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 (BEACON CRC)

• ClinicalTrials.gov Identifier: NCT02928224
• Recruitment Status: Completed
• First Posted: October 10, 2016
• Results First Posted: July 14, 2020
• Last Update Posted: December 21, 2023
• Sponsor: Pfizer
• Collaborators: Merck KGaA, Darmstadt, Germany; Pierre Fabre Medicament; Ono Pharmaceutical Co. Ltd
• Information provided by (Responsible Party): Pfizer

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: BRAF V600E-mutant Metastatic Colorectal Cancer
• Interventions: Drug: Encorafenib; Drug: Binimetinib; Drug: Cetuximab; Drug: Irinotecan; Drug: Folinic Acid; Drug: 5-Fluorouracil
• Enrollment: 702

Participant Flow

Recruitment Details	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.
Pre-assignment Details

Arm/Group Title	Combined Safety Lead-in	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3: Control Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	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.
Period Title: Overall Study
Started	37	224	220	221
Crossover Participants	0	0	0	3 [1]
Completed	0	0	0	0
Not Completed	37	224	220	221
Reason Not Completed
Lost to Follow-up	1	1	3	0
Death	30	209	193	198
Withdrawal by Subject	0	3	7	20
Study participation terminated by sponsor	3	8	12	3
Other	3	3	5	0
[1] Participants from control arm received triplet therapy.

Baseline Characteristics

Arm/Group Title		Combined Safety Lead-in (CSLI)	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3: Control Arm	Total
Arm/Group Description		Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	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 of all reporting groups
Overall Number of Baseline Participants		37	224	220	221	702
Baseline Analysis Population Description		The baseline analysis population consists of the Full Analysis Set (FAS). For participants in the CSLI, the FAS includes all participants who received at least 1 dose of study drug and had at least 1 post treatment assessment, which may include death. For the randomized Phase 3 portion of the study, the FAS consists of all randomized participants.
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	37 participants	224 participants	220 participants	221 participants	702 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	23 62.2%	141 62.9%	137 62.3%	149 67.4%	450 64.1%
	>=65 years	14 37.8%	83 37.1%	83 37.7%	72 32.6%	252 35.9%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	37 participants	224 participants	220 participants	221 participants	702 participants
		58.3 (10.34)	59.5 (11.65)	60.2 (11.65)	58.4 (12.07)	59.3 (11.80)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	37 participants	224 participants	220 participants	221 participants	702 participants
	Female	22 59.5%	119 53.1%	106 48.2%	127 57.5%	374 53.3%
	Male	15 40.5%	105 46.9%	114 51.8%	94 42.5%	328 46.7%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	37 participants	224 participants	220 participants	221 participants	702 participants
	Hispanic or Latino	0 0.0%	14 6.3%	13 5.9%	6 2.7%	33 4.7%
	Not Hispanic or Latino	37 100.0%	203 90.6%	195 88.6%	202 91.4%	637 90.7%
	Unknown or Not Reported	0 0.0%	7 3.1%	12 5.5%	13 5.9%	32 4.6%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	37 participants	224 participants	220 participants	221 participants	702 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	1 0.5%	0 0.0%	1 0.1%
	Asian	7 18.9%	20 8.9%	25 11.4%	39 17.6%	91 13.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	1 2.7%	2 0.9%	0 0.0%	0 0.0%	3 0.4%
	White	29 78.4%	195 87.1%	183 83.2%	172 77.8%	579 82.5%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	7 3.1%	11 5.0%	10 4.5%	28 4.0%
Region; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	37 participants	224 participants	220 participants	221 participants	702 participants
	North America	5 13.5%	30 13.4%	28 12.7%	29 13.1%	92 13.1%
	Europe	25 67.6%	150 67.0%	145 65.9%	125 56.6%	445 63.4%
	Rest of World	7 18.9%	44 19.6%	47 21.4%	67 30.3%	165 23.5%
Eastern Cooperative Oncology Group Performance Status (ECOG PS) at Baseline [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	37 participants	224 participants	220 participants	221 participants	702 participants
	0-Fully active	22 59.5%	116 51.8%	112 50.9%	108 48.9%	358 51.0%
	1-Restircted in physically strenuous activity	15 40.5%	108 48.2%	104 47.3%	113 51.1%	340 48.4%
	2-Ambulatory and capable of all self-care	0 0.0%	0 0.0%	4 1.8%	0 0.0%	4 0.6%
		[1] Measure Description: ECOG PS was used to assess the physical health of participants, and ranges from 0 to 5 where 0: fully active, 1: restricted in physically strenuous activity, 2: ambulatory and capable of self-care but unable to work, 3: capable only of limited self-care , 4: completely disabled; cannot carry on any self-care; totally confined to bed or chair, 5: dead.
Number of Participants According to Primary Tumor Location; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	37 participants	224 participants	220 participants	221 participants	702 participants
	Left Colon	11 29.7%	79 35.3%	83 37.7%	68 30.8%	241 34.3%
	Right Colon	23 62.2%	126 56.3%	110 50.0%	119 53.8%	378 53.8%
	Left and Right Colon	0 0.0%	8 3.6%	11 5.0%	22 10.0%	41 5.8%
	Unknown	3 8.1%	11 4.9%	16 7.3%	12 5.4%	42 6.0%
Number of Participants According to Removal of Primary Tumor; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	37 participants	224 participants	220 participants	221 participants	702 participants
	Completely Resected	20 54.1%	133 59.4%	123 55.9%	122 55.2%	398 56.7%
	Partially Resected/Unresected	17 45.9%	91 40.6%	97 44.1%	99 44.8%	304 43.3%
Number of Participants According to Number of Organs Involved; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	37 participants	224 participants	220 participants	221 participants	702 participants
	<=2	16 43.2%	114 50.9%	117 53.2%	123 55.7%	370 52.7%
	3+	21 56.8%	110 49.1%	103 46.8%	98 44.3%	332 47.3%
Sites of Metastases [1]; Measure Type: Number; Unit of measure: Sites	Number Analyzed	37 participants	224 participants	220 participants	221 participants	702 participants
Liver		24	145	134	128	431
Lung		10	86	83	86	265
Lymph Node		17	86	82	88	273
Peritoneum/Omentum		17	77	97	93	284
		[1] Measure Description: One participant may have more than one site of metastases.

Outcome Measures

1. Primary Outcome

Title	(Safety Lead-in) Number of Participants With Dose-Limiting Toxicities (DLTs)
Description	[Not Specified]
Time Frame	Cycle 1 (up to 28 days)

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Combined Safety Lead-in (CSLI)
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	37
Measure Type: Count of Participants; Unit of Measure: Participants
	5 13.5%

2. Primary Outcome

Title	(Safety Lead-in) Number of Participants With Adverse Events (AEs)
Description	An AE is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. Number of participants reporting AEs were reported in this outcome measure.
Time Frame	Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	37
Measure Type: Count of Participants; Unit of Measure: Participants
	37 100.0%

3. Primary Outcome

Title	(Safety Lead-in) Incidence of Dose Interruptions, Dose Modifications and Discontinuations Due to Adverse Events (AEs) - Interim Analysis
Description	An AE is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. Number of participants with dose interruptions, dose modifications and dose discontinuations due to AEs were reported in this outcome measure.
Time Frame	Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	37
Measure Type: Count of Participants; Unit of Measure: Participants
	26 70.3%

4. Primary Outcome

Title	(Safety Lead-in) Incidence of Dose Interruptions, Dose Modifications and Discontinuations Due to Adverse Events (AEs) - Final Analysis
Description	An AE is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. Number of participants according to incidence of dose interruptions, dose modifications and dose discontinuations due to AEs were reported in this outcome measure.
Time Frame	From start of study treatment until 30 days post last dose of study treatment (maximum treatment exposure of 280 weeks)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	37
Measure Type: Count of Participants; Unit of Measure: Participants
Dose interruptions	30 81.1%
Dose modifications	16 43.2%
Discontinuation due to AEs	8 21.6%

5. Primary Outcome

Title	(Phase 3) Overall Survival (OS) of Triplet Arm vs. Control Arm - Interim Analysis
Description	OS was defined as the time from randomization to death due to any cause.
Time Frame	From randomization to death due to any cause until 204 deaths were observed (maximum treatment exposure of 89.1 weeks for triplet arm and 52.4 weeks for control arm)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Phase 3: Triplet Arm	Phase 3: Control Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	224	221
Median (95% Confidence Interval); Unit of Measure: Months
	9.03; (8.02 to 11.43)	5.42; (4.76 to 6.57)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 3: Triplet Arm, Phase 3: Control Arm
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Stratified Log-rank
	Comments	[Not Specified]

6. Primary Outcome

Title	(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
Description	ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of complete response (CR) or partial response (PR), where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 millimeter [mm] short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Control Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	111	107
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	26.1; (18.2 to 35.3)	1.9; (0.2 to 6.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 3: Triplet Arm, Phase 3:Control Arm
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]

7. Secondary Outcome

Title	(Safety Lead-in) Objective Response Rate (ORR) by Investigator
Description	ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.
Time Frame	From start of study treatment until 30 days post last dose of study treatment (maximum treatment exposure of 280 weeks)

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	36
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	52.8; (35.5 to 69.6)

8. Secondary Outcome

Title	(Safety Lead-in) Objective Response Rate (ORR) by BICR
Description	ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.
Time Frame	From start of study treatment until 30 days post last dose of study treatment (maximum treatment exposure of 280 weeks)

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	36
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	41.7; (25.5 to 59.2)

9. Secondary Outcome

Title	(Safety Lead-in) Duration of Response (DOR) by Investigator
Description	DOR was defined as the time from first radiographic evidence of response to the earliest documented disease progression (PD) or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.
Time Frame	From time of response to the earliest documented PD or death due to underlying disease (maximum treatment exposure of 280 weeks)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	19
Median (95% Confidence Interval); Unit of Measure: Months
	6.47; (4.17 to 11.07)

10. Secondary Outcome

Title	(Safety Lead-in) Duration of Response (DOR) by BICR
Description	DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.
Time Frame	From time of response to the earliest documented PD or death due to underlying disease (maximum treatment exposure of 280 weeks)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	15
Median (95% Confidence Interval); Unit of Measure: Months
	8.15 [1]; (2.79 to NA)

[1]

NA= not reached. Insufficient number of participants with events to calculate the upper limit of the 95% confidence interval.

11. Secondary Outcome

Title	(Safety Lead-in) Time to Response by Investigator
Description	Time to response was defined as the time from first dose to first radiographic evidence of response.
Time Frame	From first dose to first radiographic evidence of response (maximum treatment exposure of 280 weeks)

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	36
Median (95% Confidence Interval); Unit of Measure: Months
	1.45; (1.38 to 1.64)

12. Secondary Outcome

Title	(Safety Lead-in) Time to Response by BICR
Description	Time to response was defined as the time from first dose to first radiographic evidence of response.
Time Frame	From first dose to first radiographic evidence of response (maximum treatment exposure of 280 weeks)

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	36
Median (95% Confidence Interval); Unit of Measure: Months
	1.45; (1.38 to 1.64)

13. Secondary Outcome

Title	(Safety Lead-in) Progression-Free Survival (PFS) by Investigator
Description	PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.
Time Frame	From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 280 weeks)

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	36
Median (95% Confidence Interval); Unit of Measure: Months
	8.08; (5.59 to 9.3)

14. Secondary Outcome

Title	(Safety Lead-in) Progression-Free Survival (PFS) by BICR
Description	PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.
Time Frame	From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 280 weeks)

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	36
Median (95% Confidence Interval); Unit of Measure: Months
	5.59; (4.44 to 9.3)

15. Secondary Outcome

Title	(Phase 3) Overall Survival (OS) in Doublet Arm vs. Control Arm
Description	OS was defined as the time from randomization to death due to any cause.
Time Frame	From randomization to death due to any cause until 204 deaths were observed (maximum treatment exposure of 89.7 weeks for doublet arm and 52.4 weeks for control arm)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Phase 3: Doublet Arm	Phase 3:Control Arm
Arm/Group Description:	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	220	221
Median (95% Confidence Interval); Unit of Measure: Months
	9.40; (8.11 to 11.24)	5.88; (5.09 to 7.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 3: Doublet Arm, Phase 3:Control Arm
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Stratified Log-rank
	Comments	[Not Specified]

16. Secondary Outcome

Title	(Phase 3) Overall Survival (OS) in Triplet Arm vs. Doublet Arm
Description	OS was defined as the time from randomization to death due to any cause.
Time Frame	From randomization to death due to any cause until 204 deaths were observed (maximum treatment exposure of 89.7 weeks for doublet arm and 89.1 weeks for triplet arm)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Phase 3: Triplet Arm	Phase 3: Doublet Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	224	220
Median (95% Confidence Interval); Unit of Measure: Months
	9.82; (8.34 to 11.73)	9.40; (8.11 to 11.24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 3: Triplet Arm, Phase 3: Doublet Arm
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5958
	Comments	[Not Specified]
	Method	Stratified Log-rank
	Comments	[Not Specified]

