Background: More than half of all pts diagnosed with metastatic melanoma (MM) will develop brain metastases. Despite this prevalence, pts with MBM are excluded from the majority of clinical trials, preventing them from potential benefit of novel therapies. Long-term outcomes of the CheckMate 204 study combining ipilimumab (ipi) (3mg/kg) plus nivo (1 mg/kg) for asymptomatic MBM reported an intracranial (IC) response in 54% of pts. The 36-month IC progression-free survival (PFS) was 54% and overall survival (OS) was 72%. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 55% of pts. RELATIVITY-047, a global phase II/III randomized study, reported on the fixed-dose combination of nivo (480 mg) and rela (a LAG-3–blocking antibody,160 mg) compared to nivo (480 mg) alone for pts with advanced unresectable and untreated melanoma. The combination demonstrated significantly improved PFS and improved OS and objective response rate (ORR) compared to monotherapy. At 19.3 months of median follow-up, only the PFS benefit was statistically significant with a hazard ratio (HR) of 0.78 (95% CI 0.64-0.94). The OS benefit was not statistically significant (HR 0.8, 95% CI 0.64-1.01), and the descriptive ORR was 43.1% compared to 32.6% for single agent nivo. Grade 3 or 4 TRAEs occurred in 21% of pts in the combination group compared to 11% in the monotherapy group with no new safety signals. The nivo/rela combination has been FDA approved for the treatment of pts with MM but has not been studied in pts with MBM. We hypothesize that nivo/rela will be safe and tolerable for pts with MBM and demonstrate favorable outcomes compared to nivo monotherapy with fewer AEs in contrast to ipi/nivo combination. Methods: This single arm, single center, open-label phase II trial will evaluate the safety and efficacy of nivo/rela in pts with MBM (NCT05704647). 30 MBM pts who are treatment naïve to anti-PD-1 therapy will be enrolled. At least one unirradiated parenchymal brain metastasis at least 5 mm or larger is required for inclusion. Asymptomatic pts not requiring steroids for the management of their neurological symptoms are eligible. Pts requiring urgent local therapy with radiation or surgery are not eligible. Pts will be treated with nivo (480 mg)/rela (160 mg) every 4 weeks for up to 25 cycles, disease progression, or unacceptable toxicity. The primary objective is to evaluate IC ORR (CR + PR) by MRI per modified RECIST 1.1 criteria. Monitoring for futility will be performed using the Bayesian Optimal Phase 2 (BOP2) design. Thirty evaluable patients will provide 82% power to detect a difference between the historical IC ORR of 20% for nivo alone to a targeted ORR of 40% for nivo/rela. Longitudinal research blood, tissue, and microbiome samples will be collected along with neurocognitive assessment and quality of life surveys. Clinical trial information: NCT05704647.