This is a randomized, double-blind, placebo-controlled, Phase 3 study to compare the
efficacy, safety, and tolerability of encorafenib and binimetinib plus pembrolizumab (Triplet
Arm) versus placebo plus pembrolizumab (Control Arm) in participants with metastatic or
unresectable locally advanced BRAF V600E/K mutation-positive melanoma. The study will have an
open-label safety lead-in (SLI) phase to determine the safety recommended phase 3 dose (RP3D)
and pharmacokinetics (PK) of encorafenib and binimetinib plus pembrolizumab combination
therapy prior to initiation of the randomized Phase 3 part of the study. Two dose levels of
encorafenib in combination with binimetinib plus pembrolizumab will be explored in parallel.
A minimum of 12 evaluable participants will be enrolled per dose level. During the
double-blind randomized Phase 3 part of the study, approximately 600 eligible participants
will be randomized in a 1:1 ratio to the Triplet Arm (at RP3D determined in the SLI) or
Control Arm (approximately 300 participants per arm). Randomization will be stratified by
prior systemic adjuvant therapy and stage of disease by AJCC (ED8)
- Male or female participants ≥ 18 years at the time of informed consent.
- Participants who are willing and able to comply with all scheduled visits, treatment
plan, laboratory tests, lifestyle considerations, and other study procedures.
- Histologically confirmed unresectable (Stage IIIB, IIIC, or IIID) or metastatic (Stage
IV) cutaneous melanoma, according to the AJCC 8th edition.
- Presence of at least 1 measurable lesion as detected by radiological and/or
photographic methods according to RECIST v1.1.
- ECOG performance status 0 or 1.
- Documented evidence of a BRAF V600E or V600K mutation in melanoma tumor tissue as
previously determined by either PCR or NGS-based local laboratory assay (eg, US
FDA-approved test, CE-marked [European conformity] in vitro diagnostic in EU
countries, or equivalent), obtained during the course of normal clinical care, in a
CLIA- or similarly certified laboratory.
- Submission of adequate tumor tissue (archival or newly obtained; block or slides to
the sponsor central laboratory(ies) during the screening period and prior to
enrollment (SLI)/randomization (Phase 3).
- Have not received prior first-line systemic therapy for metastatic or unresectable
locally advanced melanoma.
- Adequate bone marrow function, hepatic and renal function.
- Capable of giving signed informed consent.
- Other medical or psychiatric condition including recent (within the past year) or
active suicidal ideation/behavior or laboratory abnormality that may increase the risk
of study participation or, in the investigator's judgment, make the participant
inappropriate for the study.
- Mucosal or ocular melanoma.
- Diagnosis of immunodeficiency or an active autoimmune disease that required systemic
treatment in the past 2 years (ie, with use of disease modifying agents,
corticosteroids, or immunosuppressive drugs).
- Clinically significant multiple or severe drug allergies, intolerance to topical
corticosteroids, or severe post-treatment hypersensitivity reactions (including, but
not limited to, erythema multiforme major, linear IgA dermatosis, toxic epidermal
necrolysis, and exfoliative dermatitis).
- Unable to swallow, retain, and absorb oral medications.
- Impairment of GI function or disease which may significantly alter the absorption of
oral study intervention (eg, uncontrolled nausea, vomiting or diarrhea, malabsorption
syndrome, including malabsorption syndrome secondary to prior GI surgery).
- Clinically significant cardiovascular diseases,
- History of thromboembolic or cerebrovascular events ≤ 12 weeks prior to enrollment
(SLI)/randomization (Phase 3). Examples include transient ischemic attacks,
cerebrovascular accidents, hemodynamically significant (ie, massive or sub-massive)
deep vein thrombosis or pulmonary emboli.
- History or current evidence of RVO or current risk factors for RVO (eg, uncontrolled
glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability
syndromes); history of retinal degenerative disease.
- Concurrent neuromuscular disorder that is associated with the potential of elevated CK
(eg, inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis,
spinal muscular atrophy).
- Current noninfectious pneumonitis or history of noninfectious pneumonitis requiring
- Evidence of HBV or HCV infection.
- Known history of a positive test for HIV or known AIDS.
- Any active infection requiring systemic therapeutic treatment within 2 weeks prior to
enrollment (SLI)/ randomization (Phase 3).
- Participants with prior or current symptomatic brain metastasis, leptomeningeal
disease or other active CNS metastases.
- Concurrent or previous other malignancy within 2 years of study entry, except
curatively treated basal or squamous cell skin cancer, prostate intraepithelial
neoplasm, carcinoma in-situ of the cervix, Bowen's disease and Gleason ≤ 6 prostate
cancer. Participants with a history of other curatively treated cancers must be
reviewed with the sponsor or designee prior to entering the study.
- Participants who previously received and subsequently discontinued encorafenib and/or
binimetinib and/or anti-PD-1/-L1 due to severe toxicity.
- For participants in the SLI only: Current use or anticipated need for food or drugs
that are known moderate or strong CYP3A4 inhibitors during screening and through the
- Participant has not recovered to Grade ≤ 1 from toxic effects of prior therapy and/or
complications from prior surgical intervention before enrollment (SLI)/ randomization
- Receipt of protocol defined medications or treatments outside of required intervals
before enrollment (SLI)/randomization (Phase 3):
- Previous administration with an investigational drug ≤ 6 months prior to enrollment
(SLI)/randomization (Phase 3).
- Known sensitivity or contraindication to any component of study intervention
(encorafenib, binimetinib and pembrolizumab), or their excipients.
- Pregnant, confirmed by a positive β-hCG laboratory test result, or is breastfeeding
- Investigator site staff or Pfizer employees directly involved in the conduct of the
study, site staff otherwise supervised by the investigator, and their respective