17. Secondary Outcome

Title	(Phase 3) Comparison of Progression-Free Survival (PFS) in Triplet Arm vs Control Arm Per BICR
Description	PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.
Time Frame	From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Control Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	224	221
Median (95% Confidence Interval); Unit of Measure: Months
	4.30; (4.14 to 5.19)	1.51; (1.45 to 1.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 3: Triplet Arm, Phase 3:Control Arm
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Stratified Log-rank
	Comments	[Not Specified]

18. Secondary Outcome

Title	(Phase 3) Comparison of Progression-free Survival (PFS) in Triplet Arm vs Control Arm Per Investigator
Description	PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.
Time Frame	From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Control Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	224	221
Median (95% Confidence Interval); Unit of Measure: Months
	4.47; (4.24 to 5.36)	1.58; (1.51 to 2.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 3: Triplet Arm, Phase 3:Control Arm
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Stratified Log-rank
	Comments	[Not Specified]

19. Secondary Outcome

Title	(Phase 3) Comparison of Progression-Free Survival (PFS) in Doublet Arm vs Control Arm Per BICR
Description	PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.
Time Frame	From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Phase 3: Doublet Arm	Phase 3:Control Arm
Arm/Group Description:	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	220	221
Median (95% Confidence Interval); Unit of Measure: Months
	4.21; (3.71 to 5.36)	1.51; (1.45 to 1.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 3: Doublet Arm, Phase 3:Control Arm
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Stratified Log-rank
	Comments	[Not Specified]

20. Secondary Outcome

Title	(Phase 3) Comparison of Progression-Free Survival (PFS) in Doublet Arm vs Control Arm Per Investigator
Description	PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.
Time Frame	From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Phase 3: Doublet Arm	Phase 3:Control Arm
Arm/Group Description:	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	220	221
Median (95% Confidence Interval); Unit of Measure: Months
	4.27; (4.04 to 5.36)	1.58; (1.51 to 2.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 3: Doublet Arm, Phase 3:Control Arm
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Stratified Log-rank
	Comments	[Not Specified]

21. Secondary Outcome

Title	(Phase 3) Comparison of Progression-Free Survival (PFS) in Triplet Arm vs Doublet Arm Per BICR
Description	PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.
Time Frame	From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Phase 3: Triplet Arm	Phase 3: Doublet Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	224	220
Median (95% Confidence Interval); Unit of Measure: Months
	4.30; (4.14 to 5.19)	4.21; (3.71 to 5.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 3: Triplet Arm, Phase 3: Doublet Arm
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1004
	Comments	[Not Specified]
	Method	Stratified Log-rank
	Comments	[Not Specified]

22. Secondary Outcome

Title	(Phase 3) Comparison of Progression-Free Survival (PFS) in Triplet Arm vs Doublet Arm Per Investigator
Description	PFS was defined as the time from first dose to the earliest documented PD or death due to any cause. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.
Time Frame	From first dose to the earliest documented PD or death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Phase 3: Triplet Arm	Phase 3: Doublet Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	224	220
Median (95% Confidence Interval); Unit of Measure: Months
	4.47; (4.24 to 5.36)	4.27; (4.04 to 5.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 3: Triplet Arm, Phase 3: Doublet Arm
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3724
	Comments	[Not Specified]
	Method	Stratified Log-rank
	Comments	[Not Specified]

23. Secondary Outcome

Title	(Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Control Arm Per Investigator
Description	ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Control Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	111	107
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	26.1; (18.2 to 35.3)	3.7; (1.0 to 9.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 3: Triplet Arm, Phase 3:Control Arm
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]

24. Secondary Outcome

Title	(Phase 3) Comparison of Objective Response Rate (ORR) in Doublet Arm vs Control Arm Per BICR
Description	ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Doublet Arm	Phase 3:Control Arm
Arm/Group Description:	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	113	107
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	20.4; (13.4 to 29.0)	1.9; (0.2 to 6.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 3: Doublet Arm, Phase 3:Control Arm
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]

25. Secondary Outcome

Title	(Phase 3) Comparison of Objective Response Rate (ORR) in Doublet Arm vs Control Arm Per Investigator
Description	ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Doublet Arm	Phase 3:Control Arm
Arm/Group Description:	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	113	107
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	15.9; (9.7 to 24.0)	3.7; (1.0 to 9.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 3: Doublet Arm, Phase 3:Control Arm
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]

26. Secondary Outcome

Title	(Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Doublet Arm Per BICR
Description	ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3: Doublet Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	111	113
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	26.1; (18.2 to 35.3)	20.4; (13.4 to 29.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 3: Triplet Arm, Phase 3: Doublet Arm
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1928
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

27. Secondary Outcome

Title	(Phase 3) Comparison of Objective Response Rate (ORR) in Triplet Arm vs Doublet Arm Per Investigator
Description	ORR per RECIST, v1.1, was defined as the percentage of participants achieving an overall best response of CR or PR, where CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis), and PR: at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesions and/or maintenance of tumor marker level above the normal limits.
Time Frame	Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3: Doublet Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	111	113
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	26.1; (18.2 to 35.3)	15.9; (9.7 to 24.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 3: Triplet Arm, Phase 3: Doublet Arm
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0357
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

28. Secondary Outcome

Title	(Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Control Arm Per BICR
Description	DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.
Time Frame	From time of response to PD or death due to underlying disease (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Control Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	111	107
Median (95% Confidence Interval); Unit of Measure: Months
	4.80; (2.96 to 9.69)	NA [1]; (2.56 to NA)

[1]

NA= not reached. Insufficient number of participants with events to calculate the median and upper limit of the 95% confidence interval.

29. Secondary Outcome

Title	(Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Control Arm Per Investigator
Description	DOR was defined as the time from first radiographic evidence of response to the earliest documented disease progression (PD) or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.
Time Frame	From time of response to PD or death due to underlying disease (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Control Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	111	107
Median (95% Confidence Interval); Unit of Measure: Months
	4.80; (3.29 to 6.57)	5.75 [1]; (2.56 to NA)

[1]

NA= not reached. Insufficient number of participants with events to calculate the upper limit of the 95% confidence interval.

30. Secondary Outcome

Title	(Phase 3) Comparison of Duration of Response (DOR) in Doublet Arm vs Control Arm Per BICR
Description	DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.
Time Frame	From time of response to PD or death due to underlying disease (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Doublet Arm	Phase 3:Control Arm
Arm/Group Description:	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	113	107
Median (95% Confidence Interval); Unit of Measure: Months
	6.06; (4.07 to 8.28)	NA [1]; (2.56 to NA)

[1]

NA= not reached. Insufficient number of participants with events to calculate the median and upper limit of the 95% confidence interval.

31. Secondary Outcome

Title	(Phase 3) Comparison of Duration of Response (DOR) in Doublet Arm vs Control Arm Per Investigator
Description	DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.
Time Frame	From time of response to PD or death due to underlying disease (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Doublet Arm	Phase 3:Control Arm
Arm/Group Description:	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	113	107
Median (95% Confidence Interval); Unit of Measure: Months
	5.70; (3.65 to 6.74)	5.75 [1]; (2.56 to NA)

[1]

NA= not reached. Insufficient number of participants with events to calculate the upper limit of the 95% confidence interval.

32. Secondary Outcome

Title	(Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Doublet Arm by BICR
Description	DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.
Time Frame	From time of response to PD or death due to underlying disease (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Doublet Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	111	113
Median (95% Confidence Interval); Unit of Measure: Months
	4.80; (2.96 to 9.69)	6.06; (4.07 to 8.28)

33. Secondary Outcome

Title	(Phase 3) Comparison of Duration of Response (DOR) in Triplet Arm vs Doublet Arm by Investigator
Description	DOR was defined as the time from first radiographic evidence of response to the earliest documented PD or death due to underlying disease. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions were evaluated.
Time Frame	From time of response to PD or death due to underlying disease (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Doublet Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	111	113
Median (95% Confidence Interval); Unit of Measure: Months
	4.80; (3.29 to 6.57)	5.70; (3.65 to 6.74)

34. Secondary Outcome

Title	(Phase 3) Comparison of Time to Response in Triplet Arm vs Control Arm Per BICR
Description	Time to response was defined as the time from first dose to first radiographic evidence of response.
Time Frame	From first dose to first radiographic evidence of response (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Control Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	50	3
Median (95% Confidence Interval); Unit of Measure: Months
	1.43; (1.41 to 1.51)	1.45; (1.41 to 2.63)

35. Secondary Outcome

Title	(Phase 3) Comparison of Time to Response in Triplet Arm vs Control Arm Per Investigator
Description	Time to response was defined as the time from first dose to first radiographic evidence of response.
Time Frame	From first dose to first radiographic evidence of response (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Control Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	49	7
Median (95% Confidence Interval); Unit of Measure: Months
	1.48; (1.41 to 1.51)	2.63; (1.45 to 2.79)

36. Secondary Outcome

Title	(Phase 3) Comparison of Time to Response in Doublet Arm vs Control Arm Per BICR
Description	Time to response was defined as the time from first dose to first radiographic evidence of response.
Time Frame	From first dose to first radiographic evidence of response (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Doublet Arm	Phase 3:Control Arm
Arm/Group Description:	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	36	3
Median (95% Confidence Interval); Unit of Measure: Months
	1.48; (1.41 to 1.58)	1.45; (1.41 to 2.63)

37. Secondary Outcome

Title	(Phase 3) Comparison of Time to Response in Doublet Arm vs Control Arm Per Investigator
Description	Time to response was defined as the time from first dose to first radiographic evidence of response.
Time Frame	From first dose to first radiographic evidence of response (maximum treatment exposure of 268 weeks for doublet arm and 108 weeks for control arm)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Doublet Arm	Phase 3:Control Arm
Arm/Group Description:	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	31	7
Median (95% Confidence Interval); Unit of Measure: Months
	1.48; (1.41 to 1.54)	2.63; (1.45 to 2.79)

38. Secondary Outcome

Title	(Phase 3) Comparison of Time to Response in Triplet Arm vs Doublet Arm Per BICR
Description	Time to response was defined as the time from first dose to first radiographic evidence of response.
Time Frame	From first dose to first radiographic evidence of response (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Doublet Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	50	36
Median (95% Confidence Interval); Unit of Measure: Months
	1.43; (1.41 to 1.51)	1.48; (1.41 to 1.58)

39. Secondary Outcome

Title	(Phase 3) Comparison of Time to Response in Triplet Arm vs Doublet Arm Per Investigator
Description	Time to response was defined as the time from first dose to first radiographic evidence of response.
Time Frame	From first dose to first radiographic evidence of response (maximum treatment exposure of 277.4 weeks for triplet arm and 268 weeks for doublet arm)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Doublet Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	49	31
Median (95% Confidence Interval); Unit of Measure: Months
	1.48; (1.41 to 1.51)	1.48; (1.41 to 1.54)

