Study of Encorafenib + Cetuximab Plus or Minus Binimetinib vs. Irinotecan/Cetuximab or Infusional 5-Fluorouracil (5-FU)/Folinic Acid (FA)/Irinotecan (FOLFIRI)/Cetuximab With a Safety Lead-in of Encorafenib + Binimetinib + Cetuximab in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer

ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of complete response (CR) or partial response (PR), where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (\<10 millimeter \[mm\] short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.

Time frame: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Population: The Phase 3 Response Efficacy Set consisted of the first 330 participants randomized into the Phase 3 portion of the study and any additional participants randomized on the same day as the 330th randomized participant.

OS was defined as the time from randomization to death due to any cause.

Time frame: From randomization to death due to any cause until 204 deaths were observed (maximum treatment exposure of 89.1 weeks for triplet arm and 52.4 weeks for control arm)

Population: The Full Analysis Set (FAS) for the Phase 3 portion of the study consisted of all randomized Phase 3 participants.

An AE is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. Number of participants according to incidence of dose interruptions, dose modifications and dose discontinuations due to AEs were reported in this outcome measure.

Time frame: From start of study treatment until 30 days post last dose of study treatment (maximum treatment exposure of 280 weeks)

Population: The safety set consisted of all participants who received at least 1 dose of study drug and had at least 1 posttreatment assessment, which may have included death. Participants were analyzed according to treatment received.

An AE is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. Number of participants with dose interruptions, dose modifications and dose discontinuations due to AEs were reported in this outcome measure.

Time frame: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Population: The safety set consisted of all participants who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Participants were analyzed according to treatment received.

An AE is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. Number of participants reporting AEs were reported in this outcome measure.

Time frame: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Population: The safety set consisted of all participants who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Participants were analyzed according to treatment received.

Time frame: Cycle 1 (up to 28 days)

Population: The dose-determining set (DDS) consisted of all CSLI participants from the safety set who either completed a minimum exposure requirement (received \>= 75% dose intensity of the planned dose for each binimetinib, encorafenib and cetuximab) and had sufficient safety evaluations or experienced a dose-limiting toxicity (DLT).

The EORTC QLQ-C30 questionnaire consisted of 30 questions generating 5 functional scores (physical, role, cognitive, emotional, & social); a global health (GH) status/global quality of life scale score; 3 symptom scale scores (fatigue, pain, & nausea & vomiting); & 6 standalone one-item scores that capture additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, & diarrhea) & perceived financial burden. All items were graded by severity experienced during previous week & used 4-point-scale (1: not at all, 2: a little, 3: quite a bit, 4: very much). The scores were converted to health-related quality of life (HRQoL) scale ranging from 0-100. Higher scores indicating higher response levels (i.e., higher functioning, higher symptom severity).

Time frame: Baseline, Cycle(C)1 Day(D)1 , C2 D1, C3 D1, C4 D1, C5 D1, C6 D1, C7 D1, C8 D1, C9 D1, C10 D1, C11 D1, C12 D1, C13 D1, C14 D1, C15 D1, C16 D1, C17 D1, C18 D1, C19 D1, C20 D1, C21 D1, C22 D1, C23 D1, End of Treatment, 30 Day Follow Up(each cycle of 28 days)

Population: The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 participants. Here, 'Number Analyzed' signifies number of participants evaluable for the specified timepoints. All participants reported under 'Overall Number of Participants Analyzed' contributed data to the table but may not have evaluable data for every row.

The EQ-5D-5L contains 1 item for each of 5 dimensions of health-related QoL (i.e., mobility, self-care, usual activities, pain or discomfort and anxiety or depression). Response options for each item varied from having no problems to moderate problems or extreme problems. The EQ-5D-5L (v4.0) is a standardized measure of health utility that provides a single index value for one's health status. The EQ-5D-5L is frequently used for economic evaluations of health care and has been recognized as a valid and reliable instrument for this purpose. The EQ visual analog scale (VAS) is a score that is directly reported by the participant and ranges from 0 to 100 (higher is better quality health).

Time frame: Baseline,Cycle (C)1 Day (D)1, C2 D1, C3 D1, C4 D1, C5 D1, C6 D1, C7 D1, C8 D1, C9 D1, C10 D1, C11 D1, C12 D1, C13 D1, C14 D1, C15 D1, C16 D1, C17 D1, C18 D1, C19 D1, C20 D1, C21 D1, C22 D1, C23 D1, End of Treatment, 30 Day Follow Up(each cycle of 28 days)

Population: The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 participants. Here, 'Number Analyzed' signifies number of participants evaluable for the specified timepoints. All participants reported under 'Overall Number of Participants Analyzed' contributed data to the table but may not have evaluable data for every row.

