A Study of Encorafenib Plus Cetuximab With or Without Chemotherapy in People With Previously Untreated Metastatic Colorectal Cancer

The purpose of the study is to evaluate whether encorafenib plus cetuximab (EC), alone or in combination with chemotherapy, can improve clinical outcomes relative to current standard of-care chemotherapy in participants with previously untreated BRAF V600E-mutant mCRC. Since encorafenib has not previously been combined with chemotherapy, the tolerability and PK of EC in combination with mFOLFOX6 and in combination with FOLFIRI will be evaluated in separate cohorts in the safety lead-in portion of the trial in order to identify which chemotherapy combination is to be used in the Phase 3 portion of the study.

• Encorafenib (Drug), also known as Braftovi, PF-07263896, LGX818, ONO-7702: 75 mg capsules
• Cetuximab (Drug), also known as Erbitux: Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vial
• Oxaliplatin (Drug), also known as Eloxatin: Powder for solution for intravenous use 50 mg/vial, 100 mg/vial, or 200 mg/vial
• Irinotecan (Drug), also known as Campostar: Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vial
• Leucovorin (Drug), also known as Wellcovorin, Fusilev, Khapzory: Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial
• 5-FU (Drug), also known as Fluorouracil: Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial
• Capecitabine (Drug), also known as Xeloda: 150 mg or 500 mg Tablet
• Bevacizumab (Drug), also known as Zirabev: Optional Injection for intravenous use 100 mg/vial or 400 mg/vial

Primary outcomes

• SLI: Number of Participants With Dose Limiting Toxicity (DLTs) [Cycle 1 (28 days)]: DLT: Any AE/lab value during first 28 days (D) of treatment that met at least 1 criteria: AE/lab value unrelated to underlying disease,PD,intercurrent illness,concomitant medications resulting in inability to tolerate atleast 75% of planned dose intensity of study drug,fatigue grade (G)3>14 consecutive D, interstitial lung disease G>=2,rash,hand foot skin reaction G3>14 consecutive D or G4,diarrhea G3 >=48 hours or G4,nausea/vomiting G3>=48 hours or G4,mucositis G>=3,total bilirubin G>=3, aspartate aminotransferase/alanine aminotransferase G>=3 in conjunction with total bilirubin G>=2 or G3 >7 consecutive D or G4,Serum creatinine G>=3,absolute neutrophil count G4 >7 consecutive D, >=G3 febrile neutropenia,G3 platelet count decreased with signs of bleeding,platelet count G4,ECG QTcF prolonged >=G3,G>=3 uveitis >21 consecutive D,G4 confirmed by ophthalmic examination,paresthesia/dysesthesias G>=3,other G>=3 hematologic/nonhematologic toxicity except lymphocyte count decreased G>=3.
• Phase 3: Progression Free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR) for Arm B vs Arm C - FAS [From date of randomization to earliest documentation of PD by BICR or death or censoring date, whichever occurred first (maximum up to 37.25 months)]: PFS was defined as the time from date of randomization to earliest documented disease progression (PD) per Response Evaluation Criteria in Solid Tumors (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 millimeter (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.
• Phase 3: Objective Response Rate (ORR) as Assessed by BICR for Arm B vs Arm C - FAS ORR Subset [From date of randomization to until documented PD by BICR, or start of subsequent anticancer therapy or death, whichever occurred first (maximum up to 24.71 months)]: ORR was defined as the percentage of participants who achieved best overall response (BOR) of confirmed complete response (CR) or partial response (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.
• Cohort 3: ORR as Assessed by BICR for Arm D vs Arm E - FAS [From date of randomization until documented PD by BICR, or start of subsequent anticancer therapy or death, whichever occurred first (maximum up to 14.1 months)]: 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.