40. Secondary Outcome

Title	(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
Description	The EORTC QLQ-C30 questionnaire consisted of 30 questions generating 5 functional scores (physical, role, cognitive, emotional, & social); a global health (GH) status/global quality of life scale score; 3 symptom scale scores (fatigue, pain, & nausea & vomiting); & 6 standalone one-item scores that capture additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, & diarrhea) & perceived financial burden. All items were graded by severity experienced during previous week & used 4-point-scale (1: not at all, 2: a little, 3: quite a bit, 4: very much). The scores were converted to health-related quality of life (HRQoL) scale ranging from 0-100. Higher scores indicating higher response levels (i.e., higher functioning, higher symptom severity).
Time Frame	Baseline, Cycle(C)1 Day(D)1 , C2 D1, C3 D1, C4 D1, C5 D1, C6 D1, C7 D1, C8 D1, C9 D1, C10 D1, C11 D1, C12 D1, C13 D1, C14 D1, C15 D1, C16 D1, C17 D1, C18 D1, C19 D1, C20 D1, C21 D1, C22 D1, C23 D1, End of Treatment, 30 Day Follow Up(each cycle of 28 days)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Phase 3: Triplet Arm	Phase 3:Doublet Arm	Phase 3:Control Arm
Arm/Group Description:		Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed		224	220	221
Mean (Standard Deviation); Unit of Measure: Units on a scale
Baseline	Number Analyzed	209 participants	201 participants	200 participants
		62.8 (22.18)	60.7 (21.33)	62.8 (21.82)
Change at Cycle 1 Day 1	Number Analyzed	138 participants	133 participants	120 participants
		-2.4 (13.44)	-4.3 (16.27)	-3.4 (15.60)
Change at Cycle 2 Day 1	Number Analyzed	181 participants	180 participants	123 participants
		-1.6 (19.06)	3.8 (18.46)	-1.9 (22.45)
Change at Cycle 3 Day 1	Number Analyzed	148 participants	142 participants	51 participants
		0.7 (18.86)	3.5 (19.96)	-0.2 (24.07)
Change at Cycle 4 Day 1	Number Analyzed	119 participants	105 participants	37 participants
		0.2 (15.63)	4.2 (22.17)	1.4 (21.65)
Change at Cycle 5 Day 1	Number Analyzed	99 participants	81 participants	26 participants
		-1.1 (18.66)	4.3 (22.09)	-2.2 (22.06)
Change at Cycle 6 Day 1	Number Analyzed	68 participants	60 participants	13 participants
		-4.0 (16.76)	5.6 (23.25)	-4.5 (19.43)
Change at Cycle 7 Day 1	Number Analyzed	47 participants	50 participants	10 participants
		-2.5 (16.01)	4.3 (21.77)	1.7 (12.30)
Change at Cycle 8 Day 1	Number Analyzed	39 participants	40 participants	7 participants
		-2.6 (14.83)	4.2 (16.98)	0.0 (27.64)
Change at Cycle 9 Day 1	Number Analyzed	33 participants	31 participants	7 participants
		-5.8 (17.74)	-5.6 (16.44)	-4.8 (12.60)
Change at Cycle 10 Day 1	Number Analyzed	23 participants	24 participants	4 participants
		-3.3 (17.90)	-2.8 (16.97)	2.1 (20.83)
Change at Cycle 11 Day 1	Number Analyzed	16 participants	19 participants	1 participants
		-5.2 (20.38)	3.9 (15.31)	33.3 [1] (NA)
Change at Cycle 12 Day 1	Number Analyzed	14 participants	18 participants	2 participants
		0.0 (22.41)	-4.6 (13.77)	4.2 (53.03)
Change at Cycle 13 Day 1	Number Analyzed	9 participants	13 participants	1 participants
		0.0 (20.41)	-3.2 (14.25)	0.0 [2] (NA)
Change at Cycle 14 Day 1	Number Analyzed	7 participants	7 participants	0 participants
		-1.2 (24.26)	-6.0 (15.00)
Change at Cycle 15 Day 1	Number Analyzed	7 participants	6 participants	0 participants
		3.6 (33.63)	2.8 (8.61)
Change at Cycle 16 Day 1	Number Analyzed	5 participants	3 participants	0 participants
		-16.7 (42.08)	-5.6 (9.62)
Change at Cycle 17 Day 1	Number Analyzed	3 participants	3 participants	0 participants
		-27.8 (20.97)	-2.8 (12.73)
Change at Cycle 18 Day 1	Number Analyzed	1 participants	3 participants	0 participants
		-16.7 [2] (NA)	-8.3 (8.33)
Change at Cycle 19 Day 1	Number Analyzed	1 participants	2 participants	0 participants
		0.0 [2] (NA)	-8.3 (11.79)
Change at Cycle 20 Day 1	Number Analyzed	1 participants	1 participants	0 participants
		-25 [2] (NA)	-8 [2] (NA)
Change at Cycle 21 Day 1	Number Analyzed	1 participants	1 participants	0 participants
		0.0 [2] (NA)	-16.7 [2] (NA)
Change at Cycle 22 Day 1	Number Analyzed	0 participants	1 participants	0 participants
			-16.7 [2] (NA)
Change at Cycle 23 Day 1	Number Analyzed	0 participants	1 participants	0 participants
			0.0 [2] (NA)
Change at End of Treatment	Number Analyzed	74 participants	72 participants	79 participants
		-14.1 (22.66)	-13.1 (21.61)	-15.5 (27.04)
Change at 30 Day Follow Up	Number Analyzed	24 participants	16 participants	21 participants
		-17.4 (22.51)	-10.4 (15.96)	-24.6 (24.08)

[1]

Number analyzed is 1 so standard deviation (SD) is not available.

[2]

Number analyzed is 1 so SD is not available.

41. Secondary Outcome

Title	(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
Description	FACT-C= Functional Assessment of Chronic Illness Therapy (FACIT), which assessed HRQoL of cancer participants & participants with other chronic illnesses. It consists of total 36 items (27 items of general version of FACT-C and disease-specific subscale containing 9 CRC-specific items), summarized to 5 subscales: physical well-being (7 items), functional well-being (7 items), social/family well-being (7 items); all 3 subscales range:0-28, emotional well-being (6 items) range: 0-24, colorectal cancer subscale (9 items) range: 0-36; higher subscale score= better QoL. All single-item measures range: 0= 'Not at all' to 4= 'Very much'. Table summarizes functional well-being subscale, individual questions are linearly scaled & combined to form functional well-being subscale score (range 0-28). High score represents better QoL.
Time Frame	Baseline,Cycle (C)1 Day (D)1, C2 D1, C3 D1, C4 D1, C5 D1, C6 D1, C7 D1, C8 D1, C9 D1, C10 D1, C11 D1, C12 D1, C13 D1, C14 D1, C15 D1, C16 D1, C17 D1, C18 D1, C19 D1, C20 D1, C21 D1, C22 D1, C23 D1, End of Treatment, 30 Day Follow Up(each cycle of 28 days)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Phase 3: Triplet Arm	Phase 3:Doublet Arm	Phase 3:Control Arm
Arm/Group Description:		Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed		224	220	221
Mean (Standard Deviation); Unit of Measure: Units on a scale
Baseline	Number Analyzed	211 participants	199 participants	200 participants
		16.3 (6.22)	16.2 (5.9)	16.8 (6.07)
Change at Cycle 1 Day 1	Number Analyzed	142 participants	130 participants	117 participants
		-0.2 (3.36)	-0.9 (4.06)	-1.4 (3.32)
Change at Cycle 2 Day 1	Number Analyzed	183 participants	176 participants	123 participants
		-0.3 (4.28)	-0.6 (5.08)	-0.9 (4.48)
Change at Cycle 3 Day 1	Number Analyzed	148 participants	137 participants	50 participants
		-0.2 (5.15)	-0.2 (5.23)	-0.7 (5.03)
Change at Cycle 4 Day 1	Number Analyzed	119 participants	105 participants	37 participants
		0.4 (4.53)	-0.1 (4.66)	-1.8 (6.48)
Change at Cycle 5 Day 1	Number Analyzed	100 participants	81 participants	26 participants
		0.7 (6.4)	-0.2 (4.5)	-1.6 (4.58)
Change at Cycle 6 Day 1	Number Analyzed	68 participants	58 participants	13 participants
		0.7 (6.05)	0.6 (4.56)	-1.9 (5.3)
Change at Cycle 7 Day 1	Number Analyzed	47 participants	49 participants	10 participants
		0.5 (5.85)	-0.1 (4.70)	-0.5 (5.41)
Change at Cycle 8 Day 1	Number Analyzed	40 participants	39 participants	8 participants
		0.9 (6.35)	0.2 (4.24)	-2.1 (4.97)
Change at Cycle 9 Day 1	Number Analyzed	32 participants	30 participants	7 participants
		-1.9 (4.32)	-0.8 (3.74)	-2.6 (2.30)
Change at Cycle 10 Day 1	Number Analyzed	22 participants	24 participants	4 participants
		-1.7 (4.76)	-1.3 (3.59)	0.5 (4.36)
Change at Cycle 11 Day 1	Number Analyzed	17 participants	19 participants	2 participants
		-1.5 (4.47)	-0.5 (4.65)	-4.5 (7.78)
Change at Cycle 12 Day 1	Number Analyzed	14 participants	18 participants	2 participants
		-1.5 (4.93)	-1.1 (4.61)	-4.5 (9.19)
Change at Cycle 13 Day 1	Number Analyzed	9 participants	13 participants	1 participants
		-2.0 (6.76)	-3.2 (5.34)	-8.0 [1] (NA)
Change at Cycle 14 Day 1	Number Analyzed	7 participants	7 participants	0 participants
		-2.4 (5.22)	-4.0 (5.74)
Change at Cycle 15 Day 1	Number Analyzed	7 participants	6 participants	0 participants
		-2.3 (6.85)	-1.5 (4.72)
Change at Cycle 16 Day 1	Number Analyzed	5 participants	3 participants	0 participants
		-4.2 (4.02)	-0.7 (0.58)
Change at Cycle 17 Day 1	Number Analyzed	3 participants	3 participants	0 participants
		-6.7 (5.51)	-0.7 (4.51)
Change at Cycle 18 Day 1	Number Analyzed	1 participants	3 participants	0 participants
		-5.0 [1] (NA)	-3.0 (4.36)
Change at Cycle 19 Day 1	Number Analyzed	1 participants	2 participants	0 participants
		-7.0 [1] (NA)	-6.0 (0.00)
Change at Cycle 20 Day 1	Number Analyzed	1 participants	1 participants	0 participants
		-6.0 [1] (NA)	-5.0 [1] (NA)
Change at Cycle 21 Day 1	Number Analyzed	1 participants	1 participants	0 participants
		-9.0	-5.0
Change at Cycle 22 Day 1	Number Analyzed	0 participants	1 participants	0 participants
			-12.0 [1] (NA)
Change at Cycle 23 Day 1	Number Analyzed	0 participants	1 participants	0 participants
			-9.0 [1] (NA)
Change at End of Treatment	Number Analyzed	74 participants	73 participants	79 participants
		-2.4 (4.84)	-2.2 (5.14)	-3.1 (6.06)
Change at 30 Day Follow Up	Number Analyzed	24 participants	16 participants	21 participants
		-3.5 (6.44)	-0.8 (5.42)	-4.2 (6.41)

[1]

Number analyzed is 1 so SD is not available.

42. Secondary Outcome

Title	(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
Description	The EQ-5D-5L contains 1 item for each of 5 dimensions of health-related QoL (i.e., mobility, self-care, usual activities, pain or discomfort and anxiety or depression). Response options for each item varied from having no problems to moderate problems or extreme problems. The EQ-5D-5L (v4.0) is a standardized measure of health utility that provides a single index value for one's health status. The EQ-5D-5L is frequently used for economic evaluations of health care and has been recognized as a valid and reliable instrument for this purpose. The EQ visual analog scale (VAS) is a score that is directly reported by the participant and ranges from 0 to 100 (higher is better quality health).
Time Frame	Baseline,Cycle (C)1 Day (D)1, C2 D1, C3 D1, C4 D1, C5 D1, C6 D1, C7 D1, C8 D1, C9 D1, C10 D1, C11 D1, C12 D1, C13 D1, C14 D1, C15 D1, C16 D1, C17 D1, C18 D1, C19 D1, C20 D1, C21 D1, C22 D1, C23 D1, End of Treatment, 30 Day Follow Up(each cycle of 28 days)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Phase 3: Triplet Arm	Phase 3:Doublet Arm	Phase 3:Control Arm
Arm/Group Description:		Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed		224	220	221
Mean (Standard Deviation); Unit of Measure: Units on a scale
Baseline	Number Analyzed	210 participants	203 participants	199 participants
		69.0 (19.03)	66.5 (19.51)	68.3 (19.71)
Change at Cycle 1 Day 1	Number Analyzed	141 participants	135 participants	120 participants
		0.8 (10.89)	-0.9 (14.09)	-2.1 (15.02)
Change at Cycle 2 Day 1	Number Analyzed	183 participants	181 participants	124 participants
		1.4 (14.74)	1.9 (14.81)	-2.4 (17.20)
Change at Cycle 3 Day 1	Number Analyzed	150 participants	141 participants	52 participants
		3.0 (13.94)	4.2 (17.32)	-1.4 (17.40)
Change at Cycle 4 Day 1	Number Analyzed	118 participants	105 participants	37 participants
		4.0 (13.06)	5.6 (14.87)	-0.4 (15.14)
Change at Cycle 5 Day 1	Number Analyzed	99 participants	80 participants	26 participants
		3.3 (14.66)	5.1 (15.11)	2.5 (11.17)
Change at Cycle 6 Day 1	Number Analyzed	66 participants	58 participants	13 participants
		1.3 (13.33)	2.9 (16.84)	-3.6 (13.26)
Change at Cycle 7 Day 1	Number Analyzed	46 participants	47 participants	10 participants
		1.4 (13.64)	3.6 (16.71)	2.4 (7.44)
Change at Cycle 8 Day 1	Number Analyzed	39 participants	39 participants	8 participants
		4.1 (10.77)	2.0 (16.11)	-2.8 (12.95)
Change at Cycle 9 Day 1	Number Analyzed	33 participants	30 participants	7 participants
		0.3 (15.16)	-4.0 (12.99)	-8.1 (8.80)
Change at Cycle 10 Day 1	Number Analyzed	23 participants	23 participants	4 participants
		0.2 (13.34)	-8.1 (13.68)	-1.8 (2.36)
Change at Cycle 11 Day 1	Number Analyzed	17 participants	18 participants	2 participants
		0.2 (13.87)	-0.1 (10.15)	4.0 (8.49)
Change at Cycle 12 Day 1	Number Analyzed	13 participants	17 participants	2 participants
		-4.0 (20.11)	-0.6 (11.67)	1.5 (12.02)
Change at Cycle 13 Day 1	Number Analyzed	9 participants	12 participants	1 participants
		-3.0 (17.17)	-4.1 (14.41)	-2.0 [1] (NA)
Change at Cycle 14 Day 1	Number Analyzed	7 participants	7 participants	0 participants
		-4.0 (18.06)	-0.4 (13.99)
Change at Cycle 15 Day 1	Number Analyzed	7 participants	6 participants	0 participants
		-3.4 (14.67)	4.2 (7.36)
Change at Cycle 16 Day 1	Number Analyzed	5 participants	3 participants	0 participants
		-10.4 (24.87)	3.3 (2.89)
Change at Cycle 17 Day 1	Number Analyzed	3 participants	3 participants	0 participants
		-18.3 (20.21)	1.7 (5.77)
Change at Cycle 18 Day 1	Number Analyzed	1 participants	3 participants	0 participants
		7.0 [1] (NA)	-3.3 (2.89)
Change at Cycle 19 Day 1	Number Analyzed	1 participants	2 participants	0 participants
		8.0 [1] (NA)	-5.5 (13.44)
Change at Cycle 20 Day 1	Number Analyzed	1 participants	1 participants	0 participants
		8.0 [1] (NA)	2.0 [1] (NA)
Change at Cycle 21 Day 1	Number Analyzed	1 participants	1 participants	0 participants
		8.0 [1] (NA)	-5.0 [1] (NA)
Change at Cycle 22 Day 1	Number Analyzed	0 participants	1 participants	0 participants
			-5.0 [1] (NA)
Change at Cycle 23 Day 1	Number Analyzed	0 participants	1 participants	0 participants
			-5.0 [1] (NA)
Change at End of Treatment	Number Analyzed	75 participants	72 participants	80 participants
		-8.5 (17.40)	-8.0 (18.99)	-12.7 (21.34)
Change at 30 Day Follow Up	Number Analyzed	24 participants	16 participants	21 participants
		-11.1 (20.23)	-5.9 (20.18)	-11.0 (17.51)

[1]

Number analyzed is 1 so SD is not available.