FACT-C= Functional Assessment of Chronic Illness Therapy (FACIT), which assessed HRQoL of cancer participants & participants with other chronic illnesses. It consists of total 36 items (27 items of general version of FACT-C and disease-specific subscale containing 9 CRC-specific items), summarized to 5 subscales: physical well-being (7 items), functional well-being (7 items), social/family well-being (7 items); all 3 subscales range:0-28, emotional well-being (6 items) range: 0-24, colorectal cancer subscale (9 items) range: 0-36; higher subscale score= better QoL. All single-item measures range: 0= 'Not at all' to 4= 'Very much'. Table summarizes functional well-being subscale, individual questions are linearly scaled & combined to form functional well-being subscale score (range 0-28). High score represents better QoL.

Time frame: Baseline,Cycle (C)1 Day (D)1, C2 D1, C3 D1, C4 D1, C5 D1, C6 D1, C7 D1, C8 D1, C9 D1, C10 D1, C11 D1, C12 D1, C13 D1, C14 D1, C15 D1, C16 D1, C17 D1, C18 D1, C19 D1, C20 D1, C21 D1, C22 D1, C23 D1, End of Treatment, 30 Day Follow Up(each cycle of 28 days)

Population: The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 participants. Here, 'Number Analyzed' signifies number of participants evaluable for the specified timepoints. All participants reported under 'Overall Number of Participants Analyzed' contributed data to the table but may not have evaluable data for every row.

The PGIC is a measure of participant's perceptions of change in their symptoms over time that can be used as an anchoring method to determine the minimal clinically important difference for other participant reported outcome (PROs). For this assessment, participants answered the following question: Since starting treatment, my colorectal cancer symptoms are: (1) very much improved, (2) much improved, (3) minimally improved, (4) no change, (5) minimally worse, (6) much worse or (7) very much worse.

Time frame: Baseline,Cycle (C)1 Day (D)1, C2 D1, C3 D1, C4 D1, C5 D1, C6 D1, C7 D1, C8 D1, C9 D1, C10 D1, C11 D1, C12 D1, C13 D1, C14 D1, C15 D1, C16 D1, C17 D1, C18 D1, C19 D1, C20 D1, C21 D1, C22 D1, C23 D1, End of Treatment, 30 Day Follow Up(each cycle of 28 days)

Population: The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 participants. Here, 'Number Analyzed' signifies number of participants evaluable for the specified timepoints. All participants reported under 'Overall Number of Participants Analyzed' contributed data to the table but may not have evaluable data for every row.

DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

Time frame: From time of response to PD or death due to underlying disease (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm)

Population: The Phase 3 Response Efficacy Set consisted of the first 330 participants randomized into the Phase 3 portion of the study and any additional participants randomized on the same day as the 330th randomized participant. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.

DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

Time frame: From time of response to PD or death due to underlying disease (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm)

Population: The Phase 3 Response Efficacy Set consisted of the first 330 participants randomized into the Phase 3 portion of the study and any additional participants randomized on the same day as the 330th randomized participant. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.

DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

Time frame: From time of response to PD or death due to underlying disease (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)

Population: The Phase 3 Response Efficacy Set consisted of the first 330 participants randomized into the Phase 3 portion of the study and any additional participants randomized on the same day as the 330th randomized participant. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.

DOR was defined as the time from first radiographic evidence of response to the earliest documented disease progression (PD) or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

Time frame: From time of response to PD or death due to underlying disease (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)

Population: The Phase 3 Response Efficacy Set consisted of the first 330 participants randomized into the Phase 3 portion of the study and any additional participants randomized on the same day as the 330th randomized participant. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.

DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

Time frame: From time of response to PD or death due to underlying disease (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm)

Population: The Phase 3 Response Efficacy Set consisted of the first 330 participants randomized into the Phase 3 portion of the study and any additional participants randomized on the same day as the 330th randomized participant. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.

DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

Time frame: From time of response to PD or death due to underlying disease (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm)

Population: The Phase 3 Response Efficacy Set consisted of the first 330 participants randomized into the Phase 3 portion of the study and any additional participants randomized on the same day as the 330th randomized participant. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.

ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (\<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.

Time frame: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Population: The Phase 3 Response Efficacy Set consisted of the first 330 participants randomized into the Phase 3 portion of the study and any additional participants randomized on the same day as the 330th randomized participant. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.

ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (\<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.

Time frame: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Population: The Phase 3 Response Efficacy Set consisted of the first 330 participants randomized into the Phase 3 portion of the study and any additional participants randomized on the same day as the 330th randomized participant. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.

ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (\<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.

Time frame: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Population: The Phase 3 Response Efficacy Set consisted of the first 330 participants randomized into the Phase 3 portion of the study and any additional participants randomized on the same day as the 330th randomized participant. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.

ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (\<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.

Time frame: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Population: The Phase 3 Response Efficacy Set consisted of the first 330 participants randomized into the Phase 3 portion of the study and any additional participants randomized on the same day as the 330th randomized participant. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.

ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (\<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.

Time frame: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Population: The Phase 3 Response Efficacy Set consisted of the first 330 participants randomized into the Phase 3 portion of the study and any additional participants randomized on the same day as the 330th randomized participant. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.

PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

Time frame: From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm)

Population: The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 participants.

PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

Time frame: From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm)

Population: The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 participants.

PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

Time frame: From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)

Population: The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 participants.

PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

Time frame: From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)

Population: The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 participants.

PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

Time frame: From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm)

Population: The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 participants.

PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

Time frame: From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm)

Population: The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 participants.

Time to response was defined as the time from first dose to first radiographic evidence of response.

Time frame: From first dose to first radiographic evidence of response (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm)

Population: The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 participants. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.

Time to response was defined as the time from first dose to first radiographic evidence of response.

Time frame: From first dose to first radiographic evidence of response (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm)

Population: The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 participants. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.

Time to response was defined as the time from first dose to first radiographic evidence of response.

Time frame: From first dose to first radiographic evidence of response (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)

Population: The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 participants. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.

Time to response was defined as the time from first dose to first radiographic evidence of response.

Time frame: From first dose to first radiographic evidence of response (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)

Population: The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 participants. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.

Time to response was defined as the time from first dose to first radiographic evidence of response.

Time frame: From first dose to first radiographic evidence of response (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm)

Population: The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 participants. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.

Time to response was defined as the time from first dose to first radiographic evidence of response.

Time frame: From first dose to first radiographic evidence of response (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm)

Population: The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 participants. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.

The reported cross-arm CL/F value is a fixed-effect parameter determined from a population PK analysis. The analysis included pooled data from participants enrolled in multiple studies including those who were not enrolled in this study. The NCTID include: NCT01719380, NCT01543698, and NCT01436656. An additional study ARRAY-162-105 is not required to register.

Time frame: 2 and 6 hours post-dose on Day 1 of Cycle 1, Predose and 2 hours post-dose on Day 1 of Cycle 2 (each cycle of 28 days)

Population: The analysis set included all participants in the PK set with measurable plasma concentrations of the test drug plus concentrations from subjects from 4 additional clinical studies. Participants were analyzed according to the actual treatment and dose received.

The reported cross-arm CL/F value is a fixed-effect parameter determined from a population PK analysis. The analysis included pooled data from participants enrolled in multiple studies including those who were not enrolled in this study. The NCTID include: NCT01719380, NCT01543698, and NCT01436656. An additional study ARRAY-162-105 is not required to register.

Time frame: 2 and 6 hours post-dose on Day 1 of Cycle 1, Predose and 2 hours post-dose on Day 1 of Cycle 2 (each cycle of 28 days)

Population: The analysis set included all participants in the PK set with measurable plasma concentrations of the test drug plus concentrations from subjects from 4 additional clinical studies. Participants were analyzed according to the actual treatment and dose received.

The reported cross-arm CL/F value is a fixed-effect parameter determined from a population PK analysis. The analysis included pooled data from participants enrolled in multiple studies including those who were not enrolled in this study. The NCTID include: NCT01719380, NCT01543698, and NCT01436656. An additional study ARRAY-162-105 is not required to register.

Time frame: 2 and 6 hours post-dose on Day 1 of Cycle 1, Predose and 2 hours post-dose on Day 1 of Cycle 2 (each cycle of 28 days)

Population: The analysis set included all participants in the PK set with measurable plasma concentrations of the test drug plus concentrations from subjects from 4 additional clinical studies. Participants were analyzed according to the actual treatment and dose received.

Clinically notable shifts was defined as worsening by at least 2 grades or to more than or equal to (\>=) Grade 3 based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 where Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life threatening and Grade 5: death.

Time frame: From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks)

Population: The safety set consisted of all participants who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Participants were analyzed according to treatment received.

Clinically notable shifts was defined as worsening by at least 2 grades or to \>= Grade 3 based on CTCAE version 4.03 where Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life threatening and Grade 5: death.

Time frame: From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks)

Population: The safety set consisted of all participants who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Participants were analyzed according to treatment received.

