Trial Outcomes & Findings for 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 (NCT NCT02928224)

Last Updated: 2023-12-21

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

702 participants

Primary outcome timeframe

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

Results posted on

2023-12-21

Participant Flow

Participants were at least 18 years of age with confirmed metastatic colorectal cancer (CRC) whose disease had progressed after 1 or 2 prior regimens in the metastatic setting and whose tumor tissue was BRAF V600E-mutant as previously determined by a local assay at any time prior to Screening.

Participant milestones

Participant milestones
Measure	Combined Safety Lead-in Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Triplet Arm Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Doublet Arm Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	Phase 3: Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
Overall Study STARTED	37	224	220	221
Overall Study Crossover Participants	0	0	0	3
Overall Study COMPLETED	0	0	0	0
Overall Study NOT COMPLETED	37	224	220	221

Reasons for withdrawal

Reasons for withdrawal
Measure	Combined Safety Lead-in Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Triplet Arm Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Doublet Arm Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	Phase 3: Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
Overall Study Lost to Follow-up	1	1	3	0
Overall Study Death	30	209	193	198
Overall Study Withdrawal by Subject	0	3	7	20
Overall Study Study participation terminated by sponsor	3	8	12	3
Overall Study Other	3	3	5	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Combined Safety Lead-in (CSLI) n=37 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Triplet Arm n=224 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Doublet Arm n=220 Participants Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=221 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Total n=702 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Age, Categorical Between 18 and 65 years	23 Participants n=5 Participants	141 Participants n=7 Participants	137 Participants n=5 Participants	149 Participants n=4 Participants	450 Participants n=21 Participants
Age, Categorical >=65 years	14 Participants n=5 Participants	83 Participants n=7 Participants	83 Participants n=5 Participants	72 Participants n=4 Participants	252 Participants n=21 Participants
Age, Continuous	58.3 years STANDARD_DEVIATION 10.34 • n=5 Participants	59.5 years STANDARD_DEVIATION 11.65 • n=7 Participants	60.2 years STANDARD_DEVIATION 11.65 • n=5 Participants	58.4 years STANDARD_DEVIATION 12.07 • n=4 Participants	59.3 years STANDARD_DEVIATION 11.80 • n=21 Participants
Sex: Female, Male Female	22 Participants n=5 Participants	119 Participants n=7 Participants	106 Participants n=5 Participants	127 Participants n=4 Participants	374 Participants n=21 Participants
Sex: Female, Male Male	15 Participants n=5 Participants	105 Participants n=7 Participants	114 Participants n=5 Participants	94 Participants n=4 Participants	328 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	14 Participants n=7 Participants	13 Participants n=5 Participants	6 Participants n=4 Participants	33 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	37 Participants n=5 Participants	203 Participants n=7 Participants	195 Participants n=5 Participants	202 Participants n=4 Participants	637 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	7 Participants n=7 Participants	12 Participants n=5 Participants	13 Participants n=4 Participants	32 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Race (NIH/OMB) Asian	7 Participants n=5 Participants	20 Participants n=7 Participants	25 Participants n=5 Participants	39 Participants n=4 Participants	91 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	3 Participants n=21 Participants
Race (NIH/OMB) White	29 Participants n=5 Participants	195 Participants n=7 Participants	183 Participants n=5 Participants	172 Participants n=4 Participants	579 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	7 Participants n=7 Participants	11 Participants n=5 Participants	10 Participants n=4 Participants	28 Participants n=21 Participants