43. Secondary Outcome

Title	(Phase 3) Change From Baseline in the Participant Global Impression of Change (PGIC) in Triplet Arm vs Control Arm, Doublet Arm vs Control, and Triplet vs Doublet
Description	The PGIC is a measure of participant's perceptions of change in their symptoms over time that can be used as an anchoring method to determine the minimal clinically important difference for other participant reported outcome (PROs). For this assessment, participants answered the following question: "Since starting treatment, my colorectal cancer symptoms are: (1) very much improved, (2) much improved, (3) minimally improved, (4) no change, (5) minimally worse, (6) much worse or (7) very much worse."
Time Frame	Baseline,Cycle (C)1 Day (D)1, C2 D1, C3 D1, C4 D1, C5 D1, C6 D1, C7 D1, C8 D1, C9 D1, C10 D1, C11 D1, C12 D1, C13 D1, C14 D1, C15 D1, C16 D1, C17 D1, C18 D1, C19 D1, C20 D1, C21 D1, C22 D1, C23 D1, End of Treatment, 30 Day Follow Up(each cycle of 28 days)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Phase 3: Triplet Arm	Phase 3:Doublet Arm	Phase 3:Control Arm
Arm/Group Description:		Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed		224	220	221
Mean (Standard Deviation); Unit of Measure: Units on a scale
Baseline	Number Analyzed	153 participants	152 participants	149 participants
		3.8 (1.30)	3.8 (1.30)	3.9 (1.28)
Change at Cycle 1 Day 1	Number Analyzed	91 participants	92 participants	83 participants
		-0.1 (0.93)	0.1 (1.21)	0.0 (0.90)
Change at Cycle 2 Day 1	Number Analyzed	127 participants	130 participants	90 participants
		-0.7 (1.44)	-0.8 (1.60)	-0.3 (1.52)
Change at Cycle 3 Day 1	Number Analyzed	101 participants	105 participants	37 participants
		-0.9 (1.44)	-1.2 (1.53)	-0.5 (1.56)
Change at Cycle 4 Day 1	Number Analyzed	80 participants	79 participants	28 participants
		-0.9 (1.49)	-1.1 (1.68)	-0.5 (1.35)
Change at Cycle 5 Day 1	Number Analyzed	66 participants	59 participants	19 participants
		-0.9 (1.61)	-1.1 (1.69)	-0.7 (1.41)
Change at Cycle 6 Day 1	Number Analyzed	45 participants	40 participants	9 participants
		-0.8 (1.31)	-1.2 (1.70)	-0.8 (1.39)
Change at Cycle 7 Day 1	Number Analyzed	30 participants	36 participants	7 participants
		-1.1 (1.44)	-1.0 (1.61)	-1.1 (1.07)
Change at Cycle 8 Day 1	Number Analyzed	23 participants	27 participants	5 participants
		-1.2 (1.56)	-1.1 (1.58)	-1.0 (0.71)
Change at Cycle 9 Day 1	Number Analyzed	21 participants	21 participants	5 participants
		-0.8 (1.26)	-0.9 (1.37)	-1.0 (0.71)
Change at Cycle 10 Day 1	Number Analyzed	15 participants	17 participants	3 participants
		-0.5 (1.51)	-0.6 (1.28)	-0.3 (0.58)
Change at Cycle 11 Day 1	Number Analyzed	13 participants	13 participants	2 participants
		-0.9 (1.38)	-1.1 (1.38)	0.0 (0.00)
Change at Cycle 12 Day 1	Number Analyzed	11 participants	12 participants	2 participants
		-0.9 (1.45)	-0.8 (1.36)	-0.5 (0.71)
Change at Cycle 13 Day 1	Number Analyzed	8 participants	10 participants	1 participants
		-1.3 (1.39)	-0.9 (1.52)	-1.0 [1] (NA)
Change at Cycle 14 Day 1	Number Analyzed	7 participants	6 participants	0 participants
		-1.1 (1.46)	-1.5 (1.05)
Change at Cycle 15 Day 1	Number Analyzed	6 participants	5 participants	0 participants
		-1.2 (1.47)	-1.6 (0.89)
Change at Cycle 16 Day 1	Number Analyzed	4 participants	3 participants	0 participants
		-2.0 (0.82)	-0.7 (1.53)
Change at Cycle 17 Day 1	Number Analyzed	3 participants	3 participants	0 participants
		-1.3 (1.53)	-1.0 (1.00)
Change at Cycle 18 Day 1	Number Analyzed	1 participants	3 participants	0 participants
		-2.0 [1] (NA)	-1.0 (1.00)
Change at Cycle 19 Day 1	Number Analyzed	1 participants	2 participants	0 participants
		-3.0 [1] (NA)	-0.5 (2.12)
Change at Cycle 20 Day 1	Number Analyzed	1 participants	1 participants	0 participants
		-3.0 [1] (NA)	-2.0 [1] (NA)
Change at Cycle 21 Day 1	Number Analyzed	1 participants	1 participants	0 participants
		-3.0 [1] (NA)	-2.0 [1] (NA)
Change at Cycle 22 Day 1	Number Analyzed	0 participants	1 participants	0 participants
			-2.0 [1] (NA)
Change at Cycle 23 Day 1	Number Analyzed	0 participants	1 participants	0 participants
			-2.0 [1] (NA)
Change at End of Treatment	Number Analyzed	52 participants	54 participants	63 participants
		0.3 (1.85)	0.1 (1.82)	0.4 (1.58)
Change at 30 Day Follow Up	Number Analyzed	18 participants	10 participants	19 participants
		-0.1 (2.08)	0.5 (1.43)	0.7 (1.34)

[1]

Number analyzed is 1 so SD is not available.

44. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Area Under the Concentration-Time Curve From Zero to the Last Measurable Time Point (AUClast) for Cetuximab
Description	[Not Specified]
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Combined Safety Lead-in
Arm/Group Description:		Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed		37
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: Nanogram/milliliter *hour
Cycle 1	Number Analyzed	34 participants
		841000; (22.2%)
Cycle 2	Number Analyzed	32 participants
		970000; (20.6%)

45. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Area Under the Concentration-Time Curve From Zero to the Last Measurable Time Point (AUClast) for Encorafenib
Description	[Not Specified]
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Combined Safety Lead-in
Arm/Group Description:		Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed		37
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: Nanogram/milliliter *hour
Cycle 1	Number Analyzed	34 participants
		11300; (61.5%)
Cycle 2	Number Analyzed	29 participants
		6660; (61.7%)

46. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Area Under the Concentration-Time Curve From Zero to the Last Measurable Time Point (AUClast) for Binimetinib
Description	[Not Specified]
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Combined Safety Lead-in
Arm/Group Description:		Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed		37
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: Nanogram/milliliter *hour
Cycle 1	Number Analyzed	34 participants
		1960; (43.6%)
Cycle 2	Number Analyzed	29 participants
		1540; (44.7%)

47. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Area Under the Concentration-time Curve From Zero to the Last Measurable Time Point (AUClast) for Metabolite of Binimetinib (AR00426032)
Description	[Not Specified]
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Combined Safety Lead-in
Arm/Group Description:		Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed		37
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: Nanogram/milliliter *hour
Cycle 1	Number Analyzed	35 participants
		206; (46.7%)
Cycle 2	Number Analyzed	26 participants
		70.0; (95.5%)

48. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Cetuximab
Description	[Not Specified]
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Combined Safety Lead-in
Arm/Group Description:		Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed		37
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: Nanogram/milliliter
Cycle 1	Number Analyzed	34 participants
		195000; (22.2%)
Cycle 2	Number Analyzed	32 participants
		199000; (26.8%)

49. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Encorafenib
Description	[Not Specified]
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Combined Safety Lead-in
Arm/Group Description:		Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed		37
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: Nanogram/milliliter
Cycle 1	Number Analyzed	34 participants
		3360; (65.1%)
Cycle 2	Number Analyzed	29 participants
		2490; (75.6%)

50. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Binimetinib
Description	[Not Specified]
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Combined Safety Lead-in
Arm/Group Description:		Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed		37
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: Nanogram/milliliter
Cycle 1	Number Analyzed	35 participants
		654; (50.8%)
Cycle 2	Number Analyzed	26 participants
		524; (70.1%)

51. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Maximum Concentration (Cmax) for Metabolite of Binimetinib (AR00426032)
Description	[Not Specified]
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Combined Safety Lead-in
Arm/Group Description:		Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed		37
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: Nanogram/milliliter
Cycle 1	Number Analyzed	35 participants
		59.9; (50.8%)
Cycle 2	Number Analyzed	26 participants
		20.5; (119%)

52. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Cetuximab
Description	[Not Specified]
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Combined Safety Lead-in
Arm/Group Description:		Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed		37
Median (Full Range); Unit of Measure: Hours
Cycle 1	Number Analyzed	34 participants
		3.77; (1.83 to 6.05)
Cycle 2	Number Analyzed	32 participants
		3.05; (1.00 to 6.17)

53. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Encorafenib
Description	[Not Specified]
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Combined Safety Lead-in
Arm/Group Description:		Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed		37
Median (Full Range); Unit of Measure: Hours
Cycle 1	Number Analyzed	34 participants
		2.00; (.883 to 6.25)
Cycle 2	Number Analyzed	29 participants
		2.00; (.950 to 5.73)

54. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Binimetinib
Description	[Not Specified]
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Combined Safety Lead-in
Arm/Group Description:		Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed		37
Median (Full Range); Unit of Measure: Hours
Cycle 1	Number Analyzed	35 participants
		1.98; (.883 to 5.67)
Cycle 2	Number Analyzed	26 participants
		1.04; (.900 to 4.00)

55. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Time of Maximum Observed Concentration (Tmax) for Metabolite of Binimetinib (AR00426032)
Description	[Not Specified]
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Combined Safety Lead-in
Arm/Group Description:		Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed		37
Median (Full Range); Unit of Measure: Hours
Cycle 1	Number Analyzed	35 participants
		2.00; (.833 to 5.78)
Cycle 2	Number Analyzed	26 participants
		1.58; (.933 to 6.52)

56. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Steady-State Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for Binimetinib
Description	[Not Specified]
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	37
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: Nanogram/milliliter
	55.3; (61.5%)

57. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Steady-State Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for Encorafenib
Description	[Not Specified]
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	37
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: Nanogram/milliliter
	18.9; (191%)

58. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Steady-State Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for Cetuximab
Description	[Not Specified]
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	37
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: Nanogram/milliliter
	55400; (54.8%)

59. Secondary Outcome

Title	(Safety Lead-in) Evaluation of the Steady-State Concentration Measured Just Before the Next Dose of Study Drug (Ctrough) for a Metabolite of Binimetinib
Description	[Not Specified]
Time Frame	Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 (each cycle of 28 days)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Combined Safety Lead-in
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.
Overall Number of Participants Analyzed	37
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: Nanogram/milliliter
	3.41; (68.5%)

60. Secondary Outcome

Title	(Phase 3) Evaluation of the Model-Based Oral Clearance (CL/F) for Encorafenib
Description	The reported cross-arm CL/F value is a fixed-effect parameter determined from a population PK analysis. The analysis included pooled data from participants enrolled in multiple studies including those who were not enrolled in this study. The NCTID include: NCT01719380, NCT01543698, and NCT01436656. An additional study ARRAY-162-105 is not required to register.
Time Frame	2 and 6 hours post-dose on Day 1 of Cycle 1, Predose and 2 hours post-dose on Day 1 of Cycle 2 (each cycle of 28 days)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Pharmacokinetic Population of Encorafenib
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib + cetuximab. Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab.
Overall Number of Participants Analyzed	394
Geometric Mean (95% Confidence Interval); Unit of Measure: Liter/hour
	16.4; (14.9 to 17.5)

