33P - Impact of prior treatment on baseline immune biomarkers and nivolumab + relatlimab (NIVO+RELA)-induced changes in the tumor microenvironment (TME) in patients (pts) with melanoma from RELATIVITY-020

Background

In RELATIVITY-020, NIVO+RELA was well tolerated and demonstrated durable anti-tumor activity in pts with advanced melanoma refractory to prior immunotherapy (IO-rf), with enriched responses seen in pts whose tumors expressed programmed death ligand 1 (PD-L1) or lymphocyte activation gene-3 (LAG-3). To better understand subgroups of pts that may derive increased benefit from NIVO+RELA, we performed exploratory IO biomarker analyses in RELATIVITY-020.

Methods

LAG-3, PD-L1, and CD8 levels were evaluated by immunohistochemistry in tumor samples from pts at baseline who were IO-naïve (1L) or IO-rf, and within 4 weeks on NIVO+RELA. Immune-related gene expression signatures were evaluated by RNA-seq in pts with modified definitions of primary vs secondary anti–programmed death-1/PD-L1 resistance. Association between biomarkers and response was determined by RECIST v1.1.

Results

Baseline LAG-3, PD-L1, and CD8 levels were higher in IO-rf pts whose last therapy was IO (IO-prior) vs non-IO; objective response rate (ORR) with NIVO+RELA was 12.8 vs 8.3%, respectively. Baseline biomarkers were higher in NIVO+RELA responders vs non-responders (P<0.05) only in IO-prior pts. Lower immune and inflammatory gene expression signatures were observed in pts with primary vs secondary IO resistance. Baseline LAG-3, PD-L1, and CD8 levels were similar for 1L vs IO-rf pts despite a higher response to NIVO+RELA in 1L pts. After NIVO+RELA, a significant increase in LAG-3 in the TME was noted in both IO-rf and 1L pts (log₂ fold change: 0.73 and 1.46; both P<0.01), whereas PD-L1 and CD8 increased significantly in 1L pts only.

Conclusions

IO-rf pts whose last line of therapy prior to RELATIVITY-020 was IO vs non-IO had elevated inflammation-associated tumor biomarkers and may be more responsive to NIVO+RELA, although the ORR difference was modest. Variance in immune infiltration gene-expression signatures in primary vs secondary IO-resistant tumors suggest these subgroups have distinct TMEs and IO sensitivities. Modulation of LAG-3 in both IO-rf and 1L pts suggests NIVO+RELA can alter the TME in both settings, although modulation was greater in 1L pts.

Clinical trial identification

NCT01968109.

Editorial acknowledgement

Editorial support was provided by Allyson Koyen Malashevich, PhD, and Agata Shodeke, PhD, of Spark Medica Inc., funded by Bristol Myers Squibb.

Legal entity responsible for the study

Bristol Myers Squibb.

Funding

Bristol Myers Squibb.

Disclosure

P.A. Ascierto: Financial Interests, Personal, Other, Consultant and Advisory Role: BMS, Roche Genentech, MSD, Novartis, Merck Serono, Pierre Fabre, AstraZeneca, Sun Pharma, Sanofi, Idera, Sandoz, Immunocore, 4SC, Nektar, Boehringer Ingelheim, Regeneron; Financial Interests, Personal, Other, Consultant and Advisory Role. Travel support: Pfizer/Array; Financial Interests, Personal, Other, Consultant Role: Italfarmaco; Financial Interests, Personal, Other, Advisory Role: Eisai, Seagen; Financial Interests, Personal, Other, Consultant Role: Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore; Financial Interests, Personal, Other, Consultant role and travel support: Bio-AI Health; Financial Interests, Personal, Other, Consultant role: Medicenna; Financial Interests, Personal, Advisory Board, Consultant and Advisory Role: iTeos; Financial Interests, Personal, Advisory Board, Consultant and Advisory role: ValoTx; Financial Interests, Personal, Advisory Board, Consultant and Advisor role. Travel support: Replimmune; Financial Interests, Personal, Advisory Board, Advisor role: Bayer; Financial Interests, Institutional, Funding, Clinical Trial: Pfizer/Array, Roche Genentech, Sanofi; Financial Interests, Personal, Advisory Board: Erasca; Financial Interests, Institutional, Funding, Clinical trial and translational research: BMS; Non-Financial Interests, Personal, Leadership Role, President since 2010: Fondazione Melanoma Onlus Italy; Non-Financial Interests, Personal, Leadership Role, President since 2014: Campania Society of ImmunoTherapy of Cancer (SCITO) Italy; Non-Financial Interests, Personal, Member: SITC, ASCO, EORTC Melanoma Cooperative Group, AIOM, SMR; Non-Financial Interests, Personal, Other, Member of Steering Committee since 2016: Society for Melanoma Research (SMR); Non-Financial Interests, Personal, Member of Board of Directors, November 2017 - December 2021: Society for Immunotherapy of Cancer (SITC). H. Tang, S. Dolfi: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. M.S. Nyakas: Financial Interests, Personal, Speaker, Consultant, Advisor, Lectures and/or expert meetings: Bristol Myers Squibb, Novartis, MSD, Roche, Pierre Fabre. I. Svane: Financial Interests, Personal, Advisory Board: BMS, Pierre Fabre, Novartis; Financial Interests, Personal, Invited Speaker: MSD, Pierre Fabre, Novartis, Roche, BMS; Financial Interests, Institutional, Research Grant: Enara Bio, Adaptimmune, Lytix Biopharma, TILT Biotherapeutics; Financial Interests, Personal, Writing Engagement: MSD; Financial Interests, Personal, Stocks/Shares, Cofounder and Founder warrents: IO Biotech; Financial Interests, Institutional, Funding: Evaxion; Non-Financial Interests, Personal, Principal Investigator: BMS, Novartis, Roche, TILT Biotherapeutics, Lytix Biopharma. E. 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