Abstract
PURPOSE: Administration of the lymphocyte activation gene 3 (LAG-3) inhibitor relatlimab (RELA) and the PD-1 inhibitor nivolumab (NIVO) significantly prolonged progression-free survival (PFS) versus NIVO alone in patients with advanced melanoma treated in RELATIVITY-047. This report describes correlative analyses of biospecimens collected within that trial to better understand the mechanisms of action and identify patients who could benefit from treatment with NIVO + RELA. PATIENTS AND METHODS: Pre- and on-treatment peripheral blood samples from 563 patients were analyzed using flow cytometry for changes in 77 prespecified immune cell populations and using immunoassay for peripheral IFNγ. Pretreatment tumor biopsies were evaluated using IHC and RNA sequencing. RESULTS: On-treatment expansion of 25 peripheral immune cell populations was significantly greater with NIVO + RELA versus NIVO alone. Responders to NIVO + RELA had greater on-treatment increases in LAG-3+CD4+ T cells than nonresponders. Significantly greater increases in peripheral IFNγ occurred after treatment with NIVO + RELA versus NIVO alone. A longer PFS was observed in patients treated with NIVO + RELA whose tumors had low CD8 expression compared with the NIVO arm. When evaluating the co-expression of CD8 and LAG-3, patients whose tumors had high CD8+LAG-3+ also showed a PFS benefit with NIVO + RELA versus NIVO. RNA sequencing revealed several distinct gene signatures associated with response to NIVO + RELA. CONCLUSIONS: These results highlight the unique biological effects of RELA in combination with NIVO and provide further understanding of the patient characteristics associated with increased benefit from NIVO + RELA.