Unravelling relatlimab-specific biology using biomarker analyses in patients with advanced melanoma in RELATIVITY-047

Purpose: Administration of the lymphocyte-activation gene-3 (LAG-3) inhibitor relatlimab (RELA) and programmed death-1 (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 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 by flow cytometry for changes in 77 pre-specified immune cell populations, and by immunoassay for peripheral interferon gamma (IFNγ). Pre-treatment tumor biopsies were evaluated using immunohistochemistry 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 non‑responders. 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 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.