LBA51 - Unraveling relatlimab (RELA)-specific biology using biomarker analyses in patients with advanced melanoma treated with nivolumab (NIVO)+RELA or NIVO alone in RELATIVITY-047

Background

NIVO+RELA demonstrated significant progression-free survival (PFS) benefit vs NIVO in RELATIVITY-047 (NCT03470922). Exploratory biomarker analyses were conducted to elucidate mechanisms underlying NIVO+RELA activity and identify patients (pts) more likely to derive benefit from the combination.

Methods

Blood samples at baseline and 4 weeks post dose were analyzed by flow cytometry for pharmacodynamic changes in immune cell populations, eg lymphocyte activation gene-3 (LAG-3)- or programmed death-1 (PD-1)-expressing CD4+ and CD8+ T cells, natural killer (NK) cells. Baseline tissue samples were analyzed by immunohistochemistry (IHC) for major histocompatibility complex (MHC) class I/II expression and CD8 infiltration. HALO image analysis of LAG-3+ and LAG-3− CD8+ T cells was conducted by multiplex IHC. Association between biomarkers and treatment response was assessed.

Results

Multiple peripheral immune cell types significantly increased with NIVO+RELA vs NIVO (Table). Response to NIVO+RELA was associated with increased LAG-3+ CD4+ T cells at week 4, but on-treatment modulation of peripheral CD8+ T cells was not associated with NIVO+RELA efficacy. Baseline PD-1+ CD8+ and ICOS+ CD8+ T cell numbers were higher in responders to NIVO+RELA but not NIVO. In the tumor microenvironment (TME), higher baseline MHC-I and MHC-II were associated with improved efficacy in both arms. A PFS benefit with NIVO+RELA vs NIVO was observed in pts with low/medium TME CD8 infiltration; benefit of NIVO+RELA vs NIVO was seen for high TME CD8 infiltration only when LAG-3 was also expressed.

Conclusions

TME analysis suggests RELA activity is particularly robust in tumors with lower CD8+ T-cell infiltration; peripheral data suggest CD4+ T-cell modulation may be key to its distinct mechanism of action. Further exploratory biomarker analyses are warranted to identify pts who may derive maximal benefit from NIVO+RELA. Table: LBA51

Select changes in peripheral blood 4 weeks post first dose suggesting RELA-specific activity

^aMedian.c, cytoplasmic; int, intermediate; NS, nonsignificant; s, surface; TE, terminal effector. *<0.05; **<0.01; ***<0.001; ****<0.0001 by Wilcoxon test.

Clinical trial identification

NCT03470922, EudraCT 2017-003583-12.

Editorial acknowledgement

Editorial support was provided by Keri Wellington, PhD, and Agata Shodeke, PhD, of Spark Medica Inc., according to Good Publication Practice guidelines, funded by Bristol Myers Squibb.

Legal entity responsible for the study

Bristol Myers Squibb.

Funding

Bristol Myers Squibb.