Clinically notable shifts was defined as worsening by at least 2 grades or to \>= Grade 3 based on CTCAE version 4.03 where Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life threatening and Grade 5: death.

Time frame: From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks)

Population: The safety set consisted of all participants who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Participants were analyzed according to treatment received.

Newly occurring clinically notable changes was defined as participants not meeting the criterion at baseline and meeting criterion post-baseline. The criterion included: heart rate- decrease from baseline \> 25% and to a value \< 50 and increase from baseline \> 25% and to a value \> 100. QT interval- new \> 450 (millisecond) msec, new \> 480 msec, new \> 500 msec, increase from baseline \> 30 msec and increase from baseline \> 60 msec. QTcF- new \> 450 msec, new \> 480 msec, new \> 500 msec, increase from baseline \> 30 msec and increase from baseline \> 60 msec.

Time frame: From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks)

Population: The safety set consisted of all participants who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Participants were analyzed according to treatment received.

Newly occurring clinically notable changes was defined as participants not meeting the criterion at baseline and meeting criterion post-baseline. The criterion included: low/high systolic blood pressure (SBP): \<= 90 millimeters of mercury (mmHg) with decrease from baseline of \>= 20mmHg or \>= 160mmHg with increase from baseline of \>= 20mmHg, low or high diastolic blood pressure (DBP): \<= 50mmHg with decrease from baseline of \>= 15mmHg or \>= 100mmHg with increase from baseline of \>= 15mmHg, low or high pulse: \<= 50 beats/min with decrease from baseline of \>= 15 beats/min or \>= 120 beats/min with increase from baseline of \>= 15 beats/min, low or high temperature: \<= 36 degree Celsius (deg C) or \>= 37.5 deg C.

Time frame: From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks)

Population: The safety set consisted of all participants who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Participants were analyzed according to treatment received.

Visual acuity was measured using the Snellen visual acuity conversion chart. This was determined by establishing the smallest optotypes that could be identified correctly by the participant at a given observation distance. Snellen visual acuity was reported as a Snellen fraction (m/M) in which the numerator (m) indicated the test distance and the denominator (M) indicated the distance at which the gap of the equivalent Landolt ring subtends 1 minute of arc. The LogMAR score was calculated as - log(m/M). The maximum increase in score of \<= 0, 0 to \< 0.1, 0.1 to \< 0.2, 0.2 to \< 0.3 and \>=0.3 relative to baseline in LogMAR were reported in this endpoint.

Time frame: From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks)

Population: The Safety Set consisted of all participants who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Participants were analyzed according to treatment received.

Left ventricular ejection fraction (LVEF) abnormalities were defined according to CTCAE version 4.03 where Grade 0: Non-missing value below Grade 2, Grade 2: LVEF between 40% and 50% or absolute change from baseline between -10% and \< -20%, Grade 3: LVEF between 20% and 39% or absolute change from baseline \<= -20%, Grade 4: LVEF lower than 20%. Categories with at least 1 non-zero data values showing any shift in Grade from baseline to 1 day after dose 1 (post-baseline) were reported. Participants whose grade category was unchanged (e.g. Grade 0 to Grade 0) were not reported.

Time frame: From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks)

Population: The safety set consisted of all participants who received at least 1 dose of study drug and had at least 1 post-treatment assessment, which may have included death. Participants were analyzed according to treatment received.

OS was defined as the time from randomization to death due to any cause.

Time frame: From randomization to death due to any cause until 204 deaths were observed (maximum treatment exposure of 89.7 weeks for doublet arm and 52.4 weeks for control arm)

Population: The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 participants.

OS was defined as the time from randomization to death due to any cause.

Time frame: From randomization to death due to any cause until 204 deaths were observed (maximum treatment exposure of 89.7 weeks for doublet arm and 89.1 weeks for triplet arm)

Population: The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 participants.

DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

Time frame: From time of response to the earliest documented PD or death due to underlying disease (maximum treatment exposure of 280 weeks)

Population: The SLI Efficacy Set consisted of all CSLI participants in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing). Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.

DOR was defined as the time from first radiographic evidence of response to the earliest documented disease progression (PD) or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

Time frame: From time of response to the earliest documented PD or death due to underlying disease (maximum treatment exposure of 280 weeks)

Population: The SLI Efficacy Set consisted of all CSLI participants in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing). Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.

Time frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Population: The PK set included all participants in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Participants were analyzed according to the actual treatment and dose received. All participants reported under 'Overall Number of Participants Analyzed' contributed data to the table but may not have evaluable data for every row. Here, Number Analyzed signifies participants evaluable for specified rows.

Time frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Population: The pharmacokinetics (PK) set included all participants in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Participants were analyzed according to the actual treatment and dose received.

