A Study of the Safety and Efficacy of Pembrolizumab (MK-3475) in Combination With Trametinib and Dabrafenib in Participants With Advanced Melanoma (MK-3475-022/KEYNOTE-022)

A Phase I/II Study to Assess the Safety and Efficacy of MK-3475 in Combination With Trametinib and Dabrafenib in Subjects With Advanced Melanoma

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02130466

Enrollment

184

Registered

2014-05-05

Start date

2014-05-29

Completion date

2021-07-14

Last updated

2022-08-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Melanoma, Solid Tumors

Keywords

Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1), Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)

Brief summary

This is a 5-part dose-finding and preliminary efficacy study of pembrolizumab (Pembro) + dabrafenib (D) + trametinib (T) for participants with advanced melanoma and solid tumors. Parts 1 and 2 are open-label to find and confirm the maximum tolerated dose (MTD)/maximum administered dose (MAD) for Pembro+D+T. The primary hypothesis (Parts 1 and 2) is that Pembro+D+T is sufficiently well-tolerated to permit clinical investigation. Part 3 is a double-blind study of Pembro+D+T versus placebo+D+T. The primary study hypothesis (Part 3 only) is that the Pembro+D+T improves progression-free survival (PFS) compared with placebo+D+T. Part 4 is nonrandomized and open-label and is designed to evaluate the safety and tolerability and identify the MTD or MAD of Pembro+T in participants who have v-raf murine sarcoma viral oncogene homolog B1 \[BRAF\] mutation-negative (without V600 E or K) melanoma or solid tumors \[irrespective of BRAF status\]. The primary hypothesis (Part 4) is that Pembro+T is sufficiently well-tolerated to permit clinical investigation. Part 5 will confirm the dose(s) identified in Part 4 in participants BRAF wild type \[without V600E or K\] melanoma or solid tumors \[irrespective of BRAF status\] and will further evaluate the safety and preliminary efficacy (Objective Response Rate \[ORR\]) of Pembro+T in participants who have BRAF wild type \[without V600E or K\] melanoma or solid tumors \[irrespective of BRAF status\]. The primary hypotheses (Part 5) are that Pembro+T is sufficiently well-tolerated at the MTD/MAD to permit further clinical investigation and is effective in attaining objective responses based upon Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by Investigator review in participants who have melanoma without BRAF V600 E or K mutations. With Amendment 5 (21-Mar-2019), the Part 5 expansion cohort will not be pursued following the completion of Part 5 dose confirmation. Parts 1 and 2 of the study may also explore, if needed based on tolerability, the backup combinations of open-label Pembro+T (for BRAF mutation-negative participants) or Pembro+D (for BRAF mutation-positive participants). These will run concurrently with the Pembro+D+T arm.

Interventions

BIOLOGICALPembrolizumab

IV infusion

DRUGDabrafenib

oral capsule

DRUGTrametinib

oral tablet

DRUGPlacebo

IV infusion

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Histologically-confirmed diagnosis of advanced (unresectable Stage III) or metastatic (Stage IV) melanoma excluding mucosal, or ocular melanoma (or a histologically or cytologically-documented locally-advanced or metastatic solid malignancy in Parts 4 and 5) * At least 1 measurable lesion as defined by RECIST 1.1 on imaging studies (computed tomography \[CT\] or magnetic resonance imaging \[MRI\]) * For solid tumors other than melanoma, (in Part 4 or 5 \[dose confirmation only\]), participants must have a malignancy that is incurable and has either: (a) failed prior standard therapy, (b) for which no standard therapy exists, or (c) standard therapy is not considered appropriate by the participants and treating physician. There is no limit to the number of prior treatment regimens, but prior treatment(s) should not include compounds targeting programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1), BRAF, or mitogen-activated protein kinase (MEK). Treatment must end at least 4 weeks prior to randomization * BRAF mutation-positive (V600 E or K) melanoma for Parts 1, 2 and 3, or for Parts 1, 2, 4 and 5 only BRAF mutation-negative (wild type) melanoma with documented progression of ≥1 measurable lesion after prior therapy (if prior therapy was received). The inclusion criterion does not apply to participants with solid tumors in Parts 4 and 5 (dose confirmation only) * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 * Anticipated life expectancy of at least 3 months * Able to swallow and retain oral medication and no clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels * Adequate organ function * Provide tissue for biomarker analysis from a newly or recently-obtained biopsy (within 90 days of Study Day 1) of a tumor lesion not previously irradiated * Female participants of non-childbearing potential must be willing to use highly effective contraceptive measures from the Screening Visit (Visit 1) through 120 days after the last dose of study drug; male participants must agree to use an adequate method of contraception starting with the first dose of study drug through 120 days after the last dose of study drug * Female participants of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study drug

Exclusion criteria

* Currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of study drug * Prior systemic therapy (for participants who are BRAF mutation-positive), or BRAF mutation-negative and has received \>1 prior systemic therapy for metastatic melanoma * Prior therapy with compounds targeting PD-1, PD-L1, BRAF, MEK or other molecules in the mitogen-activated protein kinase (MAPK) pathway * BRAF mutation-positive and has received prior systemic therapy with ipilimumab or other anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibodies. The BRAF exclusion criterion does not apply to participants with solid tumor in Parts 4 and 5 (dose confirmation only) * Chemotherapy, radioactive, or biological cancer therapy within 4 weeks prior to the first dose of study drug, or not recovered from clinically significant adverse events due to cancer therapeutics administered more than 4 weeks prior to the first dose of study drug * Expected to require any other form of systemic or localized antineoplastic therapy while in this study * Has a known additional malignancy that is progressing or requires active treatment. Exceptions include early stage cancers (carcinoma in situ or stage 1) treated with curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, or in situ breast cancer that has undergone potentially curative therapy * Active central nervous system (CNS) metastases and/or carcinomatous meningitis * Active infection requiring systemic therapy * Active autoimmune disease, or documented history of autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents * Previous severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb) * On chronic systemic steroid therapy (\>10 mg/day prednisone or equivalent) within 2 weeks prior to first dose of study drug or on any other form of immunosuppressive medication * History or evidence of cardiovascular risk * Uncorrectable electrolyte abnormalities, long QT syndrome or taking medications known to prolong the QT interval * History of prior or current retinal vein occlusion (RVO) * Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drugs, their excipients, and/or dimethyl sulfoxide (DMSO) * Has had an allogeneic tissue/solid organ transplant, prior stem cell or bone marrow transplant * History of (non-infectious) pneumonitis that required steroids or current pneumonitis * Human immunodeficiency virus (HIV) * Hepatitis B or C * Received a live vaccine within 30 days prior to first dose of study drug * Pregnant or breastfeeding or expecting to conceive or father children from the Screening Visit (Visit 1) through 120 days after last dose of study drug

