyte, Nektar, BMS, Deciphera; Financial Interests, Personal, Other, Travel: Adaptimmune, EMD Serono, Nektar. All other authors have declared no conflicts of interest.