Time frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Population: The PK set included all participants in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Participants were analyzed according to the actual treatment and dose received. All participants reported under 'Overall Number of Participants Analyzed' contributed data to the table but may not have evaluable data for every row. Here, Number Analyzed signifies participants evaluable for specified rows.

Time frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Population: The PK set included all participants in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Participants were analyzed according to the actual treatment and dose received. All participants reported under 'Overall Number of Participants Analyzed' contributed data to the table but may not have evaluable data for every row. Here, Number Analyzed signifies participants evaluable for specified rows.

Time frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Population: The PK set included all participants in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Participants were analyzed according to the actual treatment and dose received. All participants reported under 'Overall Number of Participants Analyzed' contributed data to the table but may not have evaluable data for every row. Here, Number Analyzed signifies participants evaluable for specified rows.

Time frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Population: The PK set included all participants in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Participants were analyzed according to the actual treatment and dose received. All participants reported under 'Overall Number of Participants Analyzed' contributed data to the table but may not have evaluable data for every row. Here, Number Analyzed signifies participants evaluable for specified rows.

Time frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Population: The PK set included all participants in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Participants were analyzed according to the actual treatment and dose received. All participants reported under 'Overall Number of Participants Analyzed' contributed data to the table but may not have evaluable data for every row. Here, Number Analyzed signifies participants evaluable for specified rows.

Time frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Population: The PK set included all participants in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Participants were analyzed according to the actual treatment and dose received. All participants reported under 'Overall Number of Participants Analyzed' contributed data to the table but may not have evaluable data for every row. Here, Number Analyzed signifies participants evaluable for specified rows.

Time frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Population: The PK set included all participants in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Participants were analyzed according to the actual treatment and dose received.

Time frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Population: The PK set included all participants in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Participants were analyzed according to the actual treatment and dose received.

Time frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Population: The PK set included all participants in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Participants were analyzed according to the actual treatment and dose received.

Time frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Population: The PK set included all participants in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Participants were analyzed according to the actual treatment and dose received.

Time frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Population: The PK set included all participants in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Participants were analyzed according to the actual treatment and dose received. All participants reported under 'Overall Number of Participants Analyzed' contributed data to the table but may not have evaluable data for every row. Here, Number Analyzed signifies participants evaluable for specified rows.

Time frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Population: The PK set included all participants in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Participants were analyzed according to the actual treatment and dose received. All participants reported under 'Overall Number of Participants Analyzed' contributed data to the table but may not have evaluable data for every row. Here, Number Analyzed signifies participants evaluable for specified rows.

Time frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Population: The PK set included all participants in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Participants were analyzed according to the actual treatment and dose received. All participants reported under 'Overall Number of Participants Analyzed' contributed data to the table but may not have evaluable data for every row. Here, Number Analyzed signifies participants evaluable for specified rows.

Time frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Population: The PK set included all participants in the Safety Set who had at least 1 post-dose blood collection for PK with associated bioanalytical results. Participants were analyzed according to the actual treatment and dose received. All participants reported under 'Overall Number of Participants Analyzed' contributed data to the table but may not have evaluable data for every row. Here, Number Analyzed signifies participants evaluable for specified rows.

ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (\<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.

Time frame: From start of study treatment until 30 days post last dose of study treatment (maximum treatment exposure of 280 weeks)

Population: The SLI Efficacy Set consisted of all CSLI participants in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing).

ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (\<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.

Time frame: From start of study treatment until 30 days post last dose of study treatment (maximum treatment exposure of 280 weeks)

Population: The Safety Lead-in (SLI) Efficacy Set consisted of all CSLI participants in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing).

PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

Time frame: From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 280 weeks)

Population: The SLI Efficacy Set consisted of all CSLI participants in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing).

PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.

Time frame: From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 280 weeks)

Population: The SLI Efficacy Set consisted of all CSLI participants in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing).

Time to response was defined as the time from first dose to first radiographic evidence of response.

Time frame: From first dose to first radiographic evidence of response (maximum treatment exposure of 280 weeks)

Population: The SLI Efficacy Set consisted of all CSLI participants in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing).

Time to response was defined as the time from first dose to first radiographic evidence of response.

Time frame: From first dose to first radiographic evidence of response (maximum treatment exposure of 280 weeks)

Population: The SLI Efficacy Set consisted of all CSLI participants in the FAS who were identified at screening as having a BRAF V600E mutation (per local or central testing).

OS was defined as the time from randomization to death due to any cause.

Time frame: From randomization to death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)

Population: The FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 participants.