A Phase 3 interventional study of Encorafenib and Cetuximab in Neoplasms, sponsored by Pfizer. Active, not recruiting at 274 sites in 29 countries. Open to participants aged 16 Years and older. Per ClinicalTrials.gov, last updated 2026-11-05.
Sponsored by Pfizer · Phase 3, Interventional, and Treatment
The purpose of this study is to evaluate two study medicines (encorafenib plus cetuximab) taken alone or together with standard chemotherapy for the potential treatment of colorectal cancer that:
Participants in this study will receive one of the following study treatments:
This study is currently enrolling participants who will receive either encorafenib plus cetuximab with chemotherapy or chemotherapy alone.
The study team will monitor how each participant responds to the study treatment for up to about 3 years.
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.
6,541 studies on the registry are indexed under Colorectal Neoplasms; 1,667 are open to participants now.
This study's enrollment of 841 is above the median of 76 across 4,800 interventional studies indexed under Colorectal Neoplasms.
Browse Colorectal Neoplasms studies →Pfizer is the lead sponsor of 3,334 studies on the registry; 149 are open to participants now.
Of its 601 completed or terminated interventional studies of FDA-regulated products, 391 (65%) have results posted.
Compared within Colorectal Neoplasms, this study's primary condition as ClinicalTrials.gg classifies it; the registry's first condition term is Neoplasms. The counts are of registry records indexed under each term, refreshed daily. How we classify →
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
The diagnosis was confirmed by looking at a sample under a microscope: tissue from a biopsy or surgery (histology), or cells from a fluid or needle sample (cytology).
Your pathology report is the document that shows this.
Cancer that has spread from where it began to other parts of the body. “Metastatic” cancer is cancer that has spread this way.
Neoadjuvant treatment is given before the main treatment (usually surgery), often to shrink a tumour. Adjuvant treatment is given after it, to lower the chance of the cancer coming back.
The amount of disease can be tracked with a defined measurement, so the study can see whether it shrinks or grows. It might be a tumour measured on a scan or, in some blood cancers such as myeloma, a marker measured in blood or urine.
The criteria or the study team say which measurement counts — having no tumour visible on a scan does not by itself rule you out.
A scale of how much an illness limits everyday activity. For people being assessed to join a study, scores run from 0 (fully active) to 4; lower is more active.
Studies most often ask for 0–1 or 0–2. Your doctor gives the score; the WHO scale uses the same steps. The full scale also has 5, which records death.
PD-1, PD-L1 and CTLA-4 are proteins that act as brakes on the immune system. Checkpoint inhibitors, such as pembrolizumab or nivolumab, block them so the immune system can attack a cancer.
PD-L1 can also be measured in a tumour sample. Some scores count stained tumour cells only (TPS); others also count certain immune cells (CPS). The study names the score and the minimum it uses.
Cancer deposits in the brain from a cancer that started elsewhere in the body (CNS metastases include the spinal cord).
Studies differ: some leave out any brain metastases, some accept ones treated and stable for some weeks. Check what this study allows.
Histologically or cytologically confirmed
The diagnosis was confirmed by looking at a sample under a microscope: tissue from a biopsy or surgery (histology), or cells from a fluid or needle sample (cytology).
Your pathology report is the document that shows this.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Metastases
Cancer that has spread from where it began to other parts of the body. “Metastatic” cancer is cancer that has spread this way.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Adjuvant and neoadjuvant
Neoadjuvant treatment is given before the main treatment (usually surgery), often to shrink a tumour. Adjuvant treatment is given after it, to lower the chance of the cancer coming back.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Measurable disease
The amount of disease can be tracked with a defined measurement, so the study can see whether it shrinks or grows. It might be a tumour measured on a scan or, in some blood cancers such as myeloma, a marker measured in blood or urine.
The criteria or the study team say which measurement counts — having no tumour visible on a scan does not by itself rule you out.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ECOG performance status
A scale of how much an illness limits everyday activity. For people being assessed to join a study, scores run from 0 (fully active) to 4; lower is more active.
Studies most often ask for 0–1 or 0–2. Your doctor gives the score; the WHO scale uses the same steps. The full scale also has 5, which records death.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
PD-1, PD-L1 and checkpoint inhibitors
PD-1, PD-L1 and CTLA-4 are proteins that act as brakes on the immune system. Checkpoint inhibitors, such as pembrolizumab or nivolumab, block them so the immune system can attack a cancer.
PD-L1 can also be measured in a tumour sample. Some scores count stained tumour cells only (TPS); others also count certain immune cells (CPS). The study names the score and the minimum it uses.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Brain metastases
Cancer deposits in the brain from a cancer that started elsewhere in the body (CNS metastases include the spinal cord).
