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

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.

• Availability of adequate tumor tissue (archival or newly obtained; block or slides)to submit to the sponsor central laboratory(ies) during the screening period forcentral biomarker analyses .

• Must have received only 1 prior line of systemic therapy for melanoma (eitheradjuvant therapy or first-line anti-PD-1 monotherapy (ie, nivolumab orpembrolizumab)

• Must have anti-PD-1 resistant disease (primary or secondary) with confirmed diseaseprogression per RECIST v1.1 either during or after receipt of an approved anti-PD-1monotherapy (ie, nivolumab or pembrolizumab) for melanoma, defined according to theSITC 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% bycardiac imaging.

Exclusion Criteria:

• Mucosal or ocular melanoma.

• Diagnosis of immunodeficiency or an active autoimmune disease that required systemictreatment with chronic systemic steroid therapy or any other form ofimmunosuppressive therapy within the past 2 years.

• Clinically significant cardiovascular diseases.

• History of thromboembolic or cerebrovascular events ≤12 weeks prior torandomization.

• History or current evidence of RVO or current risk factors for RVO.

• Concurrent neuromuscular disorder that is associated with the potential of elevatedCK.

• Active bacterial, fungal, or viral infection requiring systemic therapeutictreatment within 2 weeks prior to randomization.

• Current non-infectious pneumonitis/interstitial lung disease or history ofnoninfectious pneumonitis/interstitial lung disease requiring steroids.

• Prior or current symptomatic brain metastasis, leptomeningeal disease or otheractive CNS metastases.

• Participants who permanently discontinued prior anti-PD-1 therapy due to toxicity orwill be unable to tolerate combination therapy based on investigator judgement areexcluded.

• Prior treatment with ipilimumab; prior combined immunotherapy blockade withanti-PD-1/L-1; prior treatment with a BRAFi and/or MEKi; or previous administrationof an investigational anti-cancer agent for the adjuvant or first-line treatment ofmelanoma prior to randomization.