Design outcomes

Primary

Measure	Time frame	Description
Parts 1, 2, 4, and 5: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)	Up to approximately 6 weeks	DLTs were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Events were considered a DLT if occurred during the DLT evaluation period and met ≥1 of the following: significant hematologic toxicity; significant Grade ≥3 non-hematologic toxicity not previously identified or known to occur and cannot be controlled with routine supportive measures; drug-related toxicity that results in an interruption of any component of study therapy for \>21 consecutive days and cannot be controlled ≤2 weeks from onset; any other Grade ≥2 non-hematological toxicity that is dose limiting with some exceptions; and liver chemistries meeting study stopping guidelines. The DLT evaluable population included all participants in Parts 1, 2, 4, and 5 who received ≥66% of planned treatments during the DLT observation period or discontinued treatment due to a DLT. Per protocol, DLT outcome analysis did not include Part 3.
Part 2: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator in Participants Without BRAF V600 E or K Mutations	Up to approximately 85 months	ORR was defined as the percentage of participants without BRAF V600 E or K mutation who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: divided into very good partial response \[VGPR; \>60% tumor reduction\] and moderate partial response \[MPR; \>30-≤60% tumor reduction\]) per RECIST 1.1 as assessed by investigator. The percentage of participants who experienced a CR or PR based on RECIST 1.1 as assessed by investigator were reported.
Part 5: ORR Per RECIST 1.1 as Assessed by Investigator in Participants Without BRAF V600 E or K Mutations or With Solid Tumors Irrespective of BRAF Status	Up to approximately 85 months	ORR was defined as the percentage of participants without BRAF V600 E or K mutation who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: divided into very good partial response \[VGPR; \>60% tumor reduction\] and moderate partial response \[MPR; \>30-≤60% tumor reduction\]) per RECIST 1.1 as assessed by investigator. The percentage of participants who experienced a CR or PR based on RECIST 1.1 as assessed by investigator were reported.
Part 3: Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations	Up to approximately 85 months	PFS was defined as the time from randomization to the first documented disease progression (PD) or death due to any cause, whichever occurred first, based on RECIST 1.1 by investigator review. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. PFS was analyzed using the Kaplan-Meier method and was reported in months. Statistical analysis used a Cox regression model with treatment as a covariate and stratified by Eastern Cooperative Oncology Group performance status and Lactate Dehydrogenase.
Parts 1, 2, 4, and 5: Number of Participants Who Experienced an Adverse Event (AE)	Up to approximately 32 months	An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE was any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the study drug, was also an AE. The number of participants who experienced an AE was reported. Per protocol, AE outcome analysis did not include Part 3.
Parts 1, 2, 4, and 5: Number of Participants Who Discontinued Study Treatment Due to an AE	Up to approximately 29 months	An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily had to have a causal relationship with this treatment. An AE was any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the study drug, was also an AE. The number of participants who discontinued study treatment due to an AE was reported. Per protocol, discontinuation outcome analysis did not include Part 3.

