A Study Comparing 3 Study Medicines (Encorafenib, Binimetinib, Pembrolizumab) to 2 Study Medicines (Ipilimumab and Nivolumab) in Patients With Advanced Melanoma (PORTSIDE)

Inclusion Criteria: Male or female participants ≥18 years of age at the time of informed consent. Histologically confirmed unresectable (Stage IIIB, IIIC, or IIID) or metastatic (Stage IV) cutaneous melanoma, according to the AJCC 8th edition. Documented evidence of a BRAF V600E or V600K mutation. Submission of adequate tumor tissue for central laboratory testing of BRAF V600E-mutation and biomarkers is required for all participants during the screening period and prior to randomization. Must have received only 1 prior line of systemic therapy for melanoma (either adjuvant therapy or first-line anti-PD-1 monotherapy (ie, nivolumab or pembrolizumab) Must have anti-PD-1 resistant disease (primary or secondary) with confirmed disease progression per RECIST v1.1 either during or after receipt of an approved anti-PD-1 monotherapy (ie, nivolumab or pembrolizumab) for melanoma, defined according to the SITC Immunotherapy Resistance Taskforce (Kluger et al, 2020). Have at least one measurable lesion per RECIST v1.1. ECOG PS of 0-1, and adequate organ and cardiac function, including LVEF ≥50% by cardiac imaging. Exclusion Criteria: Mucosal or ocular melanoma. Diagnosis of immunodeficiency or an active autoimmune disease that required systemic treatment with chronic systemic steroid therapy or any other form of immunosuppressive therapy within the past 2 years. Clinically significant cardiovascular diseases. History of thromboembolic or cerebrovascular events ≤12 weeks prior to randomization. History or current evidence of RVO or current risk factors for RVO. Concurrent neuromuscular disorder that is associated with the potential of elevated CK. Active bacterial, fungal, or viral infection requiring systemic therapeutic treatment within 2 weeks prior to randomization. Current non-infectious pneumonitis/interstitial lung disease or history of noninfectious pneumonitis/interstitial lung disease requiring steroids. Prior or current symptomatic brain metastasis, leptomeningeal disease or other active CNS metastases. Participants who permanently discontinued prior anti-PD-1 therapy due to toxicity or will be unable to tolerate combination therapy based on investigator judgement are excluded. Prior treatment with ipilimumab; prior combined immunotherapy blockade with anti-PD-1/L-1; prior treatment with a BRAFi and/or MEKi; or previous administration of an investigational anti-cancer agent for the adjuvant or first-line treatment of melanoma prior to randomization.