Phase 2 Study of Encorafenib and Binimetinib Plus Pembrolizumab in Participants With BRAF V600E/K Mutation-Positive Melanoma Who Progressed During or After Prior Treatment with Anti−PD-1 Therapy

Prior treatment

• 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 anticancer agent for the adjuvant or first-line treatment of melanoma prior to randomization.
• Previous participation in the Pfizer C4221016 STARBOARD Study.
• 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.
• History of thromboembolic or cerebrovascular events ≤12 weeks prior to randomization.
• 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.
• Prior or current symptomatic brain metastasis, leptomeningeal disease or other active CNS metastases.

Other illness

• Clinically significant cardiovascular diseases.
• Current noninfectious pneumonitis/ILD or history of noninfectious pneumonitis/ILD requiring steroids.

Other

• Mucosal or ocular melanoma.
• History or current evidence of RVO or current risk factors for RVO.

• 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 for central laboratory testing of biomarkers is required for all participants during the screening period.
• 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 1 measurable lesion per RECIST v1.1.
• ECOG PS of 0-1, and adequate organ and cardiac function, including LVEF ≥50% by cardiac imaging.