Secondary

Measure	Time frame	Description
Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and Trametinib in Participants From Part 3	Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.	Cmax was defined as the maximum concentration of pembrolizumab observed after administration of 2 mg/kg pembrolizumab in combination with dabrafenib and trametinib. Blood samples were collected at multiple time points to estimate the Cmax of pembrolizumab. The Cmax of pembrolizumab is presented.
Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 4	Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.	Cmax was defined as the maximum concentration of pembrolizumab observed after administration of 200 mg pembrolizumab in combination with trametinib. Blood samples were collected at multiple time points to estimate the Cmax of pembrolizumab. The Cmax of pembrolizumab is presented.
Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 5	Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.	Cmax was defined as the maximum concentration of pembrolizumab observed after administration of 200 mg pembrolizumab in combination with trametinib. Blood samples were collected at multiple time points to estimate the Cmax of pembrolizumab. The Cmax of pembrolizumab is presented.
Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2	Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.	Ctrough was defined as the lowest concentration of pembrolizumab that occurred immediately prior to the next dose of 2 mg/kg pembrolizumab administered in combination with dabrafenib and/or trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of pembrolizumab. All participants who received pembrolizumab from Parts 1 and 2 were handled as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Ctrough of pembrolizumab is presented.
Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and Trametinib in Participants From Part 3	Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.	Ctrough was defined as the lowest concentration of pembrolizumab that occurred immediately prior to the next dose of 2 mg/kg pembrolizumab administered in combination with dabrafenib and trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of pembrolizumab. The Ctrough of pembrolizumab is presented.
Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 4	Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.	Ctrough was defined as the lowest concentration of pembrolizumab that occurred immediately prior to the next dose of 200 mg pembrolizumab administered in combination with trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of pembrolizumab. The Ctrough of pembrolizumab is presented.
Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 5	Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.	Ctrough was defined as the lowest concentration of pembrolizumab that occurred immediately prior to the next dose of 200 mg pembrolizumab administered in combination with trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of pembrolizumab. The Ctrough of pembrolizumab is presented.
Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Cmax was defined as the maximum concentration of dabrafenib observed after administration of 150 mg dabrafenib in combination with 2 mg/kg pembrolizumab and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Cmax of dabrafenib. All participants who received dabrafenib from Parts 1 and 2 were handled as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Cmax of dabrafenib is presented.
Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Cmax was defined as the maximum concentration of dabrafenib observed after administration of 150 mg dabrafenib in combination with 2 mg/kg pembrolizumab and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Cmax of dabrafenib. The Cmax of dabrafenib is presented.
Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With Placebo and 2 mg Trametinib in Participants From Part 3	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Cmax was defined as the maximum concentration of dabrafenib observed after administration of 150 mg dabrafenib in combination with saline placebo and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Cmax of dabrafenib. The Cmax of dabrafenib is presented.
Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Ctrough was defined as the lowest concentration of dabrafenib that occurred immediately prior to the next dose of 150 mg dabrafenib administered in combination with 2 mg/kg pembrolizumab and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of dabrafenib. All participants who received dabrafenib from Parts 1 and 2 were handled as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Ctrough of dabrafenib is presented.
Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Ctrough was defined as the lowest concentration of dabrafenib that occurred immediately prior to the next dose of 150 mg dabrafenib administered in combination with 2 mg/kg pembrolizumab and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of dabrafenib. The Ctrough of dabrafenib is presented.
Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With Placebo and 2 mg Trametinib in Participants From Part 3	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Ctrough was defined as the lowest concentration of dabrafenib that occurred immediately prior to the next dose of 150 mg dabrafenib administered in combination with saline placebo and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of dabrafenib. The Ctrough of dabrafenib is presented.
Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Cmax was defined as the maximum concentration of trametinib observed after administration of 2 mg trametinib in combination with 2 mg/kg pembrolizumab and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. All participants who received 2 mg trametinib from Parts 1 and 2 were treated as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Cmax of trametinib is presented.
Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Cmax was defined as the maximum concentration of trametinib observed after administration of 1.5 mg trametinib in combination with 2 mg/kg pembrolizumab. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. All participants who received 1.5 mg trametinib from Parts 1 and 2 were treated as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Cmax of trametinib is presented.
Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Cmax was defined as the maximum concentration of trametinib observed after administration of 2 mg trametinib in combination with 2 mg/kg pembrolizumab and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The Cmax of trametinib is presented.
Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination With Placebo and 150 mg Dabrafenib in Participants From Part 3	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Cmax was defined as the maximum concentration of trametinib observed after administration of 2 mg trametinib in combination with saline placebo and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The Cmax of trametinib is presented.
Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Cmax was defined as the maximum concentration of trametinib observed after administration of 2 mg trametinib in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The Cmax of trametinib is presented.
Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Cmax was defined as the maximum concentration of trametinib observed after administration of 1.5 mg trametinib in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The Cmax of trametinib is presented.
Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Cmax was defined as the maximum concentration of trametinib observed after administration of 2 mg trametinib in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The Cmax of trametinib is presented.
Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Cmax was defined as the maximum concentration of trametinib observed after administration of 1.5 mg trametinib in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The Cmax of trametinib is presented.
Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 2 mg trametinib administered in combination with 2 mg/kg pembrolizumab and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. All participants who received 2 mg trametinib from Parts 1 and 2 were treated as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Ctrough of trametinib is presented.
Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 1.5 mg trametinib administered in combination with 2 mg/kg pembrolizumab. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. All participants who received 1.5 mg trametinib from Parts 1 and 2 were treated as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Ctrough of trametinib is presented.
Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 2 mg trametinib administered in combination with 2 mg/kg pembrolizumab and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The Ctrough of trametinib is presented.
Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination With Placebo and 150 mg Dabrafenib in Participants From Part 3	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 2 mg trametinib administered in combination with saline placebo and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The Ctrough of trametinib is presented.
Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 2 mg trametinib administered in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The Ctrough of trametinib is presented.
Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 1.5 mg trametinib administered in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The Ctrough of trametinib is presented.
Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 2 mg trametinib administered in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The Ctrough of trametinib is presented.
Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 1.5 mg trametinib administered in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The Ctrough of trametinib is presented.
Clearance (Cl) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2	Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Cl of pembrolizumab, defined as the volume of plasma from which pembrolizumab is eliminated per unit time following pembrolizumab administration. This analysis was not performed.
Clearance (Cl) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and Trametinib in Participants From Part 3	Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Cl of pembrolizumab, defined as the volume of plasma from which pembrolizumab is eliminated per unit time following pembrolizumab administration. This analysis was not performed.
Clearance (Cl) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 4	Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Cl of pembrolizumab, defined as the volume of plasma from which pembrolizumab is eliminated per unit time following pembrolizumab administration. This analysis was not performed.
Clearance (Cl) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 5	Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Cl of pembrolizumab, defined as the volume of plasma from which pembrolizumab is eliminated per unit time following pembrolizumab administration. This analysis was not performed.
Clearance (Cl) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Cl of dabrafenib, defined as the volume of plasma from which dabrafenib is eliminated per unit time following dabrafenib administration. This analysis was not performed.
Clearance (Cl) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Cl of dabrafenib, defined as the volume of plasma from which dabrafenib is eliminated per unit time following dabrafenib administration. This analysis was not performed.
Clearance (Cl) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With Placebo and 2 mg Trametinib in Participants From Part 3	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Cl of dabrafenib, defined as the volume of plasma from which dabrafenib is eliminated per unit time following dabrafenib administration. This analysis was not performed.
Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.
Clearance (Cl) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.
Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.
Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination With Placebo and 150 mg Dabrafenib in Participants From Part 3	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.
Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.
Clearance (Cl) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.
Clearance (Cl) of Trametinib Following Administration of 2 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.
Clearance (Cl) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.
Volume of Distribution (Vc) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2	Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Vc of pembrolizumab, defined as the theoretical volume that would be necessary to contain the total amount of administered pembrolizumab at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Volume of Distribution (Vc) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and Trametinib in Participants From Part 3	Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Vc of pembrolizumab, defined as the theoretical volume that would be necessary to contain the total amount of administered pembrolizumab at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Volume of Distribution (Vc) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 4	Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Vc of pembrolizumab, defined as the theoretical volume that would be necessary to contain the total amount of administered pembrolizumab at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Volume of Distribution (Vc) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 5	Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Vc of pembrolizumab, defined as the theoretical volume that would be necessary to contain the total amount of administered pembrolizumab at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Volume of Distribution (Vc) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Vc of dabrafenib, defined as the theoretical volume that would be necessary to contain the total amount of administered dabrafenib at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Volume of Distribution (Vc) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Vc of dabrafenib, defined as the theoretical volume that would be necessary to contain the total amount of administered dabrafenib at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Volume of Distribution (Vc) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With Placebo and 2 mg Trametinib in Participants From Part 3	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Vc of dabrafenib, defined as the theoretical volume that would be necessary to contain the total amount of administered dabrafenib at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Volume of Distribution (Vc) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg Trametinib in Combination With Placebo and 150 mg Dabrafenib in Participants From Part 3	Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Part 1: ORR Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations	Up to approximately 85 months	ORR was defined as the percentage of participants who had a CR (Disappearance of all target lesions) or a PR (divided into very good partial response \[VGPR; \>60% tumor reduction\] and moderate partial response \[MPR; \>30-≤60% tumor reduction\]) per RECIST 1.1 as assessed by investigator. The percentage of participants who experienced a CR or PR as assessed by the investigator was presented.
Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Volume of Distribution (Vc) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Volume of Distribution (Vc) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4	Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.	Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.
Part 2: ORR Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations	Up to approximately 85 months	ORR was defined as the percentage of participants who had a CR (Disappearance of all target lesions) or a PR (divided into very good partial response \[VGPR; \>60% tumor reduction\] and moderate partial response \[MPR; \>30-≤60% tumor reduction\]) per RECIST 1.1 as assessed by investigator. The percentage of participants who experienced a CR or PR as assessed by the investigator was presented.
Part 3: ORR Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations	Up to approximately 85 months	ORR was defined as the percentage of participants who had a CR (Disappearance of all target lesions) or a PR (divided into very good partial response \[VGPR; \>60% tumor reduction\] and moderate partial response \[MPR; \>30-≤60% tumor reduction\]) per RECIST 1.1 as assessed by investigator. The percentage of participants who experienced a CR or PR as assessed by the investigator was presented.
Part 3: Duration of Response (DOR) Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations	Up to approximately 85 months	For participants who demonstrated a confirmed CR (Disappearance of all target lesions) or a confirmed PR (divided by VGPR \[\>60% tumor reduction\] and MPR \[\>30-≤60% tumor reduction\]) per RECIST 1.1 as assessed by the investigator, DOR was defined as the time from first documented evidence of CR or PR until progressive disease (PD). Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. The DOR as assessed by the investigator was analyzed using Kaplan-Meier method and reported in months.
Part 3: Overall Survival (OS) in Participants With BRAF V600 E or K Mutations	Up to approximately 85 months	OS was defined as the time from randomization to death due to any cause. OS was analyzed using the Kaplan-Meier method and was reported in months. Statistical analysis used a Cox regression model with treatment as a covariate and stratified by Eastern Cooperative Oncology Group performance status and Lactate Dehydrogenase.
Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2	Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.	Cmax was defined as the maximum concentration of pembrolizumab observed after administration of 2 mg/kg pembrolizumab in combination with dabrafenib and/or trametinib. Blood samples were collected at multiple time points to estimate the Cmax of pembrolizumab. All participants who received pembrolizumab from Parts 1 and 2 were handled as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Cmax of pembrolizumab is presented.

Participant flow

Pre-assignment details

For Parts 1 and 2 of the study the optional pembrolizumab+trametinib arm was added to the study but the optional pembrolizumab+dabrafenib arm was not implemented.

Participants by arm

Arm	Count
Part 1:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by intravenous (IV) infusion on Days 1 and 22 of each 6-week cycle (Q6W); 150 mg/day total dabrafenib orally, in a divided dose, twice a day (BID) starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally once a day (QD) starting on Day 1 and continuing up until study treatment discontinuation.	7
Part 1:Pembrolizumab 2 mg/kg+Trametinib 2 mg Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.	3
Part 1:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.	2
Part 2:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.	8
Part 2:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.	2
Part 3:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.	60
Part 3:Placebo+Dabrafenib 150 mg+Trametinib 2 mg Participants with BRAF mutant melanoma received saline placebo administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.	60
Part 4:4 Weeks Trametinib (Tra) 2mg; Pembrolizumab+Tra 2mg Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 4 weeks. Starting with Week 5, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 of each 3-week cycle (Q3W) and a concurrent dosing schedule of 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.	3
Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.	4
Part 4:4 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 4 weeks. Starting with Week 5, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.	5
Part 4:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 2 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.	6
Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Intermittent Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 1.5 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.	3
Part 5:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.	12
Part 5:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 2 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.	9
Total	184

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005	FG006	FG007	FG008	FG009	FG010	FG011	FG012	FG013
Overall Study	Death	4	1	1	3	2	30	45	2	3	4	5	3	11	7
Overall Study	Lost to Follow-up	1	0	0	0	0	1	0	0	0	0	0	0	1	0
Overall Study	Participation in Study Discontinued by Sponsor	1	2	1	5	0	27	14	1	0	1	1	0	0	2
Overall Study	Physician Decision	0	0	0	0	0	1	1	0	0	0	0	0	0	0
Overall Study	Withdrawal by Subject	1	0	0	0	0	1	0	0	1	0	0	0	0	0

Baseline characteristics

Characteristic	Part 1:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg	Part 1:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg	Part 2:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg	Part 2:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg	Part 3:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg	Part 3:Placebo+Dabrafenib 150 mg+Trametinib 2 mg	Part 4:4 Weeks Trametinib (Tra) 2mg; Pembrolizumab+Tra 2mg	Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg	Part 4:4 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg	Part 4:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent	Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Intermittent	Part 5:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg	Part 5:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent	Total	Part 1:Pembrolizumab 2 mg/kg+Trametinib 2 mg
Age, Continuous	68.0 years STANDARD_DEVIATION 2.8	52.0 years STANDARD_DEVIATION 14	42.0 years STANDARD_DEVIATION 14.2	83.0 years STANDARD_DEVIATION 5.7	55.3 years STANDARD_DEVIATION 12	57.2 years STANDARD_DEVIATION 14.6	47.3 years STANDARD_DEVIATION 19.9	50.0 years STANDARD_DEVIATION 18	57.0 years STANDARD_DEVIATION 18	55.5 years STANDARD_DEVIATION 17.9	58.0 years STANDARD_DEVIATION 12.2	55.7 years STANDARD_DEVIATION 14.1	55.9 years STANDARD_DEVIATION 13.3	55.5 years STANDARD_DEVIATION 14.2	54.0 years STANDARD_DEVIATION 15.7
BRAF Mutation Status Data Missing	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	2 Participants	2 Participants	3 Participants	2 Participants	2 Participants	1 Participants	3 Participants	15 Participants	0 Participants
BRAF Mutation Status Mutant (BRAF Positive)	0 Participants	7 Participants	8 Participants	0 Participants	60 Participants	60 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	135 Participants	0 Participants
BRAF Mutation Status Undetermined	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	2 Participants	2 Participants	0 Participants	6 Participants	1 Participants	12 Participants	0 Participants
BRAF Mutation Status Wild Type (BRAF Negative)	2 Participants	0 Participants	0 Participants	2 Participants	0 Participants	0 Participants	1 Participants	1 Participants	0 Participants	2 Participants	1 Participants	5 Participants	5 Participants	22 Participants	3 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	2 Participants	0 Participants	0 Participants	0 Participants	0 Participants	3 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	2 Participants	7 Participants	7 Participants	2 Participants	57 Participants	57 Participants	3 Participants	2 Participants	2 Participants	4 Participants	2 Participants	12 Participants	9 Participants	169 Participants	3 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	1 Participants	0 Participants	3 Participants	2 Participants	0 Participants	2 Participants	1 Participants	2 Participants	1 Participants	0 Participants	0 Participants	12 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	1 Participants	0 Participants	0 Participants	1 Participants	1 Participants	1 Participants	0 Participants	5 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	2 Participants	7 Participants	8 Participants	2 Participants	60 Participants	59 Participants	2 Participants	4 Participants	5 Participants	5 Participants	2 Participants	11 Participants	9 Participants	179 Participants	3 Participants
Sex: Female, Male Female	1 Participants	3 Participants	5 Participants	0 Participants	27 Participants	24 Participants	0 Participants	2 Participants	3 Participants	5 Participants	2 Participants	8 Participants	6 Participants	86 Participants	0 Participants
Sex: Female, Male Male	1 Participants	4 Participants	3 Participants	2 Participants	33 Participants	36 Participants	3 Participants	2 Participants	2 Participants	1 Participants	1 Participants	4 Participants	3 Participants	98 Participants	3 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk	EG007 affected / at risk	EG008 affected / at risk	EG009 affected / at risk	EG010 affected / at risk	EG011 affected / at risk	EG012 affected / at risk	EG013 affected / at risk
deaths Total, all-cause mortality	4 / 7	1 / 3	1 / 2	3 / 8	2 / 2	31 / 60	45 / 60	2 / 3	3 / 4	4 / 5	5 / 6	3 / 3	11 / 12	7 / 9
other Total, other adverse events	7 / 7	3 / 3	2 / 2	8 / 8	2 / 2	60 / 60	58 / 60	3 / 3	4 / 4	5 / 5	6 / 6	3 / 3	11 / 12	9 / 9
serious Total, serious adverse events	1 / 7	0 / 3	1 / 2	3 / 8	1 / 2	36 / 60	20 / 60	1 / 3	1 / 4	4 / 5	4 / 6	1 / 3	4 / 12	2 / 9

Outcome results

Primary

Part 2: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator in Participants Without BRAF V600 E or K Mutations

ORR was defined as the percentage of participants without BRAF V600 E or K mutation who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: divided into very good partial response \[VGPR; \>60% tumor reduction\] and moderate partial response \[MPR; \>30-≤60% tumor reduction\]) per RECIST 1.1 as assessed by investigator. The percentage of participants who experienced a CR or PR based on RECIST 1.1 as assessed by investigator were reported.

Time frame: Up to approximately 85 months

Population: All enrolled participants without BRAF V600 E or K mutations in Part 2

Arm	Measure	Value (NUMBER)
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Part 2: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator in Participants Without BRAF V600 E or K Mutations	50.0 Percentage of Participants

Primary

Part 3: Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

PFS was defined as the time from randomization to the first documented disease progression (PD) or death due to any cause, whichever occurred first, based on RECIST 1.1 by investigator review. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. PFS was analyzed using the Kaplan-Meier method and was reported in months. Statistical analysis used a Cox regression model with treatment as a covariate and stratified by Eastern Cooperative Oncology Group performance status and Lactate Dehydrogenase.

Time frame: Up to approximately 85 months

Population: All randomized participants with BRAF V600 E or K mutations in Part 3

Arm	Measure	Value (MEDIAN)
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Part 3: Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations	17.0 Months
Part 1:Pembrolizumab 2 mg/kg+Trametinib 2 mg	Part 3: Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations	9.9 Months

95% CI: [0.29, 0.74]

Primary

Part 5: ORR Per RECIST 1.1 as Assessed by Investigator in Participants Without BRAF V600 E or K Mutations or With Solid Tumors Irrespective of BRAF Status

Time frame: Up to approximately 85 months

Population: All enrolled participants without BRAF V600 E or K mutations in Part 5

Arm	Measure	Value (NUMBER)
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Part 5: ORR Per RECIST 1.1 as Assessed by Investigator in Participants Without BRAF V600 E or K Mutations or With Solid Tumors Irrespective of BRAF Status	0.0 Percentage of Participants
Part 1:Pembrolizumab 2 mg/kg+Trametinib 2 mg	Part 5: ORR Per RECIST 1.1 as Assessed by Investigator in Participants Without BRAF V600 E or K Mutations or With Solid Tumors Irrespective of BRAF Status	33.3 Percentage of Participants

Primary

Parts 1, 2, 4, and 5: Number of Participants Who Discontinued Study Treatment Due to an AE

An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily had to have a causal relationship with this treatment. An AE was any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the study drug, was also an AE. The number of participants who discontinued study treatment due to an AE was reported. Per protocol, discontinuation outcome analysis did not include Part 3.

Time frame: Up to approximately 29 months

Population: All participants who received at least one dose of study treatment in Parts 1, 2, 4, and 5.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Parts 1, 2, 4, and 5: Number of Participants Who Discontinued Study Treatment Due to an AE	2 Participants
Part 1:Pembrolizumab 2 mg/kg+Trametinib 2 mg	Parts 1, 2, 4, and 5: Number of Participants Who Discontinued Study Treatment Due to an AE	2 Participants
Part 1:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg	Parts 1, 2, 4, and 5: Number of Participants Who Discontinued Study Treatment Due to an AE	1 Participants
Part 2:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg	Parts 1, 2, 4, and 5: Number of Participants Who Discontinued Study Treatment Due to an AE	5 Participants
Part 2:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg	Parts 1, 2, 4, and 5: Number of Participants Who Discontinued Study Treatment Due to an AE	2 Participants
Part 4:4 Weeks Trametinib (Tra) 2mg; Pembrolizumab+Tra 2mg	Parts 1, 2, 4, and 5: Number of Participants Who Discontinued Study Treatment Due to an AE	1 Participants
Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg	Parts 1, 2, 4, and 5: Number of Participants Who Discontinued Study Treatment Due to an AE	0 Participants
Part 4:4 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg	Parts 1, 2, 4, and 5: Number of Participants Who Discontinued Study Treatment Due to an AE	4 Participants
Part 4:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent	Parts 1, 2, 4, and 5: Number of Participants Who Discontinued Study Treatment Due to an AE	2 Participants
Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Intermittent	Parts 1, 2, 4, and 5: Number of Participants Who Discontinued Study Treatment Due to an AE	1 Participants
Part 5:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg	Parts 1, 2, 4, and 5: Number of Participants Who Discontinued Study Treatment Due to an AE	2 Participants
Part 5:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent	Parts 1, 2, 4, and 5: Number of Participants Who Discontinued Study Treatment Due to an AE	2 Participants

Primary

Parts 1, 2, 4, and 5: Number of Participants Who Experienced an Adverse Event (AE)

An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE was any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the study drug, was also an AE. The number of participants who experienced an AE was reported. Per protocol, AE outcome analysis did not include Part 3.

Time frame: Up to approximately 32 months

Population: All participants who received at least one dose of study treatment in Parts 1, 2, 4, and 5.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Parts 1, 2, 4, and 5: Number of Participants Who Experienced an Adverse Event (AE)	7 Participants
Part 1:Pembrolizumab 2 mg/kg+Trametinib 2 mg	Parts 1, 2, 4, and 5: Number of Participants Who Experienced an Adverse Event (AE)	3 Participants
Part 1:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg	Parts 1, 2, 4, and 5: Number of Participants Who Experienced an Adverse Event (AE)	2 Participants
Part 2:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg	Parts 1, 2, 4, and 5: Number of Participants Who Experienced an Adverse Event (AE)	8 Participants
Part 2:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg	Parts 1, 2, 4, and 5: Number of Participants Who Experienced an Adverse Event (AE)	2 Participants
Part 4:4 Weeks Trametinib (Tra) 2mg; Pembrolizumab+Tra 2mg	Parts 1, 2, 4, and 5: Number of Participants Who Experienced an Adverse Event (AE)	3 Participants
Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg	Parts 1, 2, 4, and 5: Number of Participants Who Experienced an Adverse Event (AE)	4 Participants
Part 4:4 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg	Parts 1, 2, 4, and 5: Number of Participants Who Experienced an Adverse Event (AE)	5 Participants
Part 4:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent	Parts 1, 2, 4, and 5: Number of Participants Who Experienced an Adverse Event (AE)	6 Participants
Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Intermittent	Parts 1, 2, 4, and 5: Number of Participants Who Experienced an Adverse Event (AE)	3 Participants
Part 5:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg	Parts 1, 2, 4, and 5: Number of Participants Who Experienced an Adverse Event (AE)	11 Participants
Part 5:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent	Parts 1, 2, 4, and 5: Number of Participants Who Experienced an Adverse Event (AE)	9 Participants

Primary

Parts 1, 2, 4, and 5: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)

DLTs were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Events were considered a DLT if occurred during the DLT evaluation period and met ≥1 of the following: significant hematologic toxicity; significant Grade ≥3 non-hematologic toxicity not previously identified or known to occur and cannot be controlled with routine supportive measures; drug-related toxicity that results in an interruption of any component of study therapy for \>21 consecutive days and cannot be controlled ≤2 weeks from onset; any other Grade ≥2 non-hematological toxicity that is dose limiting with some exceptions; and liver chemistries meeting study stopping guidelines. The DLT evaluable population included all participants in Parts 1, 2, 4, and 5 who received ≥66% of planned treatments during the DLT observation period or discontinued treatment due to a DLT. Per protocol, DLT outcome analysis did not include Part 3.