Secondary outcomes

• SLI: Number of Participants With Adverse Events (AEs) [Through end of the study]: 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. An Serious adverse event (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.
• SLI: Number of Participants With Grade 3 or 4 AEs and Grade 5 AEs [Through end of the study]: 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.
• SLI: Number of Participants With Shift From Grade <=2 at Baseline to Grade >=3 Post-Baseline in Hematology and Coagulation Parameters [Through end of the study]: 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.
• SLI: Number of Participants With Shift From Grade <=2 at Baseline to Grade >=3 Post-Baseline in Chemistry Parameters [Through end of the study]: 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.
• SLI: Number of Participants According to Categorization of Vital Signs Data [Through end of the study]: 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.
• SLI: Number of Participants According to Categorization of Electrocardiogram (ECGs) Findings [Through end of the study]: 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.
• SLI: Number of Participants With Dose Modification of Any Study Intervention Due to AEs [Through end of the study]: 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.
• SLI: Number of Participants With Dose Discontinuation of Any Study Intervention Due to AEs [Through end of the study]: 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.
• SLI: ORR as Assessed by Investigator According to Line of Therapy - FAS [From date of randomization until documented PD, or start of subsequent anticancer therapy or death, whichever occurred first (maximum up to 33.9 months)]: 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.
• SLI: Duration of Response (DOR) as Assessed by Investigator According to Line of Therapy - FAS [From date of first radiographic evidence of response (CR or PR) to earliest documented PD or death due to any cause whichever occurred first (maximum up to 33.9 months)]: 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.
• SLI: PFS as Assessed by Investigator According to Line of Therapy - FAS [From date of randomization to earliest documentation of PD or death or censoring date, whichever occurred first (maximum up to 33.9 months)]: 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.
• SLI: Time to Response (TTR) as Assessed by Investigator According to Line of Therapy - FAS [From date of first dose to first radiographic evidence of response (CR or PR) (maximum up to 33.9 months [147.3 weeks])]: 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.
• SLI: Overall Survival (OS) According to Line of Therapy - FAS [From date of first dose to death due to any cause or censoring date, whichever occurred first (maximum up to 33.9 months)]: 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.
• SLI: Maximum Plasma Concentration (Cmax) of Encorafenib and Its Metabolite LHY746 [Cohort 1: Pre-dose (0 hour [hr]), 0.75, 1.5, 2.5, 3.5, 5.5, 7.5, and 48 hrs post-dose on Day 15 of Cycle 1; Cohort 2: Pre-dose (0 hr), 1, 2, 3, 4, 6, 8, and 48 hrs post-dose on Days 1 and 15 of Cycle 1]: Cmax was observed directly from data. LHY746 is a metabolite of Encorafenib.
• SLI: Area Under the Concentration Time Profile From Time Zero to 6 Hours (AUC6) for Encorafenib and Its Metabolite LHY746 [Cohort 1: Pre-dose (0 hr), 0.75, 1.5, 2.5, 3.5, 5.5, and 6 hrs post-dose on Day 15 of Cycle 1; Cohort 2: Predose (0 hr), 1, 2, 3, 4, and 6 hrs post-dose on Days 1 and 15 of Cycle 1]: 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.
• SLI: Area Under the Concentration-time Profile From Time Zero to the Time Tau (AUCtau) of Encorafenib and Its Metabolite LHY746 [Cohort 1: Pre-dose (0 hr), 0.75, 1.5, 2.5, 3.5, 5.5, 7.5, and 48 hrs post-dose on Day 15 of Cycle 1; Cohort 2: Pre-dose (0 hr), 1, 2, 3, 4, 6, 8, and 48 hrs post-dose on Days 1 and 15 of Cycle 1]: 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.
• SLI: Time to Maximum Plasma Concentration (Tmax) of Encorafenib and Its Metabolite LHY746 [Cohort 1: Pre-dose (0 hr), 0.75, 1.5, 2.5, 3.5, 5.5, 7.5, and 48 hrs post-dose on Day 15 of Cycle 1; Cohort 2: Pre-dose (0 hr), 1, 2, 3, 4, 6, 8, and 48 hrs post-dose on Days 1 and 15 of Cycle 1]: Tmax: time (hours) to Cmax. LHY746 is a metabolite of Encorafenib.
• SLI: Apparent Total Clearance (CL/F) of Encorafenib [Cohort 1: Pre-dose (0 hr), 0.75, 1.5, 2.5, 3.5, 5.5, 7.5, and 48 hrs post-dose on Day 15 of Cycle 1; Cohort 2: Pre-dose (0 hr), 1, 2, 3, 4, 6, 8, and 48 hrs post-dose on Days 1 and 15 of Cycle 1]: 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.
• SLI, Cohort 1: Cmax of Irinotecan and Its Metabolite SN-38 [Cohort 1: Pre-dose (0 hr), 0.75, 1.5, 2.5, 3.5, 5.5, 7.5, and 48 hrs post-dose on Days 1 and 15 of Cycle 1]: Cmax was observed directly from data. SN-38 is a metabolite of Irinotecan.
• SLI, Cohort 1: AUClast of Irinotecan and Its Metabolite SN-38 [Cohort 1: Pre-dose (0 hr), 0.75, 1.5, 2.5, 3.5, 5.5, 7.5, and 48 hrs post-dose on Days 1 and 15 of Cycle 1]: 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.
• SLI, Cohort 1: Apparent Terminal Elimination Half-Life (t1/2) of Irinotecan and Its Metabolite SN-38 [Cohort 1: Pre-dose (0 hr), 0.75, 1.5, 2.5, 3.5, 5.5, 7.5, and 48 hrs post-dose on Days 1 and 15 of Cycle 1]: 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.
• SLI, Cohort 1: CL/F of Irinotecan [Cohort 1: Pre-dose (0 hr), 0.75, 1.5, 2.5, 3.5, 5.5, 7.5, and 48 hrs post-dose on Days 1 and 15 of Cycle 1]: 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.
• SLI, Cohort 2: Cmax of Oxaliplatin [Cohort 2: Pre-dose (0 hr), 1, 2, 3, 4, 6, 8, and 48 hrs post-dose on Days 1 and 15 of Cycle 1]: Cmax was observed directly from data. Oxaliplatin was evaluated as total platinum in plasma and platinum in plasma ultrafiltrate.
• SLI, Cohort 2: AUClast of Oxaliplatin [Cohort 2: Pre-dose (0 hr), 1, 2, 3, 4, 6, 8, and 48 hrs post-dose on Days 1 and 15 of Cycle 1]: 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.
• SLI, Cohort 2: CL/F of Oxaliplatin [Cohort 2: Pre-dose (0 hr), 1, 2, 3, 4, 6, 8, and 48 hrs post-dose on Days 1 and 15 of Cycle 1]: 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.
• SLI, Cohort 1: Ratio of AUCinf on Cycle 1 Day 15 as Compared to Cycle 1 Day 1 for Irinotecan and Its Metabolite SN-38 [Cohort 1: Pre-dose (0 hr), 0.75, 1.5, 2.5, 3.5, 5.5, 7.5, and 48 hrs post-dose on Days 1 and 15 of Cycle 1]: 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".
• SLI, Cohort 1: Ratio of AUClast on Cycle 1 Day 15 as Compared to Cycle 1 Day 1 for Irinotecan and Its Metabolite SN-38 [Cohort 1: Pre-dose (0 hr), 0.75, 1.5, 2.5, 3.5, 5.5, 7.5, and 48 hrs post-dose on Days 1 and 15 of Cycle 1]: 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".
• SLI, Cohort 1: Ratio of Cmax on Cycle 1 Day 15 as Compared to Cycle 1 Day 1 for Irinotecan and Its Metabolite SN-38 [Cohort 1: Pre-dose (0 hr), 0.75, 1.5, 2.5, 3.5, 5.5, 7.5, and 48 hrs post-dose on Days 1 and 15 of Cycle 1]: 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".
• SLI, Cohort 2: Ratio of AUClast on Cycle 1 Day 15 as Compared to Cycle 1 Day 1 for Oxaliplatin [Cohort 2: Pre-dose (0 hr), 1, 2, 3, 4, 6, 8, and 48 hrs post-dose on Days 1 and 15 of Cycle 1]: 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".
• SLI, Cohort 2: Ratio of Cmax on Cycle 1 Day 15 as Compared to Cycle 1 Day 1 for Oxaliplatin [Cohort 2: Pre-dose (0 hr), 1, 2, 3, 4, 6, 8, and 48 hrs post-dose on Days 1 and 15 of Cycle 1]: 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".
• Phase 3: OS for Arm B vs Arm C - FAS [From date of first dose to death due to any cause or censoring date, whichever occurred first (maximum up to 37.25 months)]: 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.
• Phase 3: ORR by Derived Investigator Assessment for Arm B vs Arm C - FAS ORR Subset [From date of randomization until documented PD, or start of subsequent anticancer therapy, or death, whichever occurred first (maximum up to 24.71 months)]: 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.
• Phase 3: ORR as Assessed by BICR - FAS [From date of randomization until documented PD by BICR, or start of subsequent anticancer therapy, or death, whichever occurred first (maximum up to 37.25 months)]: 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.
• Phase 3: DOR as Assessed by BICR for Arm B Versus Arm C - FAS ORR Subset [From date of first radiographic evidence of response (CR or PR) to earliest documented PD or death due to any cause, whichever occurred first (maximum up to 24.71 months)]: 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.
• Phase 3: DOR by Derived Investigator Assessment for Arm B Versus Arm C - FAS ORR Subset [From date of first radiographic evidence of response (CR or PR) to earliest documented PD or death due to any cause, whichever occurred first (maximum up to 24.71 months)]: 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.
• Phase 3: PFS as Assessed by BICR - FAS [From date of randomization to earliest documentation of PD or death or censoring date, whichever occurred first (maximum up to 37.25 months)]: 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.
• Phase 3: OS - FAS [From date of first dose to death due to any cause or censoring date, whichever occurred first (maximum up to 37.25 months)]: 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.
• Phase 3: PFS by Derived Investigator Assessment - FAS [From date of first dose to death due to any cause or censoring date, whichever occurred first (maximum up to 37.25 months)]: 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.
• Phase 3: TTR as Assessed by BICR for Arm B vs Arm C - FAS ORR Subset [From date of first dose to CR or PR (maximum up to 24.71 months [107.37 weeks])]: 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.
• Phase 3: TTR by Derived Investigator Assessment for Arm B vs Arm C - FAS ORR Subset [From date of first dose to CR or PR (maximum up to 24.71 months [107.37 weeks])]: 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.
• Phase 3: Progression After Next Line of Treatment (PFS2) - FAS [From date of randomization to date of discontinuation of next-line treatment after PD or PD2 or death or censoring date, whichever occurred first (maximum up to 37.25 months)]: 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.
• Phase 3: Number of Participants With AEs [Through end of the study]: 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.
• Phase 3: Number of Participants With Grade 3 or 4 AEs and Grade 5 AEs [Through end of the study]: 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.
• Phase 3: Number of Participants With Shift From Grade <=2 at Baseline to Grade >=3 Post-Baseline in Hematology and Coagulation Parameters [Through end of the study]: 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.
• Phase 3: Number of Participants With Shift From Grade <=2 at Baseline to Grade >=3 Post-Baseline in Chemistry Parameters [Through end of the study]: 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.
• Phase 3: Number of Participants According to Categorization of Vital Signs Data [Through end of the study]: 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.
• Phase 3: Number of Participants According to Categorization of ECGs Findings [Through end of the study]: 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.
• Phase 3: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer Patients - 30 Item Core Questionnaire (EORTC QLQC30) Global Health Status/Quality of Life Scores (QoL) at Baseline and Week 72 [Baseline and Week 72]: 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.
• Phase 3: EuroQol Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L) Visual Analogue Score (VAS) at Baseline and Week 72 [Baseline and Week 72]: 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.
• Phase 3: Number of Participants According to Response to Patient Global Impression of Severity (PGIS) Assessment at Baseline and at Week 30 [Baseline and Week 30]: PGIS is a single-item scale where participants rated the severity of colorectal cancer as follows: none, mild, moderate, severe and very severe.
• Phase 3: Number of Participants According to Response to Patient Global Impression of Change (PGIC) Assessment at Week 30 [Week 30]: 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.
• Phase 3: Trough Plasma Concentration of Encorafenib and Its Metabolite LHY746 [Predose on Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1 and Cycle 6 Day 1]: Trough plasma concentration of encorafenib and its metabolite LHY746 was measured in this outcome measure.
• Phase 3: Cmax of Encorafenib and Its Metabolite LHY746 in Mainland China Participants [Pre-dose (0 hr), 0.5, 1, 2, 3, 4, 5, 6, 8 and 24 hrs post-dose on Days 1 and 15 of Cycle 1]: Cmax was observed directly from data. LHY746 is a metabolite of Encorafenib.
• Phase 3: AUC6 of Encorafenib and Its Metabolite LHY746 in Mainland China Participants [Pre-dose (0 hr), 0.5, 1, 2, 3, 4, 5 and 6 hrs post-dose on Days 1 and 15 of Cycle 1]: 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.
• Phase 3: AUCtau of Encorafenib and Its Metabolite LHY746 in Mainland China Participants [Pre-dose (0 hr), 0.5, 1, 2, 3, 4, 5, 6, 8 and 24 hrs post-dose on Days 1 and 15 of Cycle 1]: 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.
• Phase 3: Tmax of Encorafenib and Its Metabolite LHY746 in Mainland China Participants [Pre-dose (0 hr), 0.5, 1, 2, 3, 4, 5, 6, 8 and 24 hrs post-dose on Days 1 and 15 of Cycle 1]: Tmax: time (hours) to Cmax. LHY746 is a metabolite of Encorafenib.
• Phase 3: CL/F of Encorafenib in Mainland China Participants [Pre-dose (0 hr), 0.5, 1, 2, 3, 4, 5, 6, 8 and 24 hrs post-dose on Days 1 and 15 of Cycle 1]: 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.
• Phase 3: Number of Participants Classified According to Microsatellite Instability (MSI) Status as Determined by Retrospective Central Testing of Baseline Tumor Tissue [Baseline]: 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.
• Phase 3: Number of Participants According to Circulating Tumor Deoxyribonucleic Acid (ctDNA) Status [Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 15, Cycle 7 Day 1 and End of Treatment (anytime till maximum of 37.25 months)]: 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.
• Phase 3: Number of Participants According to B-Raf Serine/Threonine-Protein Kinase (BRAF) Valine 600 (V600) Status From ctDNA [Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 15, Cycle 7 Day 1 and End of Treatment (anytime till maximum of 37.25 months)]: 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.
• Cohort 3: PFS as Assessed by BICR - FAS [From date of randomization to earliest documentation of PD by BICR or death or censoring date, whichever occurred first]: 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.
• Cohort 3: ORR by Derived Investigator Assessment - FAS [From date of randomization until documented PD, or start of subsequent anticancer therapy, or death, whichever occurred first (maximum up to 14.1 months)]: 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.
• Cohort 3: DOR as Assessed by BICR - FAS [From date of first radiographic evidence of response (CR or PR) to earliest documented PD or death due to any cause, whichever occurred first (maximum up to 14.1 months)]: 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.
• Cohort 3: DOR by Derived Investigator Assessment - FAS [From date of first radiographic evidence of response (CR or PR) to earliest documented PD or death due to any cause, whichever occurred first (maximum up to 14.1 months)]: 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.
• Cohort 3: PFS by Derived Investigator Assessment - FAS [From date of randomization to earliest documentation of PD or death or censoring date, whichever occurred first]: 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.
• Cohort 3: OS - FAS [From date of first dose to death due to any cause or censoring date, whichever occurred first]: 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.
• Cohort 3: TTR as Assessed by BICR - FAS [From date of first dose to CR or PR (maximum up to 14.1 months [61.29 weeks])]: 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.
• Cohort 3: TTR by Derived Investigator Assessment - FAS [From date of first dose to CR or PR (maximum up to 14.1 months [61.29 weeks])]: 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.
• Cohort 3: Number of Participants With AEs [Through end of the study]: 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.
• Cohort 3: Number of Participants With Grade 3 or 4 AEs and Grade 5 AEs [Through end of the study]: 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.
• Cohort 3: Number of Participants With Shift From Grade <=2 at Baseline to Grade >=3 Post-Baseline in Hematology and Coagulation Parameters [Through end of the study]: 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.
• Cohort 3: Number of Participants With Shift From Grade <=2 at Baseline to Grade >=3 Post-Baseline in Chemistry Parameters [Through end of the study]: 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.
• Cohort 3: Number of Participants According to Categorization of Vital Signs Data [Through end of the study]: 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.
• Cohort 3: Number of Participants According to Categorization of ECGs Findings [Through end of the study]: 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.
• Cohort 3: EORTC QLQC30 Global Health Status/QoL [Through end of the study]: 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.
• Cohort 3: EQ-5D-5L VAS [Through end of the study]: 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.
• Cohort 3: Number of Participants According to Response to PGIS Assessment [Through end of the study]: PGIS is a single-item scale where participants rated the severity of colorectal cancer as follows: none, mild, moderate, severe and very severe.
• Cohort 3: Number of Participants According to Response to PGIC Assessment [Through end of the study]: 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.
• Cohort 3: Trough Plasma Concentration of Encorafenib and Its Metabolite LHY746 [Predose on Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1 and Cycle 6 Day 1]: Trough plasma concentration of encorafenib and its metabolite LHY746 was measured in this outcome measure.
• Cohort 3: Number of Participants Classified According to MSI Status as Determined by Retrospective Central Testing [Through end of the study]: 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.
• Cohort 3: Number of Participants According to ctDNA Status [Through end of the study]: 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.
• Cohort 3: Number of Participants According to BRAF V600 Status From ctDNA [Through end of the study]: 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.