Region North America	5 Participants n=5 Participants	30 Participants n=7 Participants	28 Participants n=5 Participants	29 Participants n=4 Participants	92 Participants n=21 Participants
Region Europe	25 Participants n=5 Participants	150 Participants n=7 Participants	145 Participants n=5 Participants	125 Participants n=4 Participants	445 Participants n=21 Participants
Region Rest of World	7 Participants n=5 Participants	44 Participants n=7 Participants	47 Participants n=5 Participants	67 Participants n=4 Participants	165 Participants n=21 Participants
Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Baseline 0-Fully active	22 Participants n=5 Participants	116 Participants n=7 Participants	112 Participants n=5 Participants	108 Participants n=4 Participants	358 Participants n=21 Participants
Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Baseline 1-Restircted in physically strenuous activity	15 Participants n=5 Participants	108 Participants n=7 Participants	104 Participants n=5 Participants	113 Participants n=4 Participants	340 Participants n=21 Participants
Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Baseline 2-Ambulatory and capable of all self-care	0 Participants n=5 Participants	0 Participants n=7 Participants	4 Participants n=5 Participants	0 Participants n=4 Participants	4 Participants n=21 Participants
Number of Participants According to Primary Tumor Location Left Colon	11 Participants n=5 Participants	79 Participants n=7 Participants	83 Participants n=5 Participants	68 Participants n=4 Participants	241 Participants n=21 Participants
Number of Participants According to Primary Tumor Location Right Colon	23 Participants n=5 Participants	126 Participants n=7 Participants	110 Participants n=5 Participants	119 Participants n=4 Participants	378 Participants n=21 Participants
Number of Participants According to Primary Tumor Location Left and Right Colon	0 Participants n=5 Participants	8 Participants n=7 Participants	11 Participants n=5 Participants	22 Participants n=4 Participants	41 Participants n=21 Participants
Number of Participants According to Primary Tumor Location Unknown	3 Participants n=5 Participants	11 Participants n=7 Participants	16 Participants n=5 Participants	12 Participants n=4 Participants	42 Participants n=21 Participants
Number of Participants According to Removal of Primary Tumor Completely Resected	20 Participants n=5 Participants	133 Participants n=7 Participants	123 Participants n=5 Participants	122 Participants n=4 Participants	398 Participants n=21 Participants
Number of Participants According to Removal of Primary Tumor Partially Resected/Unresected	17 Participants n=5 Participants	91 Participants n=7 Participants	97 Participants n=5 Participants	99 Participants n=4 Participants	304 Participants n=21 Participants
Number of Participants According to Number of Organs Involved <=2	16 Participants n=5 Participants	114 Participants n=7 Participants	117 Participants n=5 Participants	123 Participants n=4 Participants	370 Participants n=21 Participants
Number of Participants According to Number of Organs Involved 3+	21 Participants n=5 Participants	110 Participants n=7 Participants	103 Participants n=5 Participants	98 Participants n=4 Participants	332 Participants n=21 Participants
Sites of Metastases Liver	24 Sites n=5 Participants	145 Sites n=7 Participants	134 Sites n=5 Participants	128 Sites n=4 Participants	431 Sites n=21 Participants
Sites of Metastases Lung	10 Sites n=5 Participants	86 Sites n=7 Participants	83 Sites n=5 Participants	86 Sites n=4 Participants	265 Sites n=21 Participants
Sites of Metastases Lymph Node	17 Sites n=5 Participants	86 Sites n=7 Participants	82 Sites n=5 Participants	88 Sites n=4 Participants	273 Sites n=21 Participants
Sites of Metastases Peritoneum/Omentum	17 Sites n=5 Participants	77 Sites n=7 Participants	97 Sites n=5 Participants	93 Sites n=4 Participants	284 Sites n=21 Participants

PRIMARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=37 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Safety Lead-in) Number of Participants With Dose-Limiting Toxicities (DLTs)	5 Participants	—	—

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=37 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Safety Lead-in) Number of Participants With Adverse Events (AEs)	37 Participants	—	—

PRIMARY outcome

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

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.

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=37 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Safety Lead-in) Incidence of Dose Interruptions, Dose Modifications and Discontinuations Due to Adverse Events (AEs) - Interim Analysis	26 Participants	—	—

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=37 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Safety Lead-in) Incidence of Dose Interruptions, Dose Modifications and Discontinuations Due to Adverse Events (AEs) - Final Analysis Dose interruptions	30 Participants	—	—
(Safety Lead-in) Incidence of Dose Interruptions, Dose Modifications and Discontinuations Due to Adverse Events (AEs) - Final Analysis Dose modifications	16 Participants	—	—
(Safety Lead-in) Incidence of Dose Interruptions, Dose Modifications and Discontinuations Due to Adverse Events (AEs) - Final Analysis Discontinuation due to AEs	8 Participants	—	—

PRIMARY outcome

Timeframe: 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.

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

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=224 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=221 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Overall Survival (OS) of Triplet Arm vs. Control Arm - Interim Analysis	9.03 Months Interval 8.02 to 11.43	5.42 Months Interval 4.76 to 6.57	—

PRIMARY outcome

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

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.

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=111 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=107 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Objective Response Rate (ORR) by Blinded Independent Central Review (BICR) Per Response Evaluation Criteria in Solid Tumors (RECIST), v1.1 of Triplet Arm vs. Control Arm	26.1 Percentage of participants Interval 18.2 to 35.3	1.9 Percentage of participants Interval 0.2 to 6.6	—

SECONDARY outcome

Timeframe: 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).

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.

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=36 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Safety Lead-in) Objective Response Rate (ORR) by Investigator	52.8 Percentage of participants Interval 35.5 to 69.6	—	—

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=36 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Safety Lead-in) Objective Response Rate (ORR) by BICR	41.7 Percentage of participants Interval 25.5 to 59.2	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=19 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Safety Lead-in) Duration of Response (DOR) by Investigator	6.47 Months Interval 4.17 to 11.07	—	—

SECONDARY outcome

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

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.

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=15 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Safety Lead-in) Duration of Response (DOR) by BICR	8.15 Months Interval 2.79 to NA= not reached. Insufficient number of participants with events to calculate the upper limit of the 95% confidence interval.	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=36 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Safety Lead-in) Time to Response by Investigator	1.45 Months Interval 1.38 to 1.64	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=36 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Safety Lead-in) Time to Response by BICR	1.45 Months Interval 1.38 to 1.64	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=36 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Safety Lead-in) Progression-Free Survival (PFS) by Investigator	8.08 Months Interval 5.59 to 9.3	—	—

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=36 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Safety Lead-in) Progression-Free Survival (PFS) by BICR	5.59 Months Interval 4.44 to 9.3	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=220 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=221 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Overall Survival (OS) in Doublet Arm vs. Control Arm	9.40 Months Interval 8.11 to 11.24	5.88 Months Interval 5.09 to 7.16	—

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=224 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=220 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Overall Survival (OS) in Triplet Arm vs. Doublet Arm	9.82 Months Interval 8.34 to 11.73	9.40 Months Interval 8.11 to 11.24	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=224 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=221 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Comparison of Progression-Free Survival (PFS) in Triplet Arm vs Control Arm Per BICR	4.30 Months Interval 4.14 to 5.19	1.51 Months Interval 1.45 to 1.71	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=224 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=221 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Comparison of Progression-free Survival (PFS) in Triplet Arm vs Control Arm Per Investigator	4.47 Months Interval 4.24 to 5.36	1.58 Months Interval 1.51 to 2.07	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=220 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=221 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Comparison of Progression-Free Survival (PFS) in Doublet Arm vs Control Arm Per BICR	4.21 Months Interval 3.71 to 5.36	1.51 Months Interval 1.45 to 1.71	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=220 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=221 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Comparison of Progression-Free Survival (PFS) in Doublet Arm vs Control Arm Per Investigator	4.27 Months Interval 4.04 to 5.36	1.58 Months Interval 1.51 to 2.07	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=224 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=220 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Comparison of Progression-Free Survival (PFS) in Triplet Arm vs Doublet Arm Per BICR	4.30 Months Interval 4.14 to 5.19	4.21 Months Interval 3.71 to 5.36	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=224 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=220 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Comparison of Progression-Free Survival (PFS) in Triplet Arm vs Doublet Arm Per Investigator	4.47 Months Interval 4.24 to 5.36	4.27 Months Interval 4.04 to 5.36	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=111 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=107 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Control Arm Per Investigator	26.1 Percentage of participants Interval 18.2 to 35.3	3.7 Percentage of participants Interval 1.0 to 9.3	—

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=113 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=107 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Comparison of Objective Response Rate (ORR) in Doublet Arm vs Control Arm Per BICR	20.4 Percentage of participants Interval 13.4 to 29.0	1.9 Percentage of participants Interval 0.2 to 6.6	—

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=113 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=107 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Comparison of Objective Response Rate (ORR) in Doublet Arm vs Control Arm Per Investigator	15.9 Percentage of participants Interval 9.7 to 24.0	3.7 Percentage of participants Interval 1.0 to 9.3	—