Time frame: Up to approximately 6 weeks

Population: The DLT evaluable population included all participants in Parts 1, 2, 4, and 5 who received at least 66% of all planned treatments during the 6-week DLT observation period or who discontinued treatment due to a DLT.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Parts 1, 2, 4, and 5: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)	1 Participants
Part 1:Pembrolizumab 2 mg/kg+Trametinib 2 mg	Parts 1, 2, 4, and 5: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)	1 Participants
Part 1:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg	Parts 1, 2, 4, and 5: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)	1 Participants
Part 2:Pembrolizumab 2 mg/kg+Dabrafenib 150 mg+Trametinib 2 mg	Parts 1, 2, 4, and 5: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)	2 Participants
Part 2:Pembrolizumab 2 mg/kg+Trametinib 1.5 mg	Parts 1, 2, 4, and 5: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)	1 Participants
Part 4:4 Weeks Trametinib (Tra) 2mg; Pembrolizumab+Tra 2mg	Parts 1, 2, 4, and 5: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)	2 Participants
Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg	Parts 1, 2, 4, and 5: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)	0 Participants
Part 4:4 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg	Parts 1, 2, 4, and 5: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)	0 Participants
Part 4:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent	Parts 1, 2, 4, and 5: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)	2 Participants
Part 4:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg Intermittent	Parts 1, 2, 4, and 5: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)	0 Participants
Part 5:2 Weeks Tra 1.5mg; Pembrolizumab+Tra 1.5mg	Parts 1, 2, 4, and 5: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)	4 Participants
Part 5:2 Weeks Tra 2mg; Pembrolizumab+Tra 2mg Intermittent	Parts 1, 2, 4, and 5: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)	2 Participants

Secondary

Clearance (Cl) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3

Blood samples were to be collected at pre-specified time points for analysis of the Cl of dabrafenib, defined as the volume of plasma from which dabrafenib is eliminated per unit time following dabrafenib administration. This analysis was not performed.

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: As specified by the protocol, the Cl of dabrafenib was only to be analyzed if required and no data were collected since, by the time of final analysis, dabrafenib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of dabrafenib characterized across indications.

Secondary

Clearance (Cl) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Secondary

Clearance (Cl) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With Placebo and 2 mg Trametinib in Participants From Part 3

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Secondary

Clearance (Cl) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 4

Blood samples were to be collected at pre-specified time points for analysis of the Cl of pembrolizumab, defined as the volume of plasma from which pembrolizumab is eliminated per unit time following pembrolizumab administration. This analysis was not performed.

Time frame: Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

Population: As specified by the protocol, the Cl of pembrolizumab was only to be analyzed if required and no data were collected since, by the time of final analysis, pembrolizumab pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of pembrolizumab characterized across indications.

Secondary

Clearance (Cl) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 5

Time frame: Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

Secondary

Clearance (Cl) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2

Time frame: Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

Secondary

Clearance (Cl) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and Trametinib in Participants From Part 3

Time frame: Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

Secondary

Clearance (Cl) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5

Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. This analysis was not performed.

Time frame: Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: As specified by the protocol, the Cl of trametinib was only to be analyzed if required and no data were collected since, by the time of final analysis, trametinib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of trametinib characterized across indications.

Secondary

Clearance (Cl) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4

Time frame: Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Secondary

Clearance (Cl) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Secondary

Clearance (Cl) of Trametinib Following Administration of 2 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5

Time frame: Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Secondary

Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4

Time frame: Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Secondary

Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Secondary

Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Secondary

Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination With Placebo and 150 mg Dabrafenib in Participants From Part 3

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Secondary

Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants from Part 3 who received ≥1 dose of 150 mg dabrafenib and pembrolizumab and who had available data for the analysis of Cmax.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3	643 ng/mL	Standard Deviation 643

Secondary

Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2

Cmax was defined as the maximum concentration of dabrafenib observed after administration of 150 mg dabrafenib in combination with 2 mg/kg pembrolizumab and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Cmax of dabrafenib. All participants who received dabrafenib from Parts 1 and 2 were handled as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Cmax of dabrafenib is presented.

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants pooled from Parts 1 and 2 who received ≥1 dose of 150 mg dabrafenib and who had available data for the analysis of Cmax.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2	683 ng/mL	Standard Deviation 905

Secondary

Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With Placebo and 2 mg Trametinib in Participants From Part 3

Cmax was defined as the maximum concentration of dabrafenib observed after administration of 150 mg dabrafenib in combination with saline placebo and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Cmax of dabrafenib. The Cmax of dabrafenib is presented.

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants from Part 3 who received ≥1 dose of 150 mg dabrafenib and placebo and who had available data for the analysis of Cmax.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With Placebo and 2 mg Trametinib in Participants From Part 3	642 ng/mL	Standard Deviation 829

Secondary

Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 4

Cmax was defined as the maximum concentration of pembrolizumab observed after administration of 200 mg pembrolizumab in combination with trametinib. Blood samples were collected at multiple time points to estimate the Cmax of pembrolizumab. The Cmax of pembrolizumab is presented.

Time frame: Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants from Part 4 who received ≥1 dose of 200 mg pembrolizumab and who had available data for the analysis of Cmax.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 4	77.8 µg/mL	Standard Deviation 16.1

Secondary

Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 5

Time frame: Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants from Part 5 who received ≥1 dose of 200 mg pembrolizumab and who had available data for the analysis of Cmax. There were no participants with data available for the analysis of Cmax in Part 5.

Secondary

Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2

Cmax was defined as the maximum concentration of pembrolizumab observed after administration of 2 mg/kg pembrolizumab in combination with dabrafenib and/or trametinib. Blood samples were collected at multiple time points to estimate the Cmax of pembrolizumab. All participants who received pembrolizumab from Parts 1 and 2 were handled as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Cmax of pembrolizumab is presented.

Time frame: Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants pooled from Parts 1 and 2 who received ≥1 dose of 2 mg/kg pembrolizumab and who had available data for the analysis of Cmax.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2	52.3 µg/mL	Standard Deviation 9.9

Secondary

Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and Trametinib in Participants From Part 3

Cmax was defined as the maximum concentration of pembrolizumab observed after administration of 2 mg/kg pembrolizumab in combination with dabrafenib and trametinib. Blood samples were collected at multiple time points to estimate the Cmax of pembrolizumab. The Cmax of pembrolizumab is presented.

Time frame: Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants from Part 3 who received ≥1 dose of 2 mg/kg pembrolizumab and who had available data for the analysis of Cmax.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and Trametinib in Participants From Part 3	48.9 µg/mL	Standard Deviation 11.4

Secondary

Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5

Cmax was defined as the maximum concentration of trametinib observed after administration of 1.5 mg trametinib in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The Cmax of trametinib is presented.

Time frame: Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants from Part 5 who received ≥1 dose of 1.5 mg trametinib and who had available data for the analysis of Cmax.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5	14.3 ng/mL	Standard Deviation 7.75

Secondary

Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4

Time frame: Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants from Part 4 who received ≥1 dose of 1.5 mg trametinib and who had available data for the analysis of Cmax.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4	16.7 ng/mL	Standard Deviation 7.62

Secondary

Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2

Cmax was defined as the maximum concentration of trametinib observed after administration of 1.5 mg trametinib in combination with 2 mg/kg pembrolizumab. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. All participants who received 1.5 mg trametinib from Parts 1 and 2 were treated as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Cmax of trametinib is presented.

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants pooled from Parts 1 and 2 who received ≥1 dose of 1.5 mg trametinib and who had available data for the analysis of Cmax.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2	30.3 ng/mL	Standard Deviation 17.7

Secondary

Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5

Cmax was defined as the maximum concentration of trametinib observed after administration of 2 mg trametinib in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The Cmax of trametinib is presented.

