TPS9596 Background: Targeted therapy (BRAF + MEK inhibitors) and immunotherapy (anti-PD1 + anti-CTLA4) have improved overall survival for metastatic or unresectable BRAFV600E/Kmutant melanoma. Whereas targeted therapy has a high response rate, immunotherapy may deliver longer term disease control for a larger number of patients. Despite these treatments, patients with high risk metastatic melanoma such as those with brain or liver metastases, elevated lactate dehydrogenase (LDH) and bulky disease have inferior treatment outcomes with current therapies. A BRAF+MEK+PDL1 regimen has recently emerged however the role for this treatment remains unclear. Several recent trials combining MEK inhibition and immunotherapy have failed possibly because MEK inhibition can compromise T cell activation. Meanwhile the addition of CTLA4 blockade to PD1 inhibition appears to disproportionately benefit patients with non-T cell-inflamed tumors and potentially high-risk disease. For patients with high risk BRAF-mutant metastatic melanoma, further investigation of BRAF/MEK targeted and PD-1/CTLA-4 directed immunotherapy combination strategies remains a priority. Methods: This is an open label, multi-site, Phase 1/2 study of encorafenib (Enco) +/- binimetinib (Bini) + nivolumab (Nivo) + ipilimumab (Ipi) for the treatment of patients with unresectable or metastatic BRAF-mutated melanoma in high-risk cohorts (NCT04655157). An initial regimen confirming Phase I approach will be pursued on two schedules concurrently, with patients accruing equally to each group. Group 1 will receive 3mg/kg Nivo, and 1 mg/kg Ipi and 300mg Enco (12 participants, triple therapy) and Group 2 will receive 3mg/kg Nivo and 1mg/kg Ipi and 450mg Enco and 45mg Bini, (12 participants, quadruple therapy). Dose limiting toxicity (DLT) will be evaluated weeks 1-6. A recommended Phase II regimen (RP2R) [either triple or quadruple therapy] will be carried forward into two high risk metastatic disease cohort expansions of 30 participants each. Cohort 1 will include patients with symptomatic brain metastases, while cohort 2 will include patients with elevated LDH as well as either liver metastases OR bulky visceral disease (sum of longest diameters > 44mm). Patients meeting criteria for cohorts 1 and 2 will be placed in cohort 1. Patients with symptomatic brain metastases will be included with an ECOG up to 2 and on ≤ 4mg of dexamethasone or equivalent. Continuous Bayesian toxicity monitoring will be used throughout to monitor DLT. Pre and on-treatment tumor biopsies will assess changes in the tumor microenvironment while peripheral blood ctDNA and T cell Ki67% changes will assess early response and immune activation during triplet and quadruplet therapy. Clinical trial information: NCT04655157.