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=111 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=113 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Doublet Arm Per BICR	26.1 Percentage of participants Interval 18.2 to 35.3	20.4 Percentage of participants Interval 13.4 to 29.0	—

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=111 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=113 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Doublet Arm Per Investigator	26.1 Percentage of participants Interval 18.2 to 35.3	15.9 Percentage of participants Interval 9.7 to 24.0	—

SECONDARY outcome

Timeframe: 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)

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=111 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=107 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Control Arm Per BICR	4.80 Months Interval 2.96 to 9.69	NA Months Interval 2.56 to NA= not reached. Insufficient number of participants with events to calculate the median and upper limit of the 95% confidence interval.	—

SECONDARY outcome

Timeframe: 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)

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=111 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=107 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Control Arm Per Investigator	4.80 Months Interval 3.29 to 6.57	5.75 Months Interval 2.56 to NA= not reached. Insufficient number of participants with events to calculate the upper limit of the 95% confidence interval.	—

SECONDARY outcome

Timeframe: 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)

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=113 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=107 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Comparison of Duration of Response (DOR) in Doublet Arm vs Control Arm Per BICR	6.06 Months Interval 4.07 to 8.28	NA Months Interval 2.56 to NA= not reached. Insufficient number of participants with events to calculate the median and upper limit of the 95% confidence interval.	—

SECONDARY outcome

Timeframe: 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)

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=113 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=107 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Comparison of Duration of Response (DOR) in Doublet Arm vs Control Arm Per Investigator	5.70 Months Interval 3.65 to 6.74	5.75 Months Interval 2.56 to NA= not reached. Insufficient number of participants with events to calculate the upper limit of the 95% confidence interval.	—

SECONDARY outcome

Timeframe: 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)

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=111 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=113 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Doublet Arm by BICR	4.80 Months Interval 2.96 to 9.69	6.06 Months Interval 4.07 to 8.28	—

SECONDARY outcome

Timeframe: 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)

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=111 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=113 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Doublet Arm by Investigator	4.80 Months Interval 3.29 to 6.57	5.70 Months Interval 3.65 to 6.74	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=50 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=3 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Comparison of Time to Response in Triplet Arm vs Control Arm Per BICR	1.43 Months Interval 1.41 to 1.51	1.45 Months Interval 1.41 to 2.63	—

SECONDARY outcome

Timeframe: 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)

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

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=49 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=7 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Comparison of Time to Response in Triplet Arm vs Control Arm Per Investigator	1.48 Months Interval 1.41 to 1.51	2.63 Months Interval 1.45 to 2.79	—

SECONDARY outcome

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

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

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=36 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=3 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Comparison of Time to Response in Doublet Arm vs Control Arm Per BICR	1.48 Months Interval 1.41 to 1.58	1.45 Months Interval 1.41 to 2.63	—

SECONDARY outcome

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

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

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=31 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=7 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Comparison of Time to Response in Doublet Arm vs Control Arm Per Investigator	1.48 Months Interval 1.41 to 1.54	2.63 Months Interval 1.45 to 2.79	—

SECONDARY outcome

Timeframe: 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)

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

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=50 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=36 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Comparison of Time to Response in Triplet Arm vs Doublet Arm Per BICR	1.43 Months Interval 1.41 to 1.51	1.48 Months Interval 1.41 to 1.58	—

SECONDARY outcome

Timeframe: 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)

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

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=49 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=31 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Comparison of Time to Response in Triplet Arm vs Doublet Arm Per Investigator	1.48 Months Interval 1.41 to 1.51	1.48 Months Interval 1.41 to 1.54	—

SECONDARY outcome

Timeframe: 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 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).

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=224 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=220 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm n=221 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Baseline	62.8 Units on a scale Standard Deviation 22.18	60.7 Units on a scale Standard Deviation 21.33	62.8 Units on a scale Standard Deviation 21.82
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 1 Day 1	-2.4 Units on a scale Standard Deviation 13.44	-4.3 Units on a scale Standard Deviation 16.27	-3.4 Units on a scale Standard Deviation 15.60
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 2 Day 1	-1.6 Units on a scale Standard Deviation 19.06	3.8 Units on a scale Standard Deviation 18.46	-1.9 Units on a scale Standard Deviation 22.45
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 3 Day 1	0.7 Units on a scale Standard Deviation 18.86	3.5 Units on a scale Standard Deviation 19.96	-0.2 Units on a scale Standard Deviation 24.07
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 4 Day 1	0.2 Units on a scale Standard Deviation 15.63	4.2 Units on a scale Standard Deviation 22.17	1.4 Units on a scale Standard Deviation 21.65
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 5 Day 1	-1.1 Units on a scale Standard Deviation 18.66	4.3 Units on a scale Standard Deviation 22.09	-2.2 Units on a scale Standard Deviation 22.06
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 6 Day 1	-4.0 Units on a scale Standard Deviation 16.76	5.6 Units on a scale Standard Deviation 23.25	-4.5 Units on a scale Standard Deviation 19.43
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 7 Day 1	-2.5 Units on a scale Standard Deviation 16.01	4.3 Units on a scale Standard Deviation 21.77	1.7 Units on a scale Standard Deviation 12.30
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 8 Day 1	-2.6 Units on a scale Standard Deviation 14.83	4.2 Units on a scale Standard Deviation 16.98	0.0 Units on a scale Standard Deviation 27.64
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 9 Day 1	-5.8 Units on a scale Standard Deviation 17.74	-5.6 Units on a scale Standard Deviation 16.44	-4.8 Units on a scale Standard Deviation 12.60
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 10 Day 1	-3.3 Units on a scale Standard Deviation 17.90	-2.8 Units on a scale Standard Deviation 16.97	2.1 Units on a scale Standard Deviation 20.83
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 11 Day 1	-5.2 Units on a scale Standard Deviation 20.38	3.9 Units on a scale Standard Deviation 15.31	33.3 Units on a scale Standard Deviation NA Number analyzed is 1 so standard deviation (SD) is not available.
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 12 Day 1	0.0 Units on a scale Standard Deviation 22.41	-4.6 Units on a scale Standard Deviation 13.77	4.2 Units on a scale Standard Deviation 53.03
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 13 Day 1	0.0 Units on a scale Standard Deviation 20.41	-3.2 Units on a scale Standard Deviation 14.25	0.0 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 14 Day 1	-1.2 Units on a scale Standard Deviation 24.26	-6.0 Units on a scale Standard Deviation 15.00	—
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 15 Day 1	3.6 Units on a scale Standard Deviation 33.63	2.8 Units on a scale Standard Deviation 8.61	—
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 16 Day 1	-16.7 Units on a scale Standard Deviation 42.08	-5.6 Units on a scale Standard Deviation 9.62	—
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 17 Day 1	-27.8 Units on a scale Standard Deviation 20.97	-2.8 Units on a scale Standard Deviation 12.73	—
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 18 Day 1	-16.7 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.	-8.3 Units on a scale Standard Deviation 8.33	—
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 19 Day 1	0.0 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.	-8.3 Units on a scale Standard Deviation 11.79	—
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 20 Day 1	-25 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.	-8 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.	—
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 21 Day 1	0.0 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.	-16.7 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.	—
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 22 Day 1	—	-16.7 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.	—
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 23 Day 1	—	0.0 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.	—
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at End of Treatment	-14.1 Units on a scale Standard Deviation 22.66	-13.1 Units on a scale Standard Deviation 21.61	-15.5 Units on a scale Standard Deviation 27.04
(Phase 3) Change From Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Participants (QLQ-C30) Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at 30 Day Follow Up	-17.4 Units on a scale Standard Deviation 22.51	-10.4 Units on a scale Standard Deviation 15.96	-24.6 Units on a scale Standard Deviation 24.08

SECONDARY outcome

Timeframe: 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)

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.

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=224 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=220 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm n=221 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Baseline	16.3 Units on a scale Standard Deviation 6.22	16.2 Units on a scale Standard Deviation 5.9	16.8 Units on a scale Standard Deviation 6.07
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 1 Day 1	-0.2 Units on a scale Standard Deviation 3.36	-0.9 Units on a scale Standard Deviation 4.06	-1.4 Units on a scale Standard Deviation 3.32
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 2 Day 1	-0.3 Units on a scale Standard Deviation 4.28	-0.6 Units on a scale Standard Deviation 5.08	-0.9 Units on a scale Standard Deviation 4.48
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 3 Day 1	-0.2 Units on a scale Standard Deviation 5.15	-0.2 Units on a scale Standard Deviation 5.23	-0.7 Units on a scale Standard Deviation 5.03
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 4 Day 1	0.4 Units on a scale Standard Deviation 4.53	-0.1 Units on a scale Standard Deviation 4.66	-1.8 Units on a scale Standard Deviation 6.48
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 5 Day 1	0.7 Units on a scale Standard Deviation 6.4	-0.2 Units on a scale Standard Deviation 4.5	-1.6 Units on a scale Standard Deviation 4.58
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 6 Day 1	0.7 Units on a scale Standard Deviation 6.05	0.6 Units on a scale Standard Deviation 4.56	-1.9 Units on a scale Standard Deviation 5.3
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 7 Day 1	0.5 Units on a scale Standard Deviation 5.85	-0.1 Units on a scale Standard Deviation 4.70	-0.5 Units on a scale Standard Deviation 5.41
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 8 Day 1	0.9 Units on a scale Standard Deviation 6.35	0.2 Units on a scale Standard Deviation 4.24	-2.1 Units on a scale Standard Deviation 4.97
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 9 Day 1	-1.9 Units on a scale Standard Deviation 4.32	-0.8 Units on a scale Standard Deviation 3.74	-2.6 Units on a scale Standard Deviation 2.30
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 10 Day 1	-1.7 Units on a scale Standard Deviation 4.76	-1.3 Units on a scale Standard Deviation 3.59	0.5 Units on a scale Standard Deviation 4.36
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 11 Day 1	-1.5 Units on a scale Standard Deviation 4.47	-0.5 Units on a scale Standard Deviation 4.65	-4.5 Units on a scale Standard Deviation 7.78
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 12 Day 1	-1.5 Units on a scale Standard Deviation 4.93	-1.1 Units on a scale Standard Deviation 4.61	-4.5 Units on a scale Standard Deviation 9.19
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 13 Day 1	-2.0 Units on a scale Standard Deviation 6.76	-3.2 Units on a scale Standard Deviation 5.34	-8.0 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 14 Day 1	-2.4 Units on a scale Standard Deviation 5.22	-4.0 Units on a scale Standard Deviation 5.74	—
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 15 Day 1	-2.3 Units on a scale Standard Deviation 6.85	-1.5 Units on a scale Standard Deviation 4.72	—
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 16 Day 1	-4.2 Units on a scale Standard Deviation 4.02	-0.7 Units on a scale Standard Deviation 0.58	—
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 17 Day 1	-6.7 Units on a scale Standard Deviation 5.51	-0.7 Units on a scale Standard Deviation 4.51	—
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 18 Day 1	-5.0 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.	-3.0 Units on a scale Standard Deviation 4.36	—
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 19 Day 1	-7.0 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.	-6.0 Units on a scale Standard Deviation 0.00	—
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 20 Day 1	-6.0 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.	-5.0 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.	—
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 21 Day 1	-9.0 Units on a scale	-5.0 Units on a scale	—
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 22 Day 1	—	-12.0 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.	—
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 23 Day 1	—	-9.0 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.	—
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at End of Treatment	-2.4 Units on a scale Standard Deviation 4.84	-2.2 Units on a scale Standard Deviation 5.14	-3.1 Units on a scale Standard Deviation 6.06
(Phase 3) Change From Baseline in the Functional Assessment of Cancer Therapy-Colon Cancer (FACT-C) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at 30 Day Follow Up	-3.5 Units on a scale Standard Deviation 6.44	-0.8 Units on a scale Standard Deviation 5.42	-4.2 Units on a scale Standard Deviation 6.41

SECONDARY outcome

Timeframe: 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)

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).

Outcome measures

Outcome measures
Measure	Combined Safety Lead-in (CSLI) n=224 Participants Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Phase 3: Control Arm n=220 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.	Phase 3:Control Arm n=221 Participants Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab. Cetuximab: Standard of care. Irinotecan: Standard of care. Folinic Acid: Standard of care. 5-Fluorouracil: Standard of care. Following protocol amendment, eligible participants could crossover to receive either triplet or doublet regimen.
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Baseline	69.0 Units on a scale Standard Deviation 19.03	66.5 Units on a scale Standard Deviation 19.51	68.3 Units on a scale Standard Deviation 19.71
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 1 Day 1	0.8 Units on a scale Standard Deviation 10.89	-0.9 Units on a scale Standard Deviation 14.09	-2.1 Units on a scale Standard Deviation 15.02
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 2 Day 1	1.4 Units on a scale Standard Deviation 14.74	1.9 Units on a scale Standard Deviation 14.81	-2.4 Units on a scale Standard Deviation 17.20
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 3 Day 1	3.0 Units on a scale Standard Deviation 13.94	4.2 Units on a scale Standard Deviation 17.32	-1.4 Units on a scale Standard Deviation 17.40
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 4 Day 1	4.0 Units on a scale Standard Deviation 13.06	5.6 Units on a scale Standard Deviation 14.87	-0.4 Units on a scale Standard Deviation 15.14
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 5 Day 1	3.3 Units on a scale Standard Deviation 14.66	5.1 Units on a scale Standard Deviation 15.11	2.5 Units on a scale Standard Deviation 11.17
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 6 Day 1	1.3 Units on a scale Standard Deviation 13.33	2.9 Units on a scale Standard Deviation 16.84	-3.6 Units on a scale Standard Deviation 13.26
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 7 Day 1	1.4 Units on a scale Standard Deviation 13.64	3.6 Units on a scale Standard Deviation 16.71	2.4 Units on a scale Standard Deviation 7.44
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 8 Day 1	4.1 Units on a scale Standard Deviation 10.77	2.0 Units on a scale Standard Deviation 16.11	-2.8 Units on a scale Standard Deviation 12.95
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 9 Day 1	0.3 Units on a scale Standard Deviation 15.16	-4.0 Units on a scale Standard Deviation 12.99	-8.1 Units on a scale Standard Deviation 8.80
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 10 Day 1	0.2 Units on a scale Standard Deviation 13.34	-8.1 Units on a scale Standard Deviation 13.68	-1.8 Units on a scale Standard Deviation 2.36
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 11 Day 1	0.2 Units on a scale Standard Deviation 13.87	-0.1 Units on a scale Standard Deviation 10.15	4.0 Units on a scale Standard Deviation 8.49
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 12 Day 1	-4.0 Units on a scale Standard Deviation 20.11	-0.6 Units on a scale Standard Deviation 11.67	1.5 Units on a scale Standard Deviation 12.02
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 13 Day 1	-3.0 Units on a scale Standard Deviation 17.17	-4.1 Units on a scale Standard Deviation 14.41	-2.0 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 14 Day 1	-4.0 Units on a scale Standard Deviation 18.06	-0.4 Units on a scale Standard Deviation 13.99	—
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 15 Day 1	-3.4 Units on a scale Standard Deviation 14.67	4.2 Units on a scale Standard Deviation 7.36	—
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 16 Day 1	-10.4 Units on a scale Standard Deviation 24.87	3.3 Units on a scale Standard Deviation 2.89	—
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 17 Day 1	-18.3 Units on a scale Standard Deviation 20.21	1.7 Units on a scale Standard Deviation 5.77	—
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 18 Day 1	7.0 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.	-3.3 Units on a scale Standard Deviation 2.89	—
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 19 Day 1	8.0 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.	-5.5 Units on a scale Standard Deviation 13.44	—
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 20 Day 1	8.0 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.	2.0 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.	—
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 21 Day 1	8.0 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.	-5.0 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.	—
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 22 Day 1	—	-5.0 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.	—
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at Cycle 23 Day 1	—	-5.0 Units on a scale Standard Deviation NA Number analyzed is 1 so SD is not available.	—
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at End of Treatment	-8.5 Units on a scale Standard Deviation 17.40	-8.0 Units on a scale Standard Deviation 18.99	-12.7 Units on a scale Standard Deviation 21.34
(Phase 3) Change From Baseline in the EuroQol-5D-5L Visual Analog Scale (EQ-5D-5L VAS) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet Change at 30 Day Follow Up	-11.1 Units on a scale Standard Deviation 20.23	-5.9 Units on a scale Standard Deviation 20.18	-11.0 Units on a scale Standard Deviation 17.51

SECONDARY outcome

Timeframe: 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)

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."