Time frame: Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants from Part 5 who received ≥1 dose of 2 mg trametinib and who had available data for the analysis of Cmax.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5	7.54 ng/mL	Standard Deviation 8.89

Secondary

Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4

Time frame: Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants from Part 4 who received ≥1 dose of 2 mg trametinib and who had available data for the analysis of Cmax.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4	18.5 ng/mL	Standard Deviation 12.9

Secondary

Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants from Part 3 who received ≥1 dose of 2 mg trametinib and pembrolizumab and who had available data for the analysis of Cmax.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3	16.3 ng/mL	Standard Deviation 6.8

Secondary

Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2

Cmax was defined as the maximum concentration of trametinib observed after administration of 2 mg trametinib in combination with 2 mg/kg pembrolizumab and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. All participants who received 2 mg trametinib from Parts 1 and 2 were treated as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Cmax of trametinib is presented.

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants pooled from Parts 1 and 2 who received ≥1 dose of 2 mg trametinib and who had available data for the analysis of Cmax.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2	19.3 ng/mL	Standard Deviation 8.13

Secondary

Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination With Placebo and 150 mg Dabrafenib in Participants From Part 3

Cmax was defined as the maximum concentration of trametinib observed after administration of 2 mg trametinib in combination with saline placebo and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The Cmax of trametinib is presented.

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants from Part 3 who received ≥1 dose of 2 mg trametinib and placebo and who had available data for the analysis of Cmax.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination With Placebo and 150 mg Dabrafenib in Participants From Part 3	16.2 ng/mL	Standard Deviation 6.15

Secondary

Part 1: ORR Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

ORR was defined as the percentage of participants who had a CR (Disappearance of all target lesions) or a PR (divided into very good partial response \[VGPR; \>60% tumor reduction\] and moderate partial response \[MPR; \>30-≤60% tumor reduction\]) per RECIST 1.1 as assessed by investigator. The percentage of participants who experienced a CR or PR as assessed by the investigator was presented.

Time frame: Up to approximately 85 months

Population: All enrolled participants with BRAF V600 E or K mutations in Part 1

Arm	Measure	Value (NUMBER)
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Part 1: ORR Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations	57.1 Percentage of participants

Secondary

Part 2: ORR Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

Time frame: Up to approximately 85 months

Population: All enrolled participants with BRAF V600 E or K mutations in Part 2

Arm	Measure	Value (NUMBER)
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Part 2: ORR Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations	75.0 Percentage of Participants

Secondary

Part 3: Duration of Response (DOR) Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

For participants who demonstrated a confirmed CR (Disappearance of all target lesions) or a confirmed PR (divided by VGPR \[\>60% tumor reduction\] and MPR \[\>30-≤60% tumor reduction\]) per RECIST 1.1 as assessed by the investigator, DOR was defined as the time from first documented evidence of CR or PR until progressive disease (PD). Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. The DOR as assessed by the investigator was analyzed using Kaplan-Meier method and reported in months.

Time frame: Up to approximately 85 months

Population: All randomized participants with BRAF V600 E or K mutations who had a confirmed CR or PR in Part 3

Arm	Measure	Value (MEDIAN)
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Part 3: Duration of Response (DOR) Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations	30.2 Months
Part 1:Pembrolizumab 2 mg/kg+Trametinib 2 mg	Part 3: Duration of Response (DOR) Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations	12.1 Months

Secondary

Part 3: ORR Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

Time frame: Up to approximately 85 months

Population: All randomized participants with BRAF V600 E or K mutations in Part 3

Arm	Measure	Value (NUMBER)
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Part 3: ORR Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations	65.0 Percentage of Participants
Part 1:Pembrolizumab 2 mg/kg+Trametinib 2 mg	Part 3: ORR Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations	71.7 Percentage of Participants

Secondary

Part 3: Overall Survival (OS) in Participants With BRAF V600 E or K Mutations

OS was defined as the time from randomization to death due to any cause. OS was analyzed using the Kaplan-Meier method and was reported in months. Statistical analysis used a Cox regression model with treatment as a covariate and stratified by Eastern Cooperative Oncology Group performance status and Lactate Dehydrogenase.

Time frame: Up to approximately 85 months

Population: All randomized participants with BRAF V600 E or K mutations in Part 3

Arm	Measure	Value (MEDIAN)
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Part 3: Overall Survival (OS) in Participants With BRAF V600 E or K Mutations	46.3 Months
Part 1:Pembrolizumab 2 mg/kg+Trametinib 2 mg	Part 3: Overall Survival (OS) in Participants With BRAF V600 E or K Mutations	26.3 Months

95% CI: [0.38, 0.95]

Secondary

Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants from Part 3 who received ≥1 dose of 150 mg dabrafenib and pembrolizumab and who had available data for the analysis of Ctrough.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3	103 ng/mL	Standard Deviation 204

Secondary

Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2

Ctrough was defined as the lowest concentration of dabrafenib that occurred immediately prior to the next dose of 150 mg dabrafenib administered in combination with 2 mg/kg pembrolizumab and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of dabrafenib. All participants who received dabrafenib from Parts 1 and 2 were handled as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Ctrough of dabrafenib is presented.

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants pooled from Parts 1 and 2 who received ≥1 dose of 150 mg dabrafenib and who had available data for the analysis of Ctrough.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2	156 ng/mL	Standard Deviation 367

Secondary

Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With Placebo and 2 mg Trametinib in Participants From Part 3

Ctrough was defined as the lowest concentration of dabrafenib that occurred immediately prior to the next dose of 150 mg dabrafenib administered in combination with saline placebo and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of dabrafenib. The Ctrough of dabrafenib is presented.

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants from Part 3 who received ≥1 dose of 150 mg dabrafenib and placebo and who had available data for the analysis of Ctrough.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With Placebo and 2 mg Trametinib in Participants From Part 3	183 ng/mL	Standard Deviation 384

Secondary

Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 4

Ctrough was defined as the lowest concentration of pembrolizumab that occurred immediately prior to the next dose of 200 mg pembrolizumab administered in combination with trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of pembrolizumab. The Ctrough of pembrolizumab is presented.

Time frame: Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants from Part 4 who received ≥1 dose of 200 mg pembrolizumab and who had available data for the analysis of Ctrough.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 4	17.0 µg/mL	Standard Deviation 7.1

Secondary

Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 5

Time frame: Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants from Part 5 who received ≥1 dose of 200 mg pembrolizumab and who had available data for the analysis of Ctrough. There were no participants with data available for the analysis of Ctrough in Part 5.

Secondary

Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2

Ctrough was defined as the lowest concentration of pembrolizumab that occurred immediately prior to the next dose of 2 mg/kg pembrolizumab administered in combination with dabrafenib and/or trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of pembrolizumab. All participants who received pembrolizumab from Parts 1 and 2 were handled as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Ctrough of pembrolizumab is presented.

Time frame: Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants pooled from Parts 1 and 2 who received ≥1 dose of 2 mg/kg pembrolizumab and who had available data for the analysis of Ctrough.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2	11.2 µg/mL	Standard Deviation 2.6

Secondary

Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and Trametinib in Participants From Part 3

Time frame: Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants from Part 3 who received ≥1 dose of 2 mg/kg pembrolizumab and who had available data for the analysis of Ctrough.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and Trametinib in Participants From Part 3	10.6 µg/mL	Standard Deviation 3.4

Secondary

Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5

Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 1.5 mg trametinib administered in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The Ctrough of trametinib is presented.