Studies differ: some leave out any brain metastases, some accept ones treated and stable for some weeks. Check what this study allows.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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
Drug: Encorafenib · Drug: Cetuximab · Drug: Irinotecan · Drug: Leucovorin · Drug: 5-FU
Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120 minute IV infusion) every two weeks Oxaliplatin 85 mg/m2 (120-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
Drug: Encorafenib · Drug: Cetuximab · Drug: Oxaliplatin · Drug: Leucovorin · Drug: 5-FU
Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120-minute IV infusion) every two weeks
Drug: Encorafenib · Drug: Cetuximab
Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120 minute IV infusion) every two weeks Oxaliplatin 85 mg/m2 (120-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
Drug: Encorafenib · Drug: Cetuximab · Drug: Oxaliplatin · Drug: Leucovorin · Drug: 5-FU
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)
Drug: Oxaliplatin · Drug: Irinotecan · Drug: Leucovorin · Drug: 5-FU · Drug: Capecitabine · Drug: Bevacizumab
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
Drug: Encorafenib · Drug: Cetuximab · Drug: Irinotecan · Drug: Leucovorin · Drug: 5-FU
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)
Drug: Irinotecan · Drug: Leucovorin · Drug: 5-FU · Drug: Bevacizumab
75 mg capsules
Also known as: Braftovi, PF-07263896, LGX818, ONO-7702
Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vial
Also known as: Erbitux
Powder for solution for intravenous use 50 mg/vial, 100 mg/vial, or 200 mg/vial
Also known as: Eloxatin
Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vial
Also known as: Campostar
Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial
Also known as: Wellcovorin, Fusilev, Khapzory
Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial
Also known as: Fluorouracil
150 mg or 500 mg Tablet
Also known as: Xeloda
Optional Injection for intravenous use 100 mg/vial or 400 mg/vial
Also known as: Zirabev
SLI: Number of Participants With Dose Limiting Toxicity (DLTs)
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.
Time frame: Cycle 1 (28 days)
Phase 3: Progression Free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR) for Arm B vs Arm C - FAS
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.
Time frame: 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)
Phase 3: Objective Response Rate (ORR) as Assessed by BICR for Arm B vs Arm C - FAS ORR Subset
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.
Time frame: 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)
Cohort 3: ORR as Assessed by BICR for Arm D vs Arm E - FAS
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.
Time frame: 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)
SLI: Number of Participants With Adverse Events (AEs)
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.
Time frame: Through end of the study
SLI: Number of Participants With Grade 3 or 4 AEs and Grade 5 AEs
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.
Time frame: Through end of the study
SLI: Number of Participants With Shift From Grade <=2 at Baseline to Grade >=3 Post-Baseline in Hematology and Coagulation Parameters
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.
Time frame: Through end of the study
SLI: Number of Participants With Shift From Grade <=2 at Baseline to Grade >=3 Post-Baseline in Chemistry Parameters
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.
Time frame: Through end of the study
SLI: Number of Participants According to Categorization of Vital Signs Data
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.
Time frame: Through end of the study
SLI: Number of Participants According to Categorization of Electrocardiogram (ECGs) Findings
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.
Time frame: Through end of the study
SLI: Number of Participants With Dose Modification of Any Study Intervention Due to AEs
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.
Time frame: Through end of the study
SLI: Number of Participants With Dose Discontinuation of Any Study Intervention Due to AEs
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.
Time frame: Through end of the study
SLI: ORR as Assessed by Investigator According to Line of Therapy - FAS
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.
Time frame: From date of randomization until documented PD, or start of subsequent anticancer therapy or death, whichever occurred first (maximum up to 33.9 months)
SLI: Duration of Response (DOR) as Assessed by Investigator According to Line of Therapy - FAS
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.
Time frame: 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)
SLI: PFS as Assessed by Investigator According to Line of Therapy - FAS
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.
Time frame: From date of randomization to earliest documentation of PD or death or censoring date, whichever occurred first (maximum up to 33.9 months)
SLI: Time to Response (TTR) as Assessed by Investigator According to Line of Therapy - FAS
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.
Time frame: From date of first dose to first radiographic evidence of response (CR or PR) (maximum up to 33.9 months [147.3 weeks])
SLI: Overall Survival (OS) According to Line of Therapy - FAS
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.
Time frame: From date of first dose to death due to any cause or censoring date, whichever occurred first (maximum up to 33.9 months)
SLI: Maximum Plasma Concentration (Cmