Every two weeks: Oxaliplatin 85 mg/m2 (120-minute IV infusion) Leucovorin 400 mg/m2 (120-minute IV infusion) 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours Bevacizumab (optional; given per prescribing instructions) -OR- Every two weeks: Irinotecan 165 mg/m2 (90-minute IV infusion) Oxaliplatin 85 mg/m2 (120-minute IV infusion) Leucovorin 400 mg/m2 (120-minute IV infusion) 5-FU 2400 or 3200 mg/m2 continuous IV infusion over 46 48 hours Bevacizumab (optional; given per prescribing instructions) -OR- Oxaliplatin 130 mg/m2 (120-minute IV infusion) every 3 weeks Capecitabine 1000 mg/m2 oral tablet twice daily on Days 1-14 Bevacizumab (optional; given per prescribing instructions)

Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120-minute IV infusion) every two weeks Irinotecan 180 mg/m2 (90-minute IV infusion) every two weeks Leucovorin 400 mg/m2 (120-minute IV infusion) every two weeks 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours every two weeks

Irinotecan 180 mg/m2 (90-minute IV infusion) every 2 weeks, Leucovorin 400 mg/m2 (120-minute IV infusion) every 2 weeks, 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours every two weeks, Bevacizumab (optional; given per prescribing instructions)

Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vial

Powder for solution for intravenous use 50 mg/vial, 100 mg/vial, or 200 mg/vial

Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vial

Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial

Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial

150 mg or 500 mg Tablet

Optional Injection for intravenous use 100 mg/vial or 400 mg/vial

ORR was defined as the percentage of participants who achieved BOR of confirmed CR or PR according to RECIST v 1.1 as assessed by BICR. CR: complete disappearance of all target lesions (with the exception of nodal disease) and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: >=30% decrease under baseline of the sum of diameters of all target measurable lesions. PD: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm for target disease or unequivocal progression of pre-existing lesions for non-target disease or any new lesion.

An AE was any untoward medical occurrence in clinical study participant temporally associated with use of study intervention, whether or not considered related to study intervention. AEs were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version (v) 4.03 where grade 1= mild, grade 2= moderate, grade 3= severe, grade 4= life-threatening and grade 5= death related to AE. In this outcome measure, number of participants with grade 3 or 4 AEs and grade 5 AEs were reported.

The following hematology and coagulation parameters were assessed: activated partial thromboplastin time prolonged, anemia, hemoglobin increased, international normalized ratio (INR) increased, leukocytosis, neutrophil count decreased, platelet count decreased, and white blood cell decreased. Laboratory abnormalities were graded according to NCI CTCAE version 4.03 where grade 1= mild, grade 2= moderate, grade 3= severe, grade 4= life-threatening event due to AE, and grade 5= death. Only those hematology and coagulation parameters in which at least 1 participant in any of the reporting arm had any shift from grade <=2 at baseline to grade >=3 post-baseline are reported in this outcome measure.

The following chemistry parameters were assessed: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatinine increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, and lipase increased. Laboratory abnormalities were graded according to NCI CTCAE v4.03 where grade 1= mild, grade 2= moderate, grade 3= severe, grade 4= life-threatening, and grade 5= death related to AE. Only those chemistry parameters in which at least 1 participant in any of the reporting arm had any shift from grade <=2 at baseline to grade >=3 post-baseline are reported in this outcome measure.

The criteria for vital signs included: Systolic blood pressure (millimeters of mercury [mmHg]): value <= 90 mmHg and decrease from baseline >= 20 mmHg, and value >= 160 mmHg and increase from baseline >= 20 mmHg. Diastolic blood pressure (mmHg): value <= 50 mmHg and decrease from baseline >= 15 mmHg, and value >= 100 mmHg and increase from baseline >= 15 mmHg. Pulse rate (beats per minute [bpm]): value <= 50 bpm and decrease from baseline >= 15 bpm, and value >= 120 bpm and increase from baseline >= 15 bpm. Weight (kilograms [kg]): change >= 20 % decrease from baseline, and change >=10% increase from baseline. Temperature (degree Celsius): value <=36 degree Celsius, and value >=37.5 degree Celsius. Only those criteria in which at least 1 participant in any of the reporting arm had any vital signs data are reported in this outcome measure.

ECG criteria included: ECG mean heart rate (beats per minute [bpm]): increase from baseline >25% and to a value >100 bpm; decrease from baseline >25% and to a value <50 bpm, PR interval not otherwise specified (milliseconds [msec]): new >280 msec, QRS interval not otherwise specified (msec): new >120 msec, QT Interval Corrected Using Fridericia's Formula (QTcF) not otherwise specified: new >450 msec; new >480 msec; new >500 msec; increase from baseline >30 msec and increase from baseline >60 msec. Only those criteria in which at least 1 participant in any of the reporting arm had any ECG findings are reported in this outcome measure.

An AE was any untoward medical occurrence in clinical study participant temporally associated with use of study intervention, whether or not considered related to study intervention. Dose interruption: for encorafenib = 0 mg dose administered for >=1 days; for cetuximab, oxaliplatin, leucovorin, fluorouracil, irinotecan: >20 days between successive start dates with non-zero actual doses. Dose reduction: decrease in dose of at least 10%, from the protocol-planned dose and a decrease from the previous non-zero dose; for encorafenib to qualify as a dose reduction, it should have lasted for >=2 days. Dose modifications included both dose interruptions and reduction.

An AE was any untoward medical occurrence in clinical study participant temporally associated with use of study intervention, whether or not considered related to study intervention. Number of participants with dose discontinuation due to AEs were reported in this outcome measure.

ORR: percentage of participants who achieved BOR of confirmed CR/PR per RECIST v1.1 as assessed by response reported by investigator on eCRF. CR: complete disappearance of all target lesions (with exception of nodal disease) and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis <10 mm. PR: >=30% decrease under baseline of sum of diameters of all target measurable lesions. PD: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm for target disease or unequivocal progression of pre-existing lesions for non-target disease or any new lesion. Percentage of participants with ORR for first line (no prior treatment) and second line (participant received prior treatment viz. advanced/metastatic or locoregional disease or maintenance or if neoadjuvant/adjuvant with a disease recurrence occurred during or within 6 months of last therapy dose) is presented.

DOR: time from date of first radiographic evidence of response (CR/PR) to earliest documented PD per RECIST v1.1 as assessed by response reported by investigator on eCRF, or death by any cause. CR: disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis <10 mm. PR: >=30% decrease under baseline of sum of diameters of all target measurable lesions. PD: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm for target disease or unequivocal progression of pre-existing lesions for non-target disease or any new lesion. DOR for first line and second line is presented. Analysis performed by Kaplan Meier method.

PFS: time from date of randomization to earliest documented PD per RECIST version 1.1 or death due to any cause as assessed by response reported by investigator on eCRF. PD: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm for target disease or unequivocal progression of pre-existing lesions for non-target disease or any new lesion. Censoring details: no adequate baseline assessment, including no disease at baseline: participants were censored to randomization date; no PD, lost to follow-up, withdrawal of consent, PD or death >12 (or 16) weeks after the last adequate tumor assessment, and start of new anticancer treatment: participants were censored to last adequate tumor assessment documenting no PD prior to new anticancer therapy, or missed assessments. Participants with PFS for first line and second line were presented. Analysis performed using Kaplan Meier method.

TTR was defined as the time from the date of first dose to first radiographic evidence of response (CR or PR) per RECIST v1.1 as assessed by response reported by investigator on eCRF. CR: disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: >= 30% decrease under baseline of the sum of diameters of all target measurable lesions. In this outcome measure, TTR for first line (no prior treatment) and second line (participant received a prior treatment defined as advanced/metastatic or locoregional disease or maintenance or if neoadjuvant/adjuvant with a disease recurrence occurred during or within 6 months of the last dose of therapy) were reported.

OS was defined as the time from the date of first dose to death due to any cause. If a participant was not known to have died at the time of the cutoff for analysis, then OS was censored at the date of last contact. In this outcome measure, OS for first line (no prior treatment) and second line (participant received a prior treatment defined as advanced/metastatic or locoregional disease or maintenance or if neoadjuvant/adjuvant with a disease recurrence occurred during or within 6 months of the last dose of therapy) was presented. Analysis was performed using Kaplan Meier method.

Cmax was observed directly from data. LHY746 is a metabolite of Encorafenib.

The AUC was estimated from time 0 to 6 hours post dose. AUC6 was computed using the Linear/Log trapezoidal method. LHY746 is a metabolite of Encorafenib.

AUCtau was area under the concentration-time profile from time zero to time tau, the dosing interval. tau = 24 hrs for QD dosing of encorafenib. LHY746 is a metabolite of encorafenib. AUCtau can be calculated directly from the data using 24 hrs (tau) sample or can be approximately calculated by kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

Tmax: time (hours) to Cmax. LHY746 is a metabolite of Encorafenib.

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as Dose/AUCinf where dose is the dose administered divided by area under the concentration curve from time 0 extrapolated to infinite time (AUCinf). AUCinf was calculated as AUClast + (Clast*/kel), where Clast is last plasma concentration from the log-linear regression analysis, and kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

Cmax was observed directly from data. SN-38 is a metabolite of Irinotecan.

AUClast was defined as area under the plasma concentration time curve from time zero to the last measurable concentration. AUClast was calculated using linear/log trapezoidal method. SN-38 is a metabolite of Irinotecan.

t1/2 was the time measured for the drug concentration to decrease by one half. t1/2 was determined by Loge (2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. SN-38 is a metabolite of Irinotecan.

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as dose administered divided by area under the concentration curve from time 0 extrapolated to infinite time (AUCinf). AUCinf was calculated as AUClast + (Clast*/kel), where Clast is the predicted plasma concentration at the last quantifiable time point from the log-linear regression analysis, and kel is the terminal phase rate constant calculated by a linear regression of the loglinear concentration-time curve.

Cmax was observed directly from data. Oxaliplatin was evaluated as total platinum in plasma and platinum in plasma ultrafiltrate.

AUClast was defined as area under the plasma concentration time curve from time zero to the last measurable concentration. AUClast was calculated using linear/log trapezoidal method. Oxaliplatin was evaluated as total platinum in plasma and platinum in plasma ultrafiltrate.

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as dose administered divided by area under the concentration curve from time 0 extrapolated to infinite time (AUCinf). AUCinf was calculated as AUClast + (Clast*/kel), where Clast is the predicted plasma concentration at the last quantifiable time point from the log-linear regression analysis, and kel is the terminal phase rate constant calculated by a linear regression of the loglinear concentration-time curve. Oxaliplatin consisted of platinum of plasma and platinum in plasma-ultrafiltrate. The clearance of platinum-ultrafiltrate has been presented in this outcome measure.

AUCinf was calculated as AUClast + (Clast*/kel), where Clast was the predicted plasma concentration at the last quantifiable time point from the log-linear regression analysis, and kel was the terminal phase rate constant calculated by a linear regression of the loglinear concentration-time curve. The ratio between geometric least square (LS) mean (within Cohort 1) for AUCinf on Cycle 1 Day 15 and geometric LS mean (within Cohort 1) for AUCinf on Cycle 1 Day 1 for irinotecan and its metabolite SN-38 has been presented in this outcome measure, which explains the data reported for this outcome measure using measure type as "Number".

AUClast was defined as area under the plasma concentration time curve from time zero to the last measurable concentration. AUClast was calculated using linear/log trapezoidal method. The ratio between geometric LS mean (within Cohort 1) for AUClast on Cycle 1 Day 15 and geometric LS mean (within Cohort 1) for AUClast on Cycle 1 Day 1 for irinotecan and its metabolite SN-38 has been presented in this outcome measure, which explains the data reported for this outcome measure using measure type as "Number".

Cmax was observed directly from data. The ratio between geometric LS mean (within Cohort 1) for Cmax on Cycle 1 Day 15 and geometric LS mean (within Cohort 1) for Cmax on Cycle 1 Day 1 for irinotecan and its metabolite SN-38 has been presented in this outcome measure, which explains the data reported for this outcome measure using measure type as "Number".

AUClast was defined as area under the plasma concentration time curve from time zero to the last measurable concentration. AUClast was calculated using linear/log trapezoidal method. Oxaliplatin was evaluated as total platinum in plasma and platinum in plasma ultrafiltrate. The ratio between geometric LS mean (within Cohort 2) for AUClast on Cycle 1 Day 15 and geometric LS mean (within Cohort 2) for AUClast on Cycle 1 Day 1 for Oxaliplatin has been presented in this outcome measure, which explains the data reported for this outcome measure using measure type as "Number".

Cmax was observed directly from data. Oxaliplatin was evaluated as total platinum in plasma and platinum in plasma ultrafiltrate. The ratio between geometric LS mean (within Cohort 2) for Cmax on Cycle 1 Day 15 and geometric LS mean (within Cohort 2) for Cmax on Cycle 1 Day 1 for Oxaliplatin has been presented in this outcome measure, which explains the data reported for this outcome measure using measure type as "Number".

OS was defined as the time from the date of first dose to death due to any cause. If a participant was not known to have died at the time of the cutoff for analysis, then OS was censored at the date of last contact. Analysis was performed using Kaplan Meier method.

ORR was defined as the percentage of participants who achieved BOR of confirmed CR or PR according to RECIST v 1.1 by derived investigator assessment. CR: complete disappearance of all target lesions (with the exception of nodal disease) and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: >=30% decrease under baseline of the sum of diameters of all target measurable lesions. PD: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm for target disease or unequivocal progression of pre-existing lesions for non-target disease or any new lesion.

ORR was defined as the percentage of participants who achieved BOR of confirmed CR or PR according to RECIST v 1.1 as assessed by BICR. CR: complete disappearance of all target lesions (with the exception of nodal disease) and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: >=30% decrease under baseline of the sum of diameters of all target measurable lesions. PD: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm for target disease or unequivocal progression of pre-existing lesions for non-target disease or any new lesion.

DOR was defined as the time from the date of first radiographic evidence of response (CR or PR) to the earliest documented PD per RECIST v1.1 as assessed by BICR, or death due to any cause. CR: disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: >= 30% decrease under baseline of the sum of diameters of all target measurable lesions. PD: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm for target disease or unequivocal progression of pre-existing lesions for non-target disease or any new lesion. Analysis was performed using Kaplan Meier method.

DOR was defined as the time from the date of first radiographic evidence of response (CR or PR) to the earliest documented PD per RECIST v1.1 by derived investigator assessment, or death due to any cause. CR: disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: >= 30% decrease under baseline of the sum of diameters of all target measurable lesions. PD: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm for target disease or unequivocal progression of pre-existing lesions for non-target disease or any new lesion. Analysis was performed using Kaplan Meier method.

PFS was defined as the time from date of randomization to earliest documented PD per RECIST version 1.1 or death due to any cause as assessed by BICR. PD: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm for target disease or unequivocal progression of pre-existing lesions for non-target disease or any new lesion. Censoring details: no adequate baseline assessment, including no disease at baseline: participants were censored to randomization date; no PD, lost to follow-up, withdrawal of consent, PD or death >12 (or 16) weeks after the last adequate tumor assessment, and start of new anticancer treatment: participants were censored to last adequate tumor assessment documenting no PD prior to new anticancer therapy, or missed assessments. Analysis was performed using Kaplan Meier method.

OS was defined as the time from the date of first dose to death due to any cause. If a participant was not known to have died at the time of the cutoff for analysis, then OS was censored at the date of last contact. Analysis was performed using Kaplan Meier method.

PFS was defined as the time from date of randomization to earliest documented PD per RECIST version 1.1 or death due to any cause by derived investigator assessment. PD: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm for target disease or unequivocal progression of pre-existing lesions for non-target disease or any new lesion. Censoring details: no adequate baseline assessment, including no disease at baseline: participants were censored to randomization date; no PD, lost to follow-up, withdrawal of consent, PD or death >12 (or 16) weeks after the last adequate tumor assessment, and start of new anticancer treatment: participants were censored to last adequate tumor assessment documenting no PD prior to new anticancer therapy, or missed assessments. Analysis was performed using Kaplan Meier method.

TTR was defined as the time from the date of first dose to first radiographic evidence of response (CR or PR) per RECIST v1.1 as assessed by BICR. CR: disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: >= 30% decrease under baseline of the sum of diameters of all target measurable lesions.

TTR was defined as the time from the date of first dose to first radiographic evidence of response (CR or PR) per RECIST v1.1 by derived investigator assessment. CR: disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: >= 30% decrease under baseline of the sum of diameters of all target measurable lesions.

PFS2 was defined as the time from the date of randomization to the date of discontinuation of next-line treatment after first objective PD by investigator assessment, to second objective disease progression (PD2), or death from any cause, whichever occurred first. PD2: was progressive disease after the start of subsequent anticancer therapy based on investigator assessment. PFS2 was censored at start date of next-line anticancer treatment (NTX) if PD date > NTX start date and there was no death, at last contact date if withdrawal of consent date >= date of randomization or end of study or if participant lost to follow-up or if no prior conditions are met or PD and no NTX and there was no death.

An AE was any untoward medical occurrence in clinical study participant temporally associated with use of study intervention, whether/ not considered related to study intervention. SAE was defined as any untoward medical occurrence that, at any dose, met one or more of the following criteria - resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or other important medical event. AEs included both SAEs and all non-SAEs.

An AE was any untoward medical occurrence in clinical study participant temporally associated with use of study intervention, whether/ not considered related to study intervention. AEs were graded according to NCI-CTCAE v4.03 where grade 1= mild, grade 2= moderate, grade 3= severe, grade 4= life-threatening and grade 5= death related to AE. In this outcome measure, number of participants with grade 3 or 4 AEs and grade 5 AEs were reported.

The following hematology and coagulation parameters were assessed: activated partial thromboplastin time prolonged, anemia, hemoglobin increased, INR increased, leukocytosis, neutrophil count decreased, platelet count decreased, and white blood cell decreased. Laboratory abnormalities were graded according to NCI CTCAE v4.03 where grade 1= mild, grade 2= moderate, grade 3= severe, grade 4= life-threatening event due to AE, and grade 5= death. Only those hematology and coagulation parameters in which at least 1 participant in any of the reporting arm had any shift from grade <=2 at baseline to grade >=3 post-baseline are reported in this outcome measure.

The following chemistry parameters were assessed: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatinine increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, and lipase increased. Laboratory abnormalities were graded according to NCI CTCAE v4.03 where grade 1= mild, grade 2= moderate, grade 3= severe, grade 4= life-threatening and grade 5= death related to AE. Only those chemistry parameters in which at least 1 participant in any of the reporting arm had any shift from grade <=2 at baseline to grade >=3 post-baseline are reported in this outcome measure.

The criteria for vital signs included: Systolic blood pressure (mmHg): value <= 90 mmHg and decrease from baseline >= 20 mmHg, and value >= 160 mmHg and increase from baseline >= 20 mmHg. Diastolic blood pressure (mmHg): value <= 50 mmHg and decrease from baseline >= 15 mmHg, and value >= 100 mmHg and increase from baseline >= 15 mmHg. Pulse rate (bpm): value <= 50 bpm and decrease from baseline >= 15 bpm, and value >= 120 bpm and increase from baseline >= 15 bpm. Weight (kg): change >= 20 % decrease from baseline, and change >=10% increase from baseline. Temperature (degree Celsius): value <=36 degree Celsius, and value >=37.5 degree Celsius. Only those criteria in which at least 1 participant in any of the reporting arm had any vital signs data are reported in this outcome measure.

ECG criteria included: ECG mean heart rate (bpm): increase from baseline >25% and to a value >100 bpm; decrease from baseline >25% and to a value <50 bpm, PR interval not otherwise specified (msec): new >280 msec, QRS interval not otherwise specified (msec): new >120 msec, QTcF not otherwise specified: new >450 msec; new >480 msec; new >500 msec; increase from baseline >30 msec and increase from baseline >60 msec. Only those criteria in which at least 1 participant in any of the reporting arm had any ECG findings are reported in this outcome measure.

EORTC QLQ-C30 contains 30 items and is composed of both multi-item scales and single-item measures. These included five functional scales (physical, role, emotional, cognitive and social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/QoL scale. Global health status/QoL scale ranged from 0 to 100; the higher score represents better level of functioning. In this outcome measure, global health status/QoL scores are presented.

EQ-5D-5L is a standardized measure of health status. The EQ-5D-5L consisted of EQ-5D-5L descriptive system and the EQ VAS. For EQ VAS participant rated their overall health status from 0 (worst imaginable) to 100 (best imaginable), higher scores indicating a better health state.

PGIS is a single-item scale where participants rated the severity of colorectal cancer as follows: none, mild, moderate, severe and very severe.

The PGIC is a single-item scale where participants rated the overall change in colorectal cancer since participant started taking the study medication as follows: much better, a little better, no change, a little worse, and much worse.

Trough plasma concentration of encorafenib and its metabolite LHY746 was measured in this outcome measure.

Cmax was observed directly from data. LHY746 is a metabolite of Encorafenib.

The AUC was estimated from time 0 to 6 hours post dose. AUC6 was computed using the Linear/Log trapezoidal method. LHY746 is a metabolite of Encorafenib.

AUCtau was area under the concentration-time profile from time zero to time tau, the dosing interval. tau = 24 hrs for QD dosing of encorafenib. LHY746 is a metabolite of encorafenib.

Tmax: time (hours) to Cmax. LHY746 is a metabolite of Encorafenib.

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as dose administered divided by area under the concentration curve from time 0 extrapolated to infinite time (AUCinf). AUCinf was calculated as AUClast + (Clast*/kel), where Clast is the predicted plasma concentration at the last quantifiable time point from the log-linear regression analysis, and kel is the terminal phase rate constant calculated by a linear regression of the loglinear concentration-time curve.

MSI status was classified as follows; microsatellite instability-high (MSI-H): included participants with no negative test results and at least one positive test result, microsatellite stable (MSS): included participants with at least one negative test result and MSI-unknown: included participants with intermediate test results or not analyzed for MSI. The number of participants as per their MSI status (MSI-H, MSS, and MSI-unknown) have been reported in this outcome measure.

ctDNA status was classified as follows; detected: overall variant allele frequency (VAF) was greater than zero, not detected: overall VAF equalled zero, and not evaluable: overall VAF could not be calculated. The VAF was defined as percentage of deoxyribonucleic acid (DNA) reads at a specific position that show a genetic variant instead of the normal (reference) sequence. The number of participants as per their ctDNA status (detected, not detected and not evaluable) have been reported in this outcome measure.

BRAF V600 status from ctDNA was classified as follows; measurable: participants with detectable ctDNA had measurable BRAF V600 tumor biomarker alterations and not measurable: participants with detectable ctDNA did not have measurable BRAF V600 biomarker alterations or overall ctDNA was not detectable. The number of participants as per their BRAF V600 status from ctDNA (measurable and not measurable) have been reported in this outcome measure. In this outcome measure, data is presented for participants outside China and Mainland China participants.

PFS was defined as the time from date of randomization to earliest documented PD per RECIST version 1.1 or death due to any cause as assessed by BICR. PD: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm for target disease or unequivocal progression of pre-existing lesions for non-target disease or any new lesion. Censoring details: no adequate baseline assessment, including no disease at baseline: participants were censored to randomization date; no PD, lost to follow-up, withdrawal of consent, PD or death >12 (or 16) weeks after the last adequate tumor assessment, and start of new anticancer treatment: participants were censored to last adequate tumor assessment documenting no PD prior to new anticancer therapy, or missed assessments. Analysis was performed using Kaplan Meier method.

ORR was defined as the percentage of participants who achieved BOR of confirmed CR or PR according to RECIST v 1.1 by derived investigator assessment. CR: complete disappearance of all target lesions (with the exception of nodal disease) and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: >=30% decrease under baseline of the sum of diameters of all target measurable lesions. PD: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm for target disease or unequivocal progression of pre-existing lesions for non-target disease or any new lesion.

DOR was defined as the time from the date of first radiographic evidence of response (CR or PR) to the earliest documented PD per RECIST v1.1 as assessed by BICR, or death due to any cause. CR: disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: >= 30% decrease under baseline of the sum of diameters of all target measurable lesions. PD: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm for target disease or unequivocal progression of pre-existing lesions for non-target disease or any new lesion. Analysis was performed using Kaplan Meier method.

DOR was defined as the time from the date of first radiographic evidence of response (CR or PR) to the earliest documented PD per RECIST v1.1 by derived investigator assessment, or death due to any cause. CR: disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: >= 30% decrease under baseline of the sum of diameters of all target measurable lesions. PD: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm for target disease or unequivocal progression of pre-existing lesions for non-target disease or any new lesion. Analysis was performed using Kaplan Meier method.

PFS was defined as the time from date of randomization to earliest documented PD per RECIST version 1.1 or death due to any cause by derived investigator assessment. PD: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm for target disease or unequivocal progression of pre-existing lesions for non-target disease or any new lesion. Censoring details: no adequate baseline assessment, including no disease at baseline: participants were censored to randomization date; no PD, lost to follow-up, withdrawal of consent, PD or death >12 (or 16) weeks after the last adequate tumor assessment, and start of new anticancer treatment: participants were censored to last adequate tumor assessment documenting no PD prior to new anticancer therapy, or missed assessments. Analysis was performed using Kaplan Meier method.

OS was defined as the time from the date of first dose to death due to any cause. If a participant was not known to have died at the time of the cutoff for analysis, then OS was censored at the date of last contact. Analysis was performed using Kaplan Meier method.

TTR was defined as the time from the date of first dose to first radiographic evidence of response (CR or PR) per RECIST v1.1 as assessed by BICR. CR: disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: >= 30% decrease under baseline of the sum of diameters of all target measurable lesions.

TTR was defined as the time from the date of first dose to first radiographic evidence of response (CR or PR) per RECIST v1.1 by derived investigator assessment. CR: disappearance of all target lesions and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: >= 30% decrease under baseline of the sum of diameters of all target measurable lesions.

An AE was any untoward medical occurrence in clinical study participant temporally associated with use of study intervention, whether/ not considered related to study intervention. SAE was defined as any untoward medical occurrence that, at any dose, met one or more of the following criteria - resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or other important medical event. AEs included both SAEs and all non-SAEs.

An AE was any untoward medical occurrence in clinical study participant temporally associated with use of study intervention, whether/ not considered related to study intervention. AEs were graded according to NCI-CTCAE v4.03 where grade 1= mild, grade 2= moderate, grade 3= severe, grade 4= life-threatening and grade 5= death related to AE. In this outcome measure, number of participants with grade 3 or 4 AEs and grade 5 AEs were reported.

The following hematology and coagulation parameters were assessed: activated partial thromboplastin time prolonged, anemia, hemoglobin increased, INR increased, leukocytosis, neutrophil count decreased, platelet count decreased, and white blood cell decreased. Laboratory abnormalities were graded according to NCI CTCAE v4.03 where grade 1= mild, grade 2= moderate, grade 3= severe, grade 4= life-threatening event due to AE, and grade 5= death. Only those hematology and coagulation parameters in which at least 1 participant in any of the reporting arm had any shift from grade <=2 at baseline to grade >=3 post-baseline are reported in this outcome measure.

The following chemistry parameters were assessed: alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatinine increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, and lipase increased. Laboratory abnormalities were graded according to NCI CTCAE v4.03 where grade 1= mild, grade 2= moderate, grade 3= severe, grade 4= life-threatening and grade 5= death related to AE. Only those chemistry parameters in which at least 1 participant in any of the reporting arm had any shift from grade <=2 at baseline to grade >=3 post-baseline are reported in this outcome measure.

The criteria for vital signs included: Systolic blood pressure (mmHg): value <= 90 mmHg and decrease from baseline >= 20 mmHg, and value >= 160 mmHg and increase from baseline >= 20 mmHg. Diastolic blood pressure (mmHg): value <= 50 mmHg and decrease from baseline >= 15 mmHg, and value >= 100 mmHg and increase from baseline >= 15 mmHg. Pulse rate (bpm): value <= 50 bpm and decrease from baseline >= 15 bpm, and value >= 120 bpm and increase from baseline >= 15 bpm. Weight (kg): change >= 20 % decrease from baseline, and change >=10% increase from baseline. Temperature (degree Celsius): value <=36 degree Celsius, and value >=37.5 degree Celsius. Only those criteria in which at least 1 participant in any of the reporting arm had any vital signs data are reported in this outcome measure.

ECG criteria included: ECG mean heart rate (bpm): increase from baseline >25% and to a value >100 bpm; decrease from baseline >25% and to a value <50 bpm, PR interval not otherwise specified (msec): new >280 msec, QRS interval not otherwise specified (msec): new >120 msec, QTcF not otherwise specified: new >450 msec; new >480 msec; new >500 msec; increase from baseline >30 msec and increase from baseline >60 msec. Only those criteria in which at least 1 participant in any of the reporting arm had any ECG findings are reported in this outcome measure.

EORTC QLQ-C30 contains 30 items and is composed of both multi-item scales and single-item measures. These included five functional scales (physical, role, emotional, cognitive and social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/QoL scale. Global health status/QoL scale ranged from 0 to 100; the higher score represents better level of functioning.

EQ-5D-5L is a standardized measure of health status. The EQ-5D-5L consisted of EQ-5D-5L descriptive system and the EQ VAS. For EQ VAS participant rated their overall health status from 0 (worst imaginable) to 100 (best imaginable), higher scores indicating a better health state.

PGIS is a single-item scale where participants rated the severity of colorectal cancer as follows: none, mild, moderate, severe and very severe.

The PGIC is a single-item scale where participants rated the overall change in colorectal cancer since participant started taking the study medication as follows: much better, a little better, no change, a little worse, and much worse.

Trough plasma concentration of encorafenib and its metabolite LHY746 was measured in this outcome measure.

MSI status was classified as follows; MSI-H: included participants with no negative test results and at least one positive test result, MSS: included participants with at least one negative test result and MSI-unknown: included participants with intermediate test results or not analyzed for MSI. The number of participants as per their MSI status (MSI-H, MSS, and MSI-unknown) have been reported in this outcome measure.

ctDNA status was classified as follows; detected: overall variant allele frequency (VAF) was greater than zero, not detected: overall VAF equalled zero, and not evaluable: overall VAF could not be calculated. The VAF was defined as percentage of deoxyribonucleic acid (DNA) reads at a specific position that show a genetic variant instead of the normal (reference) sequence. The number of participants as per their ctDNA status (detected, not detected and not evaluable) have been reported in this outcome measure.

BRAF V600 status from ctDNA was classified as follows; measurable: participants with detectable ctDNA had measurable BRAF V600 tumor biomarker alterations and not measurable: participants with detectable ctDNA did not have measurable BRAF V600 biomarker alterations or overall ctDNA was not detectable. The number of participants as per their BRAF V600 status from ctDNA (measurable and not measurable) have been reported in this outcome measure.

Participants received encorafenib 300 mg QD orally and cetuximab 500 mg/m^2 IV infusion for 120 minutes Q2W along with fluorouracil 400 mg/m^2 IV bolus then 2400 mg/m^2 continuous IV infusion over 46-48 hours Q2W; leucovorin 400 mg/m^2 IV infusion for 120 minutes Q2W and oxaliplatin 85 mg/m^2 IV infusion for 120 minutes Q2W. Participants received treatment in 28-day cycles.

Participants received encorafenib 300 mg QD orally and cetuximab 500 mg/m^2 IV infusion for 120 minutes Q2W. Participants received treatment in 28-day cycles.

Participants received encorafenib 300 mg QD orally and cetuximab 500 mg/m^2 IV infusion for 120 minutes Q2W along with fluorouracil 400 mg/m^2 IV bolus then 2400 mg/m^2 continuous IV infusion over 46-48 hours Q2W; leucovorin 400 mg/m^2 IV infusion for 120 minutes Q2W and oxaliplatin 85 mg/m^2 IV infusion for 120 minutes Q2W. Participants received treatment in 28-day cycles.

Participants received standard of care (SOC) chemotherapy per Investigator's choice: mFOLFOX6 with or without bevacizumab or FOLFOXIRI with or without bevacizumab or CAPOX with or without bevacizumab. Bevacizumab was optional and it was given per prescribing instructions of treating physician. mFOLFOX6 (28-day Cycle): fluorouracil 400 mg/m^2 IV bolus then 2400 mg/m^2 continuous IV infusion over 46-48 hours Q2W; leucovorin 400 mg/m^2 IV infusion for 120 minutes Q2W and oxaliplatin 85 mg/m^2 IV infusion for 120 minutes Q2W; FOLFOXIRI (28-day Cycle): fluorouracil 2400 or 3200 mg/m^2 continuous IV infusion over 46-48 hours Q2W (per local standard of care); leucovorin 400 mg/m^2 IV infusion for 120 minutes Q2W and oxaliplatin 85 mg/m^2 IV infusion for 120 minutes Q2W and irinotecan 165 mg/m^2 as IV infusion for 90 minutes Q2W; CAPOX (21-day Cycle): capecitabine 1000 mg/m^2 oral tablet twice daily on Days 1-14 and oxaliplatin 130 mg/m^2 IV infusion for 120 minutes Q3W.

Participants received encorafenib 300 mg QD orally and cetuximab 500 mg/m^2 IV infusion for 120 minutes Q2W along with fluorouracil 400 mg/m^2 IV bolus then 2400 mg/m^2 continuous IV infusion over 46-48 hours Q2W; leucovorin 400 mg/m^2 IV infusion for 120 minutes Q2W and irinotecan 180 mg/m^2 as IV infusion for 90 minutes Q2W. Participants received treatment in 28-day cycles.

Participants received fluorouracil 400 mg/m^2 IV bolus then 2400 mg/m^2 continuous IV infusion over 46-48 hours Q2W; leucovorin 400 mg/m^2 IV infusion for 120 minutes Q2W and irinotecan 180 mg/m^2 as IV infusion for 90 minutes Q2W with or without bevacizumab. Bevacizumab was optional and it was given per prescribing instructions of treating physician. Participants received treatment in 28-day cycles.