Time frame: Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants from Part 5 who received ≥1 dose of 1.5 mg trametinib and who had available data for the analysis of Ctrough.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5	10.6 ng/mL	Standard Deviation 6.79

Secondary

Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4

Time frame: Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants from Part 4 who received ≥1 dose of 1.5 mg trametinib and who had available data for the analysis of Ctrough.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4	8.64 ng/mL	Standard Deviation 5.65

Secondary

Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2

Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 1.5 mg trametinib administered in combination with 2 mg/kg pembrolizumab. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. All participants who received 1.5 mg trametinib from Parts 1 and 2 were treated as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Ctrough of trametinib is presented.

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants pooled from Parts 1 and 2 who received ≥1 dose of 1.5 mg trametinib and who had available data for the analysis of Ctrough.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2	20.5 ng/mL	Standard Deviation 9.23

Secondary

Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5

Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 2 mg trametinib administered in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The Ctrough of trametinib is presented.

Time frame: Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants from Part 5 who received ≥1 dose of 2 mg trametinib and who had available data for the analysis of Ctrough.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5	6.69 ng/mL	Standard Deviation 5.9

Secondary

Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4

Time frame: Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants from Part 4 who received ≥1 dose of 2 mg trametinib and who had available data for the analysis of Ctrough.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4	12.3 ng/mL	Standard Deviation 9.45

Secondary

Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants from Part 3 who received ≥1 dose of 2 mg trametinib and pembrolizumab and who had available data for the analysis of Ctrough.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3	9.93 ng/mL	Standard Deviation 5.48

Secondary

Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2

Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 2 mg trametinib administered in combination with 2 mg/kg pembrolizumab and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. All participants who received 2 mg trametinib from Parts 1 and 2 were treated as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The Ctrough of trametinib is presented.

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants pooled from Parts 1 and 2 who received ≥1 dose of 2 mg trametinib and who had available data for the analysis of Ctrough.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2	13.7 ng/mL	Standard Deviation 9.39

Secondary

Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination With Placebo and 150 mg Dabrafenib in Participants From Part 3

Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 2 mg trametinib administered in combination with saline placebo and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The Ctrough of trametinib is presented.

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: The analysis population consisted of all participants from Part 3 who received ≥1 dose of 2 mg trametinib and placebo and who had available data for the analysis of Ctrough.

Arm	Measure	Value (MEAN)	Dispersion
Part 1:Pembrolizumab 2 mg/kg+dabrafenib150 mg+Trametinib 2 mg	Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination With Placebo and 150 mg Dabrafenib in Participants From Part 3	10.7 ng/mL	Standard Deviation 5.14

Secondary

Volume of Distribution (Vc) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3

Blood samples were to be collected at pre-specified time points for analysis of the Vc of dabrafenib, defined as the theoretical volume that would be necessary to contain the total amount of administered dabrafenib at the same concentration that it is observed in the blood plasma. This analysis was not performed.

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: As specified by the protocol, the Vc of dabrafenib was only to be analyzed if required and no data were collected since, by the time of final analysis, dabrafenib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of dabrafenib characterized across indications.

Secondary

Volume of Distribution (Vc) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Secondary

Volume of Distribution (Vc) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With Placebo and 2 mg Trametinib in Participants From Part 3

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Secondary

Volume of Distribution (Vc) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 4

Blood samples were to be collected at pre-specified time points for analysis of the Vc of pembrolizumab, defined as the theoretical volume that would be necessary to contain the total amount of administered pembrolizumab at the same concentration that it is observed in the blood plasma. This analysis was not performed.

Time frame: Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

Population: As specified by the protocol, the Vc of pembrolizumab was only to be analyzed if required and no data were collected since, by the time of final analysis, pembrolizumab pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of pembrolizumab characterized across indications.

Secondary

Volume of Distribution (Vc) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 5

Time frame: Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

Secondary

Volume of Distribution (Vc) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2

Time frame: Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

Secondary

Volume of Distribution (Vc) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and Trametinib in Participants From Part 3

Time frame: Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

Secondary

Volume of Distribution (Vc) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5

Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. This analysis was not performed.

Time frame: Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Population: As specified by the protocol, the Vc of trametinib was only to be analyzed if required and no data were collected since, by the time of final analysis, trametinib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of trametinib characterized across indications.

Secondary

Volume of Distribution (Vc) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4

Time frame: Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Secondary

Volume of Distribution (Vc) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Secondary

Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5

Time frame: Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Secondary

Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4

Time frame: Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Secondary

Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Secondary

Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Secondary

Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg Trametinib in Combination With Placebo and 150 mg Dabrafenib in Participants From Part 3

Time frame: Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

Source: ClinicalTrials.gov · Data processed: Mar 2, 2026

A Study of the Safety and Efficacy of Pembrolizumab (MK-3475) in Combination With Trametinib and Dabrafenib in Participants With Advanced Melanoma (MK-3475-022/KEYNOTE-022)

Conditions

Keywords

Brief summary

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Participant flow

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Part 2: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator in Participants Without BRAF V600 E or K Mutations

Part 3: Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

Part 5: ORR Per RECIST 1.1 as Assessed by Investigator in Participants Without BRAF V600 E or K Mutations or With Solid Tumors Irrespective of BRAF Status

Parts 1, 2, 4, and 5: Number of Participants Who Discontinued Study Treatment Due to an AE

Parts 1, 2, 4, and 5: Number of Participants Who Experienced an Adverse Event (AE)

Parts 1, 2, 4, and 5: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)

Clearance (Cl) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3

Clearance (Cl) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2

Clearance (Cl) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With Placebo and 2 mg Trametinib in Participants From Part 3

Clearance (Cl) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 4

Clearance (Cl) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 5

Clearance (Cl) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2

Clearance (Cl) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and Trametinib in Participants From Part 3

Clearance (Cl) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5

Clearance (Cl) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4

Clearance (Cl) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2

Clearance (Cl) of Trametinib Following Administration of 2 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5

Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4

Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3

Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2

Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination With Placebo and 150 mg Dabrafenib in Participants From Part 3

Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3

Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2

Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With Placebo and 2 mg Trametinib in Participants From Part 3

Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 4

Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 5

Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2

Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and Trametinib in Participants From Part 3

Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5

Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4

Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2

Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5

Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4

Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3

Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2

Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination With Placebo and 150 mg Dabrafenib in Participants From Part 3

Part 1: ORR Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

Part 2: ORR Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

Part 3: Duration of Response (DOR) Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

Part 3: ORR Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

Part 3: Overall Survival (OS) in Participants With BRAF V600 E or K Mutations

Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3

Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2

Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With Placebo and 2 mg Trametinib in Participants From Part 3

Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 4

Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination With Trametinib in Participants From Part 5

Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2

Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination With Dabrafenib and Trametinib in Participants From Part 3

Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5

Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4

Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg Trametinib in Combination With 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2

Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg of Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 5

Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination With 200 mg Pembrolizumab in Participants From Part 4

Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3

Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination With 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2

Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination With Placebo and 150 mg Dabrafenib in Participants From Part 3

Volume of Distribution (Vc) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3

Volume of Distribution (Vc) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2

Volume of Distribution (Vc) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination With Placebo and 2 mg Trametinib in Participants From Part 3