Clinical and biomarker analyses of first-line nivolumab and relatlimab (nivo-rela) in advanced or resectable melanoma (mel).

9535 Background: Simultaneous blockade of lymphocyte activation gene-3 (LAG-3) and programmed death-1 (PD-1) pathways enhances antitumor activity in patients (pts) with mel. While efficacy of nivo-rela has been demonstrated in a large cohort of therapy-naïve advanced mel, it remains important to assess clinical activity of this combination in real-world settings focusing on resectable mel and on tumor microenvironment (TME) factors impacting response to nivo-rela. In this study we report the clinical activity of nivo-rela and the relation of TME characteristics to response to therapy. Methods: This study included pts with mel treated with first-line nivo-rela in the neoadjuvant or advanced settings between 2022-2024 at Moffitt. Safety, progression-free (PFS), overall survival (OS) and pathologic response rates were evaluated in relation to mel characteristics. To assess the impact of TME on response to nivo-rela in advanced mel, we performed NanoString GeoMx proteomic analysis using immune cell profiling, immune cell typing, and IO drug target panels. Differential proteomic analysis (fold change ≥0.05, FDR <0.05) was performed using selected baseline samples (n=16) from responders (R) and non-responders (NR). Results: The study included 128 mel pts treated with nivo-rela in the advanced (n=101, [C1]) and neoadjuvant (n=27, [C2]) settings, 48 female (38%) and 80 male (62%), median age 71 [IQR 62–78]. In C1, with a median follow up of 13 months, mPFS and mOS with 95% CI were 19m (10-NR), and NR (25-NR), respectively. In C2, 6 (22%) of pts did not undergo definitive surgery due to disease progression (n=4) and clinical response to therapy (n=2). Among path-evaluable pts (n=21), major pathologic response rate was 10 (48%) including 6 complete (29%) and 4 near-complete responses 19%), with partial response in 3 (14%) and non-response in 8 patients (38%). Adverse events included adrenal insufficiency and myocarditis in 12 (9%) and 4 (3%) of all pts. TME assessment revealed no significant differences in expression of LAG3, PD-1, PDL-1, CD8 + among R vs NR. Baseline tumors from NR were characterized by high expression of B7-H3 in both tumor and immune compartments. No significant correlations were found between B7-H3 and PDL-1, LAG-3, and CTLA-4. High B7-H3 ROIs were enriched by CD163 + , CD68 + , CD14 + , and fibroblast activation protein alpha. Conclusions: In a real-world setting, first-line nivo-rela in advanced mel resulted in potentially better PFS while in resectable pts the major pathologic response rate was lower than previously reported in clinical trials. Mel TME with high B7-H3 protein expression was enriched with M2-skewed macrophages and fibroblasts in association with non-response to nivo-rela. This finding warrants further investigation of B7-H3 targeting agents in mel pts.