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

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. 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. 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. 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: LBA51Select changes in peripheral blood 4 weeks post first dose suggesting RELA-specific activityNIVONIVO+RELA%ΔaP%ΔaPsLAG-3+ CD4+FoxP3− (conventional)0NS166.7****sLAG-3+ CD4+16.7NS142.9****sLAG-3+ naïve CD4+−9.10NS40.0****sLAG-3+ TE CD8+12.5NS491.7****cLAG-3+ TE CD8+5.9NS66.7****sLAG-3+ naïve CD8+0NS60.0****CD38+ HLADR+ TE CD8+7.4NS30.8***sLAG-3+ CD56+ CD16+ (int) NK9.10NS117.4****sLAG-3+ NK0NS50.0****sLAG-3+ CD56− CD16+ (mature) NK10.5NS40.2**aMedian.c, cytoplasmic; int, intermediate; NS, nonsignificant; s, surface; TE, terminal effector. *<0.05; **<0.01; ***<0.001; ****<0.0001 by Wilcoxon test. Open table in a new tab