61. Secondary Outcome

Title	(Phase 3) Evaluation of the Model-Based Oral Clearance (CL/F) for Binimetinib
Description	The reported cross-arm CL/F value is a fixed-effect parameter determined from a population PK analysis. The analysis included pooled data from participants enrolled in multiple studies including those who were not enrolled in this study. The NCTID include: NCT01719380, NCT01543698, and NCT01436656. An additional study ARRAY-162-105 is not required to register.
Time Frame	2 and 6 hours post-dose on Day 1 of Cycle 1, Predose and 2 hours post-dose on Day 1 of Cycle 2 (each cycle of 28 days)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Pharmacokinetic Population of Encorafenib
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib + cetuximab. Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab.
Overall Number of Participants Analyzed	181
Geometric Mean (95% Confidence Interval); Unit of Measure: Liter/hour
	19.0; (17.7 to 20.6)

62. Secondary Outcome

Title	(Phase 3) Evaluation of the Model-Based Clearance (CL) for Cetuximab
Description	The reported cross-arm CL/F value is a fixed-effect parameter determined from a population PK analysis. The analysis included pooled data from participants enrolled in multiple studies including those who were not enrolled in this study. The NCTID include: NCT01719380, NCT01543698, and NCT01436656. An additional study ARRAY-162-105 is not required to register.
Time Frame	2 and 6 hours post-dose on Day 1 of Cycle 1, Predose and 2 hours post-dose on Day 1 of Cycle 2 (each cycle of 28 days)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Pharmacokinetic Population of Encorafenib
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib + cetuximab. Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab.
Overall Number of Participants Analyzed	261
Geometric Mean (95% Confidence Interval); Unit of Measure: Liter/hour
	0.0154; (0.0114 to 0.0225)

63. Secondary Outcome

Title	Phase 3: Number of Participants With Clinically Notable Shifts in Hematology and Coagulation Laboratory Parameters
Description	Clinically notable shifts was defined as worsening by at least 2 grades or to more than or equal to (>=) Grade 3 based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 where Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life threatening and Grade 5: death.
Time Frame	From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3:Control Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	222	216	193
Measure Type: Count of Participants; Unit of Measure: Participants
Activated Partial Thromboplastin Time - Hyper	9 4.1%	9 4.2%	4 2.1%
Hemoglobin - Hyper	0 0.0%	0 0.0%	0 0.0%
Hemoglobin - Hypo	97 43.7%	30 13.9%	17 8.8%
Leukocytes - Hyper	0 0.0%	0 0.0%	0 0.0%
Leukocytes - Hypo	2 0.9%	9 4.2%	51 26.4%
Lymphocytes - Hyper	12 5.4%	3 1.4%	4 2.1%
Lymphocytes - Hypo	25 11.3%	47 21.8%	57 29.5%
Neutrophils - Hypo	4 1.8%	8 3.7%	65 33.7%
Platelets - Hypo	1 0.5%	5 2.3%	4 2.1%
Prothrombin Intl. Normalized Ratio - Hyper	3 1.4%	2 0.9%	2 1.0%

64. Secondary Outcome

Title	Phase 3: Number of Participants With Clinically Notable Shifts in Serum Chemistry Laboratory Parameters
Description	Clinically notable shifts was defined as worsening by at least 2 grades or to >= Grade 3 based on CTCAE version 4.03 where Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life threatening and Grade 5: death.
Time Frame	From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3: Control Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	222	216	193
Measure Type: Count of Participants; Unit of Measure: Participants
Alanine Aminotransferase - Hyper	11 5.0%	7 3.2%	10 5.2%
Albumin - Hypo	50 22.5%	16 7.4%	17 8.8%
Alkaline Phosphatase - Hyper	13 5.9%	12 5.6%	18 9.3%
Aspartate Aminotransferase - Hyper	11 5.0%	7 3.2%	9 4.7%
Bilirubin - Hyper	11 5.0%	13 6.0%	12 6.2%
Calcium - Hyper	1 0.5%	0 0.0%	0 0.0%
Calcium - Hypo	15 6.8%	8 3.7%	7 3.6%
Creatine Kinase - Hyper	18 8.1%	1 0.5%	3 1.6%
Creatinine - Hyper	45 20.3%	11 5.1%	6 3.1%
Glucose - Hyper	8 3.6%	16 7.4%	4 2.1%
Glucose - Hypo	4 1.8%	0 0.0%	1 0.5%
Magnesium - Hyper	0 0.0%	1 0.5%	2 1.0%
Magnesium - Hypo	11 5.0%	4 1.9%	9 4.7%
Potassium - Hyper	14 6.3%	10 4.6%	5 2.6%
Potassium - Hypo	5 2.3%	7 3.2%	9 4.7%
Sodium - Hyper	1 0.5%	1 0.5%	2 1.0%
Sodium - Hypo	10 4.5%	4 1.9%	5 2.6%
Troponin I - Hyper	0 0.0%	0 0.0%	0 0.0%
Urate - Hyper	4 1.8%	2 0.9%	1 0.5%

65. Secondary Outcome

Title	Phase 3: Number of Participants With Clinically Notable Shifts in Urinalysis Laboratory Parameters
Description	Clinically notable shifts was defined as worsening by at least 2 grades or to >= Grade 3 based on CTCAE version 4.03 where Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 4: life threatening and Grade 5: death.
Time Frame	From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3: Control Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	222	216	193
Measure Type: Count of Participants; Unit of Measure: Participants
	8 3.6%	8 3.7%	5 2.6%

66. Secondary Outcome

Title	Phase 3: Number of Participants With Newly Occurring Clinically Notable Vital Sign Abnormalities
Description	Newly occurring clinically notable changes was defined as participants not meeting the criterion at baseline and meeting criterion post-baseline. The criterion included: low/high systolic blood pressure (SBP): <= 90 millimeters of mercury (mmHg) with decrease from baseline of >= 20mmHg or >= 160mmHg with increase from baseline of >= 20mmHg, low or high diastolic blood pressure (DBP): <= 50mmHg with decrease from baseline of >= 15mmHg or >= 100mmHg with increase from baseline of >= 15mmHg, low or high pulse: <= 50 beats/min with decrease from baseline of >= 15 beats/min or >= 120 beats/min with increase from baseline of >= 15 beats/min, low or high temperature: <= 36 degree Celsius (deg C) or >= 37.5 deg C.
Time Frame	From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3: Control Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	222	216	193
Measure Type: Count of Participants; Unit of Measure: Participants
Diastolic Blood Pressure - High	8 3.6%	6 2.8%	7 3.6%
Diastolic Blood Pressure - Low	21 9.5%	27 12.5%	5 2.6%
Pulse Rate - High	23 10.4%	14 6.5%	20 10.4%
Pulse Rate - Low	3 1.4%	4 1.9%	3 1.6%
Systolic Blood Pressure - High	19 8.6%	13 6.0%	5 2.6%
Systolic Blood Pressure - Low	37 16.7%	28 13.0%	10 5.2%
Temperature - High	33 14.9%	23 10.6%	25 13.0%
Temperature - Low	93 41.9%	84 38.9%	55 28.5%

67. Secondary Outcome

Title	Phase 3: Number of Participants With Newly Occurring Clinically Notable Electrocardiogram (ECG) Values
Description	Newly occurring clinically notable changes was defined as participants not meeting the criterion at baseline and meeting criterion post-baseline. The criterion included: heart rate- decrease from baseline > 25% and to a value < 50 and increase from baseline > 25% and to a value > 100. QT interval- new > 450 (millisecond) msec, new > 480 msec, new > 500 msec, increase from baseline > 30 msec and increase from baseline > 60 msec. QTcF- new > 450 msec, new > 480 msec, new > 500 msec, increase from baseline > 30 msec and increase from baseline > 60 msec.
Time Frame	From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3: Control Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	222	216	193
Measure Type: Count of Participants; Unit of Measure: Participants
Heart Rate - Decrease from baseline > 25% and to a value < 50	1 0.5%	4 1.9%	0 0.0%
Heart Rate - Increase from baseline > 25% and to a value > 100	27 12.2%	24 11.1%	28 14.5%
QT Interval - New > 450 millisecond (msec)	17 7.7%	30 13.9%	7 3.6%
QT Interval - New > 480 msec	4 1.8%	7 3.2%	2 1.0%
QT Interval - New > 500 msec	3 1.4%	5 2.3%	0 0.0%
QT Interval - increase from baseline > 30 msec	97 43.7%	99 45.8%	32 16.6%
QT Interval - increase from baseline > 60 msec	22 9.9%	21 9.7%	10 5.2%
QTcF - New > 450 msec	39 17.6%	51 23.6%	23 11.9%
QTcF - New > 480 msec	9 4.1%	18 8.3%	5 2.6%
QTcF - New > 500 msec	1 0.5%	6 2.8%	2 1.0%
QTcF - increase from baseline > 30 msec	59 26.6%	75 34.7%	24 12.4%
QTcF - increase from baseline > 60 msec	12 5.4%	20 9.3%	5 2.6%

68. Secondary Outcome

Title	Phase 3: Number of Participants With Shift in Visual Acuity Logarithm of the Minimum Angle of Resolution (LogMAR) Score
Description	Visual acuity was measured using the Snellen visual acuity conversion chart. This was determined by establishing the smallest optotypes that could be identified correctly by the participant at a given observation distance. Snellen visual acuity was reported as a Snellen fraction (m/M) in which the numerator (m) indicated the test distance and the denominator (M) indicated the distance at which the gap of the equivalent Landolt ring subtends 1 minute of arc. The LogMAR score was calculated as - log(m/M). The maximum increase in score of <= 0, 0 to < 0.1, 0.1 to < 0.2, 0.2 to < 0.3 and >=0.3 relative to baseline in LogMAR were reported in this endpoint.
Time Frame	From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3: Control Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	222	216	193
Measure Type: Count of Participants; Unit of Measure: Participants
Baseline <=0 to >0-<0.1	33 14.9%	8 3.7%	0 0.0%
Baseline <=0 to 0.1-<0.2	15 6.8%	3 1.4%	0 0.0%
Baseline <=0 to 0.2-<0.3	4 1.8%	0 0.0%	0 0.0%
Baseline <=0 to >=0.3	6 2.7%	1 0.5%	0 0.0%
Baseline <=0 to missing score	9 4.1%	86 39.8%	129 66.8%
Baseline >0-<0.1 to <=0	17 7.7%	6 2.8%	0 0.0%
Baseline >0-<0.1 to 0.1-<0.2	7 3.2%	2 0.9%	0 0.0%
Baseline >0-<0.1 to 0.2-<0.3	4 1.8%	1 0.5%	0 0.0%
Baseline >0-<0.1 to >=0.3	3 1.4%	0 0.0%	0 0.0%
Baseline >0-<0.1 to missing score	3 1.4%	25 11.6%	30 15.5%
Baseline 0.1-<0.2 to <=0	5 2.3%	1 0.5%	0 0.0%
Baseline 0.1-<0.2 to >0-<0.1	1 0.5%	0 0.0%	0 0.0%
Baseline 0.2-<0.3 to <=0	1 0.5%	0 0.0%	0 0.0%
Baseline 0.2-<0.3 to >0-<0.1	3 1.4%	0 0.0%	0 0.0%
Baseline 0.2-<0.3 to 0.1-<0.2	3 1.4%	1 0.5%	0 0.0%
Baseline 0.2-<0.3 to missing score	1 0.5%	4 1.9%	5 2.6%
Baseline >=0.3 to <=0	9 4.1%	2 0.9%	0 0.0%
Baseline >=0.3 to >0-<0.1	4 1.8%	0 0.0%	0 0.0%
Baseline >=0.3 to 0.1-<0.2	1 0.5%	1 0.5%	0 0.0%
Baseline >=0.3 to 0.2-<0.3	2 0.9%	0 0.0%	0 0.0%
Baseline >=0.3 to missing score	1 0.5%	19 8.8%	13 6.7%
Baseline 0.1-<0.2 to 0.2-<0.3	0 0.0%	3 1.4%	0 0.0%
Baseline 0.1-<0.2 to missing score	0 0.0%	9 4.2%	7 3.6%

69. Secondary Outcome

Title	Phase 3: Number of Participants With Shifts in Left Ventricular Ejection Fraction (LVEF) From Baseline to Maximum Grade On-treatment
Description	Left ventricular ejection fraction (LVEF) abnormalities were defined according to CTCAE version 4.03 where Grade 0: Non-missing value below Grade 2, Grade 2: LVEF between 40% and 50% or absolute change from baseline between -10% and < -20%, Grade 3: LVEF between 20% and 39% or absolute change from baseline <= -20%, Grade 4: LVEF lower than 20%. Categories with at least 1 non-zero data values showing any shift in Grade from baseline to 1 day after dose 1 (post-baseline) were reported. Participants whose grade category was unchanged (e.g. Grade 0 to Grade 0) were not reported.
Time Frame	From start of study treatment until 30 days post last dose of study treatment (for triplet arm: maximum treatment exposure of 277.4 weeks; for doublet arm: maximum treatment exposure of 268 weeks; for Control arm: maximum treatment exposure of 108 weeks)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3: Control Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	222	216	193
Measure Type: Count of Participants; Unit of Measure: Participants
Baseline Grade 0 to Grade 2 post baseline	27 12.2%	0 0.0%	0 0.0%
Baseline Grade 0 to Grade 3 post baseline	1 0.5%	1 0.5%	0 0.0%
Baseline Grade 0 to missing grade	17 7.7%	205 94.9%	186 96.4%
Baseline Grade 2 to missing grade	0 0.0%	3 1.4%	2 1.0%
Baseline missing grade to Grade 0 post baseline	1 0.5%	0 0.0%	0 0.0%

70. Other Pre-specified Outcome

Title	(Phase 3) Overall Survival (OS) of Triplet Arm vs. Control Arm - Final Analysis
Description	OS was defined as the time from randomization to death due to any cause.
Time Frame	From randomization to death due to any cause (maximum treatment exposure of 277.4 weeks for triplet arm and 108 weeks for control arm)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Phase 3: Triplet Arm	Phase 3:Control Arm
Arm/Group Description:	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	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 Number of Participants Analyzed	224	221
Median (95% Confidence Interval); Unit of Measure: Months
	9.82; (8.34 to 11.73)	5.88; (5.09 to 7.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 3: Triplet Arm, Phase 3:Control Arm
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Stratified Log-rank
	Comments	[Not Specified]

Adverse Events

Time Frame	Adverse Events (AE) were collected from initiation of study drug through 30 days after the last dose of study drug. For CSLI: maximum treatment exposure of 280 weeks; for Phase 3- Triplet arm: maximum treatment exposure of 277.4 weeks; for Phase 3- Doublet arm: maximum treatment exposure of 268 weeks; for Phase 3- Control arm: maximum treatment exposure of 108 weeks
Adverse Event Reporting Description	An AE is defined as the appearance of (or worsening of any pre-existing) undesirable signs, symptoms, or medical conditions that occur after participant's signed informed consent has been obtained. For non-SAEs and SAEs: 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. For all-cause mortality: FAS for the Phase 3 portion of the study consisted of all randomized Phase 3 participants.
Arm/Group Title	Combined Safety Lead-in	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3: Control Arm
Arm/Group Description	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + binimetinib + cetuximab. Encorafenib: Orally, once daily. Binimetinib: Orally, twice daily. Cetuximab: Standard of care.	Encorafenib + cetuximab. Encorafenib: Orally, once daily. Cetuximab: Standard of care.	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.
All-Cause Mortality
	Combined Safety Lead-in	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3: Control Arm
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	30/37 (81.08%)	209/224 (93.30%)	193/220 (87.73%)	198/221 (89.59%)
Serious Adverse Events
	Combined Safety Lead-in	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3: Control Arm
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	22/37 (59.46%)	118/222 (53.15%)	91/216 (42.13%)	78/193 (40.41%)
Blood and lymphatic system disorders
Anaemia * 1	1/37 (2.70%)	6/222 (2.70%)	0/216 (0.00%)	1/193 (0.52%)
Pulmonary embolism * 1	1/37 (2.70%)	8/222 (3.60%)	3/216 (1.39%)	5/193 (2.59%)
Bacteraemia * 1	0/37 (0.00%)	4/222 (1.80%)	0/216 (0.00%)	1/193 (0.52%)
Febrile neutropenia * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	5/193 (2.59%)
Infusion-related reaction * 1	5/37 (13.51%)	1/222 (0.45%)	7/216 (3.24%)	6/193 (3.11%)
Neutropenia * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Cardiac disorders
Cardiac arrest * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Cardio-respiratory arrest * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	1/193 (0.52%)
Atrial fibrillation * 1	0/37 (0.00%)	0/222 (0.00%)	3/216 (1.39%)	0/193 (0.00%)
Acute myocardial infarction * 1	0/37 (0.00%)	1/222 (0.45%)	1/216 (0.46%)	0/193 (0.00%)
Cardiac failure * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Myocardial infarction * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Pericardial effusion * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Pericarditis * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Sinus tachycardia * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Ear and labyrinth disorders
Vertigo * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Gastrointestinal disorders
Diarrhoea * 1	1/37 (2.70%)	10/222 (4.50%)	0/216 (0.00%)	10/193 (5.18%)
Vomiting * 1	2/37 (5.41%)	6/222 (2.70%)	2/216 (0.93%)	4/193 (2.07%)
Gastrointestinal perforation * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Ileus * 1	0/37 (0.00%)	5/222 (2.25%)	4/216 (1.85%)	4/193 (2.07%)
Intestinal obstruction * 1	0/37 (0.00%)	11/222 (4.95%)	12/216 (5.56%)	7/193 (3.63%)
Large intestine perforation * 1	1/37 (2.70%)	3/222 (1.35%)	2/216 (0.93%)	2/193 (1.04%)
Gastrointestinal haemorrhage * 1	0/37 (0.00%)	2/222 (0.90%)	2/216 (0.93%)	0/193 (0.00%)
Subileus * 1	0/37 (0.00%)	1/222 (0.45%)	2/216 (0.93%)	4/193 (2.07%)
Abdominal pain * 1	0/37 (0.00%)	7/222 (3.15%)	5/216 (2.31%)	4/193 (2.07%)
Bile duct obstruction * 1	0/37 (0.00%)	2/222 (0.90%)	3/216 (1.39%)	2/193 (1.04%)
Large intestinal obstruction * 1	0/37 (0.00%)	1/222 (0.45%)	4/216 (1.85%)	0/193 (0.00%)
Subileus * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Small intestinal obstruction * 1	0/37 (0.00%)	6/222 (2.70%)	4/216 (1.85%)	4/193 (2.07%)
Colitis * 1	1/37 (2.70%)	2/222 (0.90%)	0/216 (0.00%)	0/193 (0.00%)
Abdominal distention * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Constipation * 1	0/37 (0.00%)	1/222 (0.45%)	1/216 (0.46%)	1/193 (0.52%)
Duodenal obstruction * 1	0/37 (0.00%)	1/222 (0.45%)	1/216 (0.46%)	0/193 (0.00%)
Dyspepsia * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Gastritis * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Haematemesis * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
intestinal perforation * 1	0/37 (0.00%)	2/222 (0.90%)	0/216 (0.00%)	0/193 (0.00%)
Melaena * 1	0/37 (0.00%)	1/222 (0.45%)	1/216 (0.46%)	0/193 (0.00%)
Pancreatitis * 1	0/37 (0.00%)	1/222 (0.45%)	1/216 (0.46%)	0/193 (0.00%)
Pancreatitis acute * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Pancreatitis relapsing * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Rectal stenosis * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Abdominal hernia * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Anal haemorrhage * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Ascites * 1	0/37 (0.00%)	1/222 (0.45%)	1/216 (0.46%)	1/193 (0.52%)
Enterocolitis * 1	0/37 (0.00%)	1/222 (0.45%)	1/216 (0.46%)	1/193 (0.52%)
Impaired gastric emptying * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Large intestine ulcer * 1	1/37 (2.70%)	2/222 (0.90%)	0/216 (0.00%)	0/193 (0.00%)
Proctalgia * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Abdominal distension * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Abdominal pain upper * 1	1/37 (2.70%)	1/222 (0.45%)	1/216 (0.46%)	0/193 (0.00%)
Anal fistula * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Haemorrhoids * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Large intestinal ulcer hemorrhage * 1	1/37 (2.70%)	0/222 (0.00%)	0/216 (0.00%)	0/193 (0.00%)
Lower gastrointestinal hemorrhage * 1	0/37 (0.00%)	2/222 (0.90%)	1/216 (0.46%)	0/193 (0.00%)
Malabsorption * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Mallory-Weiss syndrome * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Nausea * 1	1/37 (2.70%)	7/222 (3.15%)	3/216 (1.39%)	1/193 (0.52%)
Oesophageal ulcer hemorrhage * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Proctitis * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Rectal hemorrhage * 1	1/37 (2.70%)	4/222 (1.80%)	0/216 (0.00%)	0/193 (0.00%)
Small intestinal perforation * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Upper gastrointestinal hemorrhage * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Gastrointestinal obstruction * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Gastrointestinal ulcer haemorrhage * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Large intestinal haemorrhage * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Duodenal perforation * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Large intestinal ulcer * 1	1/37 (2.70%)	2/222 (0.90%)	0/216 (0.00%)	0/193 (0.00%)
Esophageal ulcer hemorrhage * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
General disorders
Death * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Pain * 1	0/37 (0.00%)	1/222 (0.45%)	1/216 (0.46%)	3/193 (1.55%)
Asthenia * 1	0/37 (0.00%)	1/222 (0.45%)	1/216 (0.46%)	1/193 (0.52%)
Catheter site thrombosis * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Fatigue * 1	1/37 (2.70%)	0/222 (0.00%)	2/216 (0.93%)	0/193 (0.00%)
General physical health deterioration * 1	0/37 (0.00%)	1/222 (0.45%)	1/216 (0.46%)	2/193 (1.04%)
Malaise * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Non-cardiac chest pain * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Oedema peripheral * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Perforation * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Pyrexia * 1	2/37 (5.41%)	5/222 (2.25%)	2/216 (0.93%)	0/193 (0.00%)
Hepatobiliary disorders
Hepatic failure * 1	0/37 (0.00%)	3/222 (1.35%)	1/216 (0.46%)	0/193 (0.00%)
Jaundice * 1	0/37 (0.00%)	1/222 (0.45%)	1/216 (0.46%)	1/193 (0.52%)
Bile duct obstruction * 1	0/37 (0.00%)	2/222 (0.90%)	3/216 (1.39%)	2/193 (1.04%)
Bile duct stenosis * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	1/193 (0.52%)
Biliary dilatation * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Cholangitis * 1	1/37 (2.70%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Cholangitis acute * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Cholecystitis * 1	0/37 (0.00%)	2/222 (0.90%)	1/216 (0.46%)	0/193 (0.00%)
Hepatic function abnormal * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Hyperbilirubinaemia * 1	0/37 (0.00%)	2/222 (0.90%)	0/216 (0.00%)	0/193 (0.00%)
Immune system disorders
Anaphylactic reaction * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	1/193 (0.52%)
Drug hypersensitivity * 1	0/37 (0.00%)	0/222 (0.00%)	2/216 (0.93%)	1/193 (0.52%)
Infections and infestations
Peritonitis * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Respiratory tract infection * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Sepsis * 1	1/37 (2.70%)	5/222 (2.25%)	3/216 (1.39%)	3/193 (1.55%)
Abdominal wall abscess * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Biliary tract infection * 1	0/37 (0.00%)	1/222 (0.45%)	1/216 (0.46%)	0/193 (0.00%)
Cholangitis infective * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Endocarditis * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Erysipelas * 1	0/37 (0.00%)	1/222 (0.45%)	1/216 (0.46%)	0/193 (0.00%)
Gastrintestinal infection * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Urosepsis * 1	0/37 (0.00%)	1/222 (0.45%)	2/216 (0.93%)	0/193 (0.00%)
Wound abscess * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Abdominal abscess * 1	1/37 (2.70%)	1/222 (0.45%)	1/216 (0.46%)	0/193 (0.00%)
Abscess limb * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Anal abscess * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Bacterial sepsis * 1	1/37 (2.70%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Campylobacter gastroenteritis * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Abdominal infection * 1	0/37 (0.00%)	2/222 (0.90%)	0/216 (0.00%)	1/193 (0.52%)
Bacteraemia * 1	0/37 (0.00%)	4/222 (1.80%)	0/216 (0.00%)	1/193 (0.52%)
Clostridial infection * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Cystitis * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Device related infection * 1	0/37 (0.00%)	4/222 (1.80%)	1/216 (0.46%)	0/193 (0.00%)
Device related sepsis * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Enteritis infectious * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Escherichia bacteraemia * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Febrile infection * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Herpes simplex * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Infection * 1	2/37 (5.41%)	0/222 (0.00%)	0/216 (0.00%)	0/193 (0.00%)
Infectious colitis * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Kidney infection * 1	1/37 (2.70%)	0/222 (0.00%)	0/216 (0.00%)	0/193 (0.00%)
Lung infection * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	1/193 (0.52%)
Ophthalmic herpes zoster * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Pneumocystis jirovecii pneumonia * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Pneumonia * 1	0/37 (0.00%)	1/222 (0.45%)	3/216 (1.39%)	0/193 (0.00%)
Pyelonephritis * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Pyelonephritis acute * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Septic shock * 1	0/37 (0.00%)	3/222 (1.35%)	1/216 (0.46%)	2/193 (1.04%)
Skin infection * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Staphylococcal bacteraemia * 1	0/37 (0.00%)	2/222 (0.90%)	0/216 (0.00%)	1/193 (0.52%)
Streptococcal bacteraemia * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Streptococcal infection * 1	1/37 (2.70%)	0/222 (0.00%)	0/216 (0.00%)	0/193 (0.00%)
Urinary tract infection * 1	4/37 (10.81%)	5/222 (2.25%)	6/216 (2.78%)	1/193 (0.52%)
Urinary tract infection bacterial * 1	1/37 (2.70%)	0/222 (0.00%)	0/216 (0.00%)	0/193 (0.00%)
Gastrointestinal infection * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Injury, poisoning and procedural complications
Anastomotic haemorrhage * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Anastomotic ulcer * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Infusion related reaction * 1	3/37 (8.11%)	1/222 (0.45%)	3/216 (1.39%)	2/193 (1.04%)
Radiation inflammation * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Rib fracture * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Toxicity to various agents * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Investigations
Alanine aminotransferase increased * 1	1/37 (2.70%)	0/222 (0.00%)	0/216 (0.00%)	0/193 (0.00%)
Aspartate aminotransferase increased * 1	2/37 (5.41%)	0/222 (0.00%)	0/216 (0.00%)	0/193 (0.00%)
Blood bilirubin increased * 1	0/37 (0.00%)	1/222 (0.45%)	2/216 (0.93%)	0/193 (0.00%)
Blood creatine phosphokinase increased * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Body temperature increased * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
International normalised ratio increased * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Neutrophil count decreased * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Metabolism and nutrition disorders
Dehydration * 1	1/37 (2.70%)	2/222 (0.90%)	1/216 (0.46%)	1/193 (0.52%)
Decreased appetite * 1	1/37 (2.70%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Cachexia * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Electrolyte imbalance * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Hypercalcaemia * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Hyperglycaemia * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Hypoalbuminaemia * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Hypokalaemia * 1	0/37 (0.00%)	1/222 (0.45%)	1/216 (0.46%)	2/193 (1.04%)