Disclosure

E.J. Lipson: Financial Interests, Personal, Advisory Board: Bristol Myers-Squibb, Merck, Sanofi, Regeneron, Genentech, Eisai, Instil Bio, Natera, Nektar Therapeutics, Pfizer, Rain Therapeutics, CareDx, Immunocore, Novartis, Replimune, HUYA Bioscience International; Financial Interests, Personal, Other, Consultant: OncoSec; Financial Interests, Institutional, Coordinating PI: Bristol-Myers Squibb; Financial Interests, Institutional, Local PI: Regeneron, Merck, Sanofi. S. Dolfi: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. H. Tang: Financial Interests, Institutional, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Institutional, Stocks/Shares: Bristol Myers Squibb. H. Gogas: Financial Interests, Institutional, Principal Investigator: Amgen, Array BioPharma, BMS, Genentech, Merck, Novartis; Financial Interests, Institutional, Advisory Board: BMS. H.A. Tawbi: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck, Novartis, Genentech, Eisai, Karyopharm, Iovance, Pfizer, Jazz Pharmaceuticals; Financial Interests, Institutional, Trial Chair: Bristol Myers Squibb; Financial Interests, Institutional, Local PI: Merck, Rapt Pharmaceuticals; Financial Interests, Institutional, Steering Committee Member: Novartis, Genentech; Financial Interests, Institutional, Funding: GSK, Eisai. F..S. Hodi: Financial Interests, Personal, Advisory Role: Bristol Myers Squibb, Merck Sharpe & Dohme, Novartis, Genentech/Roche, Gossamer, Catalym, Immunocore, Kairos, Zumuto, Corner Therapeutics, Curis, AstraZeneca; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, Novartis; Financial Interests, Personal, Advisory Board: Surface, Compass Therapeutics, Apricity, Bicara, Checkpoint Therapeutics, Bioentre, Iovance, Rheos; Financial Interests, Personal, Stocks/Shares: Apricity, Bicara, Checkpoint Therapeutics. 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, Leadership Role, President since 2010: Fondazione Melanoma Onlus Italy; Non-Financial Interests, Leadership Role, President since 2014: Campania Society of ImmunoTherapy of Cancer (SCITO) Italy; Non-Financial Interests, Other, Member of Steering Committee since 2016: Society for Melanoma Research (SMR); Non-Financial Interests, Member of Board of Directors, November 2017 - December 2021: Society for Immunotherapy of Cancer (SITC); Non-Financial Interests, Member: ASCO, SITC, EORTC Melanoma Cooperative Group, SMR, AIOM. E.C. Gutierrez: Non-Financial Interests, Institutional, Principal Investigator: FAICIC S. DE R.L. DE C.V. D. Schadendorf: Financial Interests, Personal, Invited Speaker: BMS, Novartis, MSD, Roche, Merck Serono, Sanofi; Financial Interests, Personal, Advisory Board: BMS, Novartis, MSD, Immunocore, Pierre Fabre, Sanofi/Regeneron, Pfizer, Philogen, Neracare; Financial Interests, Personal, Steering Committee Member: Novartis, BMS, MSD; Financial Interests, Institutional, Coordinating PI: Novartis, BMS, MSD, Pierre Fabre; Financial Interests, Institutional, Research Grant: BMS, MSD; Financial Interests, Institutional, Local PI: Sanofi, Philogen; Non-Financial Interests, Member of Board of Directors: EORTC-MG. F.A. Medina Soto: Non-Financial Interests, Institutional, Principal Investigator: Bristol Myers Squibb. P. Rutkowski: Financial Interests, Personal, Invited Speaker, honoraria for lectures: MSD, BMS, Pierre Fabre; Financial Interests, Personal, Advisory Board: MSD, BMS, Pierre Fabre, Merck, Sanofi, Blueprint Medicines, Philogen; Financial Interests, Personal, Invited Speaker: Merck, Sanofi, Novartis, AstraZeneca; Financial Interests, Institutional, Research Grant, research grant for ISS: Pfzer; Financial Interests, Institutional, Funding, research grant for institution: BMS; Non-Financial Interests, Member of Board of Directors: Polish Society of Surgical Oncology; Non-Financial Interests, Member of Board of Directors, President: Polish Oncological Society. M. Maio: Financial Interests, Personal, Advisory Board: bms, roche, GSK, Sanofi, ALFASIGMA, Amgen, SCICLONE, Eli Lilly, MSD, INCYTE, Pierre Fabre, AstraZeneca; Financial Interests, Personal, Stocks/Shares: Epigen, Theravance. Y. Xu: Non-Financial Interests, Institutional, Other: Bristol Myers Squibb. K. Desai: Financial Interests, Institutional, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Institutional, Stocks/Shares: Bristol Myers Squibb. A. Yu: Financial Interests, Institutional, Full or part-time Employment: Bristol Myers Squibb. K. Demers: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. K. Miller-Moslin: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. G.V. Long: Financial Interests, Personal, Advisory Role: Agenus, Amgen, Array Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., Innovent Biologics USA, Merck Sharpe & Dohme, Novartis, OncoSec, PHMR Ltd, Pierre Fabre, Provectus, Qbiotics, Regeneron. C. Garnett-Benson: Financial Interests, Institutional, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Institutional, Stocks/Shares: Bristol Myers Squibb. All other authors have declared no conflicts of interest.