Sex: All, ages: 16 Years to any

Inclusion Criteria:

* Safety Lead-In = Male/female ≥ 18 years old
* Phase 3 and Cohort 3: Male/female ≥ 16 years old (where permitted locally)
* Histologically or cytologically confirmed Stage IV CRC that contains BRAF V600E mutation
* Prior systemic treatment in metastatic setting: 0-1 regimens for Safety Lead In; none for Phase 3 and Cohort 3. (Note: Prior adjuvant or neoadjuvant therapy considered metastatic treatment if relapse/metastasis < 6 month from end of adj/neoadjuvant treatment )
* Measurable disease (Phase 3 and Cohort 3)/ Measurable or evaluable disease (Safety Lead-in)
* ECOG PS 0-1
* Adequate organ function

Exclusion Criteria:

* Tumors that are locally confirmed or unknown MSI-H or dMMR unless participant is ineligible to receive immune checkpoint inhibitors due to a pre-existing medical condition
* Active bacterial or viral infections in 2 weeks prior to starting dosing
* Symptomatic brain metastases

172 more sites not listed.

• Results publication: Kopetz S, Tabernero J, Elez E. BREAKWATER Phase III: results for encorafenib and cetuximab plus mFOLFOX6 in first-line BRAF V600E-mutant metastatic colorectal cancer. Future Oncol. 2025 Dec;21(28):3585-3588. doi: 10.1080/14796694.2025.2579882. Epub 2025 Nov 13. PMID 41230651
• Results publication: Elez E, Yoshino T, Shen L, Lonardi S, Van Cutsem E, Eng C, Kim TW, Wasan HS, Desai J, Ciardiello F, Yaeger R, Maughan TS, Morris VK, Wu C, Usari T, Laliberte R, Dychter SS, Zhang X, Tabernero J, Kopetz S; BREAKWATER Trial Investigators. Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer. N Engl J Med. 2025 Jun 26;392(24):2425-2437. doi: 10.1056/NEJMoa2501912. Epub 2025 May 30. PMID 40444708
• Results publication: Kopetz S, Yoshino T, Van Cutsem E, Eng C, Kim TW, Wasan HS, Desai J, Ciardiello F, Yaeger R, Maughan TS, Beyzarov E, Zhang X, Ferrier G, Zhang X, Tabernero J. Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial. Nat Med. 2025 Mar;31(3):901-908. doi: 10.1038/s41591-024-03443-3. Epub 2025 Jan 25. PMID 39863775
• Results publication: Van Cutsem E, Taieb J, Yaeger R, Yoshino T, Grothey A, Maiello E, Elez E, Dekervel J, Ross P, Ruiz-Casado A, Graham J, Kato T, Ruffinelli JC, Andre T, Carriere Roussel E, Klauck I, Groc M, Vedovato JC, Tabernero J. ANCHOR CRC: Results From a Single-Arm, Phase II Study of Encorafenib Plus Binimetinib and Cetuximab in Previously Untreated BRAFV600E-Mutant Metastatic Colorectal Cancer. J Clin Oncol. 2023 May 10;41(14):2628-2637. doi: 10.1200/JCO.22.01693. Epub 2023 Feb 10. PMID 36763936

• Study Protocol (PDF, 2024-05-31)
• Statistical Analysis Plan (PDF, 2024-05-07)

• Pfizer CT.gov Call Center, Study director, Pfizer

NIH grants: 2023