Relatlimab plus nivolumab versus nivolumab for advanced melanoma: 5-year survival and biomarker analyses of the phase 3 RELATIVITY-047 trial

Nivolumab plus relatlimab is approved for advanced melanoma based on the RELATIVITY-047 trial; however, long-term data are needed. Here, we report data from RELATIVITY-047 with the longest follow-up at present. In this phase 2–3, double-blind trial, patients with metastatic/unresectable melanoma were randomized 1:1 to nivolumab 480 mg plus relatlimab 160 mg (n = 355) or nivolumab 480 mg (n = 359) intravenously every 4 weeks. The primary endpoint was progression-free survival (PFS) by blinded independent central review. Secondary endpoints were overall survival (OS), response, and safety. Additional post-hoc analyses such as melanoma-specific survival (MSS), and exploratory biomarker analyses are also reported. This analysis shows clear separation in survival curves with the largest absolute differences to date in PFS, OS, and MSS. In this prespecified 5-year analysis, with a minimum follow-up of 57.3 months, nivolumab plus relatlimab demonstrated continued clinically significant benefit versus nivolumab for PFS (hazard ratio = 0.77; 95% confidence interval: 0.65–0.92), OS (hazard ratio = 0.78; 95% confidence interval: 0.64–0.95), and MSS (hazard ratio = 0.71; 95% confidence interval: 0.57–0.88). The safety profile remained consistent with prior reports. Among biomarker-evaluable patients in the programmed death ligand 1 ≥1% subgroup, analyses revealed an association between worse outcomes with nivolumab and high peripheral or tumor lymphocyte activation gene 3 (LAG-3)+ CD8 cell levels. The addition of relatlimab to nivolumab was associated with a lower prevalence of primary resistance than nivolumab alone. These data support the hypothesis that relatlimab can overcome LAG-3–mediated resistance to nivolumab and provides evidence for differential efficacy patterns observed across biomarker subgroups linked to primary versus acquired resistance states. ClinicalTrials.gov identifier: NCT03470922. As presented at the ESMO Congress 2026: In a 5 year follow-up of survival and correlative data from the pivotal phase 3 RELATIVITY-047 trial comparing relatlimab plus nivolumab versus nivolumab alone in patients with metastatic or unresectable melanoma, statistically significant differences in progression-free survival, overall survival and melanoma-specific survival were seen with high baseline levels of LAG3 high CD8+ T cells associated with improved response in the combination arm.