Clinical Trial Finder

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 for central biomarker analyses .

• - 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.

The purpose of the study is to compare the efficacy of a triplet therapy (encorafenib, binimetinib, pembrolizumab) versus a doublet/control therapy (nivolumab and ipilimumab). Participants will have metastatic or unresectable locally advanced BRAF V600E/K-mutant melanoma, which progressed during or after prior treatment in the adjuvant or first-line metastatic setting, with an approved anti-PD-1 monotherapy (pembrolizumab or nivolumab), Approximately 150 participants will be randomized in a 1:1 ratio to the triplet or the doublet/control therapy (75 participants in each arm). Randomization will be stratified by baseline serum LDH level, and by type of PD-1 resistance.

Arms

Interventions