Hyponatraemia * 1	0/37 (0.00%)	1/222 (0.45%)	2/216 (0.93%)	0/193 (0.00%)
Malnutrition * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Musculoskeletal and connective tissue disorders
Back pain * 1	1/37 (2.70%)	1/222 (0.45%)	2/216 (0.93%)	0/193 (0.00%)
Bone pain * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Chondrocalcinosis * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Fistula * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Muscle tightness * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Musculoskeletal chest pain * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Osteoarthritis * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Periostitis * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Rhabdomyolysis * 1	1/37 (2.70%)	0/222 (0.00%)	0/216 (0.00%)	0/193 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain * 1	0/37 (0.00%)	1/222 (0.45%)	5/216 (2.31%)	1/193 (0.52%)
Malignant melanoma * 1	0/37 (0.00%)	0/222 (0.00%)	3/216 (1.39%)	0/193 (0.00%)
Metastases to central nervous system * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Transitional cell carcinoma * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Tumour associated fever * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	1/193 (0.52%)
Tumor haemorrhage * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Tumour pain * 1	1/37 (2.70%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Nervous system disorders
Cerebral ischaemia * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Epilepsy * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	1/193 (0.52%)
Cerebral haematoma * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Cerebrovascular accident * 1	0/37 (0.00%)	1/222 (0.45%)	1/216 (0.46%)	0/193 (0.00%)
Cognitive disorder * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Hemiparesis * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Hepatic encephalopathy * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Ischaemic stroke * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	1/193 (0.52%)
Lethargy * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Spinal cord compression * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Syncope * 1	1/37 (2.70%)	1/222 (0.45%)	1/216 (0.46%)	0/193 (0.00%)
Transient ischaemic attack * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Product Issues
Device occlusion * 1	1/37 (2.70%)	1/222 (0.45%)	0/216 (0.00%)	1/193 (0.52%)
Psychiatric disorders
Anxiety * 1	0/37 (0.00%)	2/222 (0.90%)	0/216 (0.00%)	0/193 (0.00%)
Confusional state * 1	1/37 (2.70%)	0/222 (0.00%)	0/216 (0.00%)	0/193 (0.00%)
Renal and urinary disorders
Acute kidney injury * 1	1/37 (2.70%)	8/222 (3.60%)	4/216 (1.85%)	1/193 (0.52%)
Urinary tract infection * 1	4/37 (10.81%)	2/222 (0.90%)	5/216 (2.31%)	1/193 (0.52%)
Haematuria * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Hydronephrosis * 1	1/37 (2.70%)	2/222 (0.90%)	0/216 (0.00%)	1/193 (0.52%)
Nephritis * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Renal failure * 1	2/37 (5.41%)	2/222 (0.90%)	1/216 (0.46%)	0/193 (0.00%)
Urinary retention * 1	0/37 (0.00%)	1/222 (0.45%)	1/216 (0.46%)	0/193 (0.00%)
Prerenal failure * 1	0/37 (0.00%)	2/222 (0.90%)	0/216 (0.00%)	1/193 (0.52%)
Renal colic * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Urinary tract obstruction * 1	1/37 (2.70%)	4/222 (1.80%)	1/216 (0.46%)	0/193 (0.00%)
Reproductive system and breast disorders
Female genital tract fistula * 1	0/37 (0.00%)	2/222 (0.90%)	0/216 (0.00%)	0/193 (0.00%)
Pelvic pain * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Respiratory, thoracic and mediastinal disorders
Aspiration * 1	0/37 (0.00%)	0/222 (0.00%)	2/216 (0.93%)	0/193 (0.00%)
Respiratory failure * 1	0/37 (0.00%)	1/222 (0.45%)	1/216 (0.46%)	3/193 (1.55%)
Dyspnoea * 1	0/37 (0.00%)	2/222 (0.90%)	1/216 (0.46%)	1/193 (0.52%)
Epistaxis * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Haemoptysis * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Interstitial lung disease * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Pleural effusion * 1	2/37 (5.41%)	0/222 (0.00%)	0/216 (0.00%)	0/193 (0.00%)
Pleuritic pain * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Pneumomediastinum * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Pneumothorax * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Pulmonary embolism * 1	1/37 (2.70%)	8/222 (3.60%)	3/216 (1.39%)	5/193 (2.59%)
Skin and subcutaneous tissue disorders
Pruritus generalised * 1	0/37 (0.00%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Surgical and medical procedures
Analgesic therapy * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Vascular disorders
Deep vein thrombosis * 1	0/37 (0.00%)	0/222 (0.00%)	1/216 (0.46%)	0/193 (0.00%)
Hypertension * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Jugular vein thrombosis * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
Peripheral artery stenosis * 1	0/37 (0.00%)	0/222 (0.00%)	0/216 (0.00%)	1/193 (0.52%)
1 Term from vocabulary, MedDRA (21.0); * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Combined Safety Lead-in	Phase 3: Triplet Arm	Phase 3: Doublet Arm	Phase 3: Control Arm
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	36/37 (97.30%)	218/222 (98.20%)	212/216 (98.15%)	187/193 (96.89%)
Blood and lymphatic system disorders
Anaemia * 1	16/37 (43.24%)	105/222 (47.30%)	44/216 (20.37%)	37/193 (19.17%)
Neutropenia * 1	1/37 (2.70%)	3/222 (1.35%)	4/216 (1.85%)	36/193 (18.65%)
Cardiac disorders
Palpitations * 1	2/37 (5.41%)	3/222 (1.35%)	4/216 (1.85%)	1/193 (0.52%)
Eye disorders
Vision blurred * 1	12/37 (32.43%)	27/222 (12.16%)	10/216 (4.63%)	1/193 (0.52%)
Dry eye * 1	5/37 (13.51%)	9/222 (4.05%)	11/216 (5.09%)	3/193 (1.55%)
Retinal detachment * 1	2/37 (5.41%)	6/222 (2.70%)	1/216 (0.46%)	0/193 (0.00%)
Chorioretinopathy * 1	2/37 (5.41%)	3/222 (1.35%)	0/216 (0.00%)	0/193 (0.00%)
Macular oedema * 1	3/37 (8.11%)	1/222 (0.45%)	1/216 (0.46%)	0/193 (0.00%)
Trichiasis * 1	4/37 (10.81%)	1/222 (0.45%)	0/216 (0.00%)	0/193 (0.00%)
Trichomegaly * 1	2/37 (5.41%)	6/222 (2.70%)	1/216 (0.46%)	0/193 (0.00%)
Visual impairment * 1	3/37 (8.11%)	4/222 (1.80%)	5/216 (2.31%)	0/193 (0.00%)
Vitreous floaters * 1	4/37 (10.81%)	3/222 (1.35%)	4/216 (1.85%)	0/193 (0.00%)
Gastrointestinal disorders
Diarrhoea * 1	29/37 (78.38%)	150/222 (67.57%)	85/216 (39.35%)	96/193 (49.74%)
Nausea * 1	22/37 (59.46%)	107/222 (48.20%)	80/216 (37.04%)	84/193 (43.52%)
Vomiting * 1	19/37 (51.35%)	99/222 (44.59%)	58/216 (26.85%)	59/193 (30.57%)
Abdominal pain * 1	14/37 (37.84%)	74/222 (33.33%)	60/216 (27.78%)	54/193 (27.98%)
Constipation * 1	14/37 (37.84%)	64/222 (28.83%)	39/216 (18.06%)	39/193 (20.21%)
Abdominal pain upper * 1	5/37 (13.51%)	24/222 (10.81%)	22/216 (10.19%)	15/193 (7.77%)
Dyspepsia * 1	4/37 (10.81%)	18/222 (8.11%)	9/216 (4.17%)	7/193 (3.63%)
Flatulence * 1	0/37 (0.00%)	15/222 (6.76%)	6/216 (2.78%)	3/193 (1.55%)
Rectal haemorrhage * 1	2/37 (5.41%)	21/222 (9.46%)	6/216 (2.78%)	1/193 (0.52%)
Dry Mouth * 1	2/37 (5.41%)	11/222 (4.95%)	10/216 (4.63%)	8/193 (4.15%)
Gastroesophageal reflux disease * 1	2/37 (5.41%)	10/222 (4.50%)	6/216 (2.78%)	6/193 (3.11%)
Abdominal distension * 1	2/37 (5.41%)	10/222 (4.50%)	16/216 (7.41%)	8/193 (4.15%)
Intestinal obstruction * 1	0/37 (0.00%)	11/222 (4.95%)	12/216 (5.56%)	7/193 (3.63%)
Anal haemorrhage * 1	2/37 (5.41%)	6/222 (2.70%)	1/216 (0.46%)	2/193 (1.04%)
Ascites * 1	2/37 (5.41%)	5/222 (2.25%)	2/216 (0.93%)	4/193 (2.07%)
Colitis * 1	2/37 (5.41%)	1/222 (0.45%)	0/216 (0.00%)	1/193 (0.52%)
Stomatitis * 1	6/37 (16.22%)	32/222 (14.41%)	13/216 (6.02%)	45/193 (23.32%)
Abdominal pain lower * 1	2/37 (5.41%)	5/222 (2.25%)	4/216 (1.85%)	2/193 (1.04%)
General disorders
Fatigue * 1	20/37 (54.05%)	74/222 (33.33%)	74/216 (34.26%)	54/193 (27.98%)
Asthenia * 1	6/37 (16.22%)	63/222 (28.38%)	51/216 (23.61%)	52/193 (26.94%)
Pyrexia * 1	16/37 (43.24%)	53/222 (23.87%)	43/216 (19.91%)	30/193 (15.54%)
Chills * 1	6/37 (16.22%)	15/222 (6.76%)	6/216 (2.78%)	3/193 (1.55%)
Malaise * 1	7/37 (18.92%)	5/222 (2.25%)	6/216 (2.78%)	11/193 (5.70%)
Oedema peripheral * 1	6/37 (16.22%)	30/222 (13.51%)	24/216 (11.11%)	14/193 (7.25%)
Infections and infestations
Urinary tract infection * 1	7/37 (18.92%)	26/222 (11.71%)	16/216 (7.41%)	5/193 (2.59%)
Paronychia * 1	6/37 (16.22%)	21/222 (9.46%)	13/216 (6.02%)	20/193 (10.36%)
Rash pustular * 1	6/37 (16.22%)	13/222 (5.86%)	4/216 (1.85%)	4/193 (2.07%)
Conjunctivitis * 1	2/37 (5.41%)	16/222 (7.21%)	12/216 (5.56%)	3/193 (1.55%)
Cystitis * 1	2/37 (5.41%)	6/222 (2.70%)	2/216 (0.93%)	1/193 (0.52%)
Nasopharyngitis * 1	3/37 (8.11%)	12/222 (5.41%)	15/216 (6.94%)	3/193 (1.55%)
Upper respiratory tract infection * 1	1/37 (2.70%)	4/222 (1.80%)	9/216 (4.17%)	10/193 (5.18%)
Injury, poisoning and procedural complications
Infusion related reaction * 1	1/37 (2.70%)	5/222 (2.25%)	18/216 (8.33%)	13/193 (6.74%)
Wound * 1	2/37 (5.41%)	1/222 (0.45%)	1/216 (0.46%)	1/193 (0.52%)
Investigations
Weight decreased * 1	3/37 (8.11%)	25/222 (11.26%)	26/216 (12.04%)	12/193 (6.22%)
Neutrophil count decreased * 1	0/37 (0.00%)	2/222 (0.90%)	1/216 (0.46%)	21/193 (10.88%)
Blood creatine phosphokinase increased * 1	11/37 (29.73%)	26/222 (11.71%)	3/216 (1.39%)	4/193 (2.07%)
Blood creatine increased * 1	11/37 (29.73%)	25/222 (11.26%)	6/216 (2.78%)	1/193 (0.52%)
Alanine aminotransferase increased * 1	6/37 (16.22%)	16/222 (7.21%)	15/216 (6.94%)	14/193 (7.25%)
Aspartate aminotransferase increased * 1	7/37 (18.92%)	14/222 (6.31%)	7/216 (3.24%)	14/193 (7.25%)
Ejection fraction decreased * 1	5/37 (13.51%)	8/222 (3.60%)	0/216 (0.00%)	0/193 (0.00%)
Blood bilirubin increased * 1	3/37 (8.11%)	5/222 (2.25%)	9/216 (4.17%)	8/193 (4.15%)
White blood cell count decrease * 1	0/37 (0.00%)	2/222 (0.90%)	2/216 (0.93%)	14/193 (7.25%)
Blood alkaline phosphatase increased * 1	0/37 (0.00%)	6/222 (2.70%)	7/216 (3.24%)	10/193 (5.18%)
Metabolism and nutrition disorders
Decreased appetite * 1	15/37 (40.54%)	67/222 (30.18%)	68/216 (31.48%)	56/193 (29.02%)
Hypomagnesaemia * 1	6/37 (16.22%)	29/222 (13.06%)	28/216 (12.96%)	19/193 (9.84%)
Hypokalaemia * 1	3/37 (8.11%)	16/222 (7.21%)	14/216 (6.48%)	25/193 (12.95%)
Hypoalbuminaemia * 1	4/37 (10.81%)	20/222 (9.01%)	6/216 (2.78%)	6/193 (3.11%)
Hypocalcaemia * 1	2/37 (5.41%)	10/222 (4.50%)	5/216 (2.31%)	9/193 (4.66%)
Hypophosphataemia * 1	2/37 (5.41%)	7/222 (3.15%)	3/216 (1.39%)	4/193 (2.07%)
Iron deficiency * 1	3/37 (8.11%)	2/222 (0.90%)	3/216 (1.39%)	1/193 (0.52%)
Musculoskeletal and connective tissue disorders
Back Pain * 1	8/37 (21.62%)	36/222 (16.22%)	32/216 (14.81%)	27/193 (13.99%)
Arthralgia * 1	9/37 (24.32%)	26/222 (11.71%)	52/216 (24.07%)	3/193 (1.55%)
Myalgia * 1	9/37 (24.32%)	23/222 (10.36%)	35/216 (16.20%)	4/193 (2.07%)
Pain in extremity * 1	3/37 (8.11%)	19/222 (8.56%)	26/216 (12.04%)	2/193 (1.04%)
Musculoskeletal pain * 1	2/37 (5.41%)	12/222 (5.41%)	32/216 (14.81%)	5/193 (2.59%)
Muscle spasms * 1	2/37 (5.41%)	22/222 (9.91%)	5/216 (2.31%)	4/193 (2.07%)
Bone pain * 1	2/37 (5.41%)	2/222 (0.90%)	3/216 (1.39%)	2/193 (1.04%)
Flank pain * 1	3/37 (8.11%)	2/222 (0.90%)	1/216 (0.46%)	3/193 (1.55%)
Musculoskeletal chest pain * 1	2/37 (5.41%)	7/222 (3.15%)	5/216 (2.31%)	2/193 (1.04%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic naevus * 1	1/37 (2.70%)	1/222 (0.45%)	34/216 (15.74%)	0/193 (0.00%)
Tumour Pain * 1	4/37 (10.81%)	3/222 (1.35%)	1/216 (0.46%)	1/193 (0.52%)
Skin papilloma * 1	1/37 (2.70%)	0/222 (0.00%)	15/216 (6.94%)	0/193 (0.00%)
Nervous system disorders
Headache * 1	7/37 (18.92%)	21/222 (9.46%)	43/216 (19.91%)	5/193 (2.59%)
Dizziness * 1	8/37 (21.62%)	16/222 (7.21%)	16/216 (7.41%)	16/193 (8.29%)
Neuropathy peripheral * 1	1/37 (2.70%)	13/222 (5.86%)	11/216 (5.09%)	5/193 (2.59%)
Dysgeusia * 1	6/37 (16.22%)	11/222 (4.95%)	10/216 (4.63%)	8/193 (4.15%)
Peripheral sensory neuropathy * 1	6/37 (16.22%)	7/222 (3.15%)	5/216 (2.31%)	4/193 (2.07%)
Nervous system disorder * 1	2/37 (5.41%)	0/222 (0.00%)	0/216 (0.00%)	0/193 (0.00%)
Restless legs syndrome * 1	2/37 (5.41%)	1/222 (0.45%)	10/216 (4.63%)	1/193 (0.52%)
Psychiatric disorders
Insomnia * 1	2/37 (5.41%)	15/222 (6.76%)	25/216 (11.57%)	13/193 (6.74%)
Depression * 1	2/37 (5.41%)	5/222 (2.25%)	5/216 (2.31%)	1/193 (0.52%)
Renal and urinary disorders
Haematuria * 1	2/37 (5.41%)	16/222 (7.21%)	6/216 (2.78%)	4/193 (2.07%)
Pollakiuria * 1	4/37 (10.81%)	4/222 (1.80%)	8/216 (3.70%)	0/193 (0.00%)
Proteinuria * 1	3/37 (8.11%)	5/222 (2.25%)	6/216 (2.78%)	1/193 (0.52%)
Urinary incontinence * 1	2/37 (5.41%)	1/222 (0.45%)	5/216 (2.31%)	2/193 (1.04%)
Respiratory, thoracic and mediastinal disorders
Cough * 1	5/37 (13.51%)	26/222 (11.71%)	22/216 (10.19%)	12/193 (6.22%)
Dyspnoea * 1	13/37 (35.14%)	22/222 (9.91%)	30/216 (13.89%)	20/193 (10.36%)
Pulmonary embolism * 1	2/37 (5.41%)	4/222 (1.80%)	1/216 (0.46%)	5/193 (2.59%)
Epistaxis * 1	1/37 (2.70%)	8/222 (3.60%)	16/216 (7.41%)	8/193 (4.15%)
Dysphonia * 1	2/37 (5.41%)	5/222 (2.25%)	12/216 (5.56%)	3/193 (1.55%)
Rhinnorrhoea * 1	3/37 (8.11%)	5/222 (2.25%)	6/216 (2.78%)	1/193 (0.52%)
Pleural effusion * 1	2/37 (5.41%)	1/222 (0.45%)	3/216 (1.39%)	2/193 (1.04%)
Rhinitis allergic * 1	3/37 (8.11%)	1/222 (0.45%)	3/216 (1.39%)	1/193 (0.52%)
Skin and subcutaneous tissue disorders
Dermatitis acneiform * 1	25/37 (67.57%)	113/222 (50.90%)	65/216 (30.09%)	77/193 (39.90%)
Dry Skin * 1	19/37 (51.35%)	49/222 (22.07%)	28/216 (12.96%)	17/193 (8.81%)
Rash * 1	3/37 (8.11%)	49/222 (22.07%)	35/216 (16.20%)	28/193 (14.51%)
Pruritus * 1	3/37 (8.11%)	35/222 (15.77%)	24/216 (11.11%)	10/193 (5.18%)
Palmar-planar erythrodysaesthesia * 1	6/37 (16.22%)	31/222 (13.96%)	11/216 (5.09%)	15/193 (7.77%)
Rash maculo-papular * 1	6/37 (16.22%)	19/222 (8.56%)	19/216 (8.80%)	11/193 (5.70%)
Skin fissures * 1	9/37 (24.32%)	21/222 (9.46%)	9/216 (4.17%)	13/193 (6.74%)
Erythema * 1	2/37 (5.41%)	9/222 (4.05%)	13/216 (6.02%)	4/193 (2.07%)
Eczema * 1	2/37 (5.41%)	5/222 (2.25%)	2/216 (0.93%)	1/193 (0.52%)
Skin hyperpigmentation * 1	2/37 (5.41%)	1/222 (0.45%)	16/216 (7.41%)	2/193 (1.04%)
Skin lesion * 1	0/37 (0.00%)	2/222 (0.90%)	17/216 (7.87%)	3/193 (1.55%)
Alopecia * 1	1/37 (2.70%)	6/222 (2.70%)	10/216 (4.63%)	21/193 (10.88%)
Hyperkeratosis * 1	1/37 (2.70%)	1/222 (0.45%)	12/216 (5.56%)	0/193 (0.00%)
Hypertrichosis * 1	3/37 (8.11%)	4/222 (1.80%)	5/216 (2.31%)	1/193 (0.52%)
Nail disorder * 1	2/37 (5.41%)	4/222 (1.80%)	3/216 (1.39%)	2/193 (1.04%)
Pruritus generalised * 1	2/37 (5.41%)	6/222 (2.70%)	12/216 (5.56%)	3/193 (1.55%)
Vascular disorders
Hypotension * 1	3/37 (8.11%)	9/222 (4.05%)	9/216 (4.17%)	3/193 (1.55%)
Hypertension * 1	4/37 (10.81%)	8/222 (3.60%)	8/216 (3.70%)	6/193 (3.11%)
1 Term from vocabulary, MedDRA (21.0); * Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publication until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.

Results Point of Contact

• Name/Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer Inc.
• Phone: 1-800-718-1021
• EMail: ClinicalTrials.gov_Inquiries@pfizer.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Stintzing S, Seufferlein T, Rose C, Reichenbach F, Luftner D. Encorafenib in Combination With Cetuximab After Systemic Therapy in Patients With BRAFV600E Mutant Metastatic Colorectal Cancer: German Health Technology Assessment-Driven Analyses From the BEACON CRC Study. Clin Colorectal Cancer. 2022 Sep;21(3):244-251. doi: 10.1016/j.clcc.2022.04.002. Epub 2022 May 5.

Kopetz S, Grothey A, Van Cutsem E, Yaeger R, Wasan H, Yoshino T, Desai J, Ciardiello F, Loupakis F, Hong YS, Steeghs N, Guren TK, Arkenau HT, Garcia-Alfonso P, Belani A, Zhang X, Tabernero J. Quality of life with encorafenib plus cetuximab with or without binimetinib treatment in patients with BRAF V600E-mutant metastatic colorectal cancer: patient-reported outcomes from BEACON CRC. ESMO Open. 2022 Jun;7(3):100477. doi: 10.1016/j.esmoop.2022.100477. Epub 2022 May 30.

Tabernero J, Grothey A, Van Cutsem E, Yaeger R, Wasan H, Yoshino T, Desai J, Ciardiello F, Loupakis F, Hong YS, Steeghs N, Guren TK, Arkenau HT, Garcia-Alfonso P, Elez E, Gollerkeri A, Maharry K, Christy-Bittel J, Kopetz S. Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated BRAF V600E-Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study. J Clin Oncol. 2021 Feb 1;39(4):273-284. doi: 10.1200/JCO.20.02088.

Kopetz S, Grothey A, Yaeger R, Van Cutsem E, Desai J, Yoshino T, Wasan H, Ciardiello F, Loupakis F, Hong YS, Steeghs N, Guren TK, Arkenau HT, Garcia-Alfonso P, Pfeiffer P, Orlov S, Lonardi S, Elez E, Kim TW, Schellens JHM, Guo C, Krishnan A, Dekervel J, Morris V, Calvo Ferrandiz A, Tarpgaard LS, Braun M, Gollerkeri A, Keir C, Maharry K, Pickard M, Christy-Bittel J, Anderson L, Sandor V, Tabernero J. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer. N Engl J Med. 2019 Oct 24;381(17):1632-1643. doi: 10.1056/NEJMoa1908075. Epub 2019 Sep 30.

Van Cutsem E, Huijberts S, Grothey A, Yaeger R, Cuyle PJ, Elez E, Fakih M, Montagut C, Peeters M, Yoshino T, Wasan H, Desai J, Ciardiello F, Gollerkeri A, Christy-Bittel J, Maharry K, Sandor V, Schellens JHM, Kopetz S, Tabernero J. Binimetinib, Encorafenib, and Cetuximab Triplet Therapy for Patients With BRAF V600E-Mutant Metastatic Colorectal Cancer: Safety Lead-In Results From the Phase III BEACON Colorectal Cancer Study. J Clin Oncol. 2019 Jun 10;37(17):1460-1469. doi: 10.1200/JCO.18.02459. Epub 2019 Mar 20.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT02928224
• Other Study ID Numbers: ARRAY-818-302; BEACON CRC ( Other Identifier: Alias Study Number ); 2015-005805-35 ( EudraCT Number ); C4221009 ( Other Identifier: Pfizer )
• First Submitted: August 16, 2016
• First Posted: October 10, 2016
• Results First Submitted: May 6, 2020
• Results First Posted: July 14, 2020
• Last Update Posted: December 21, 2023