In a 5-year follow-up (minimum 57.3 months) of the RELATIVITY-047 trial, which led to the approval of nivolumab (anti-PD-1) plus relatlimab (anti-Lag3) for patients with metastatic, unresectable melanoma, Long et al. noted long-term benefits in progression-free, overall, and melanoma-specific survival versus nivolumab alone. In a subset of patients with PD-L1 ≥1%, survival curves separated after 3 years, and while those with high Lag3+ CD8+ T cells showed worse outcomes with nivolumab alone, they experienced greater late or post-progression benefits from relatlimab, suggesting mitigation of Lag3+ T cell-mediated primary resistance.
Contributed by Lauren Hitchings
ABSTRACT: 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 (HR) = 0.77; 95% confidence interval (CI): 0.65-0.92), OS (HR = 0.78; 95% CI: 0.64-0.95) and MSS (HR = 0.71; 95% CI: 0.57-0.88). The safety profile remained consistent with prior reports. Among biomarker-evaluable patients in the PD-L1 ≥1% subgroup, analyses revealed an association between worse outcomes with nivolumab and high peripheral or tumor 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 provide evidence for differential efficacy patterns observed across biomarker subgroups linked to primary versus acquired resistance states. ClinicalTrials.gov identifier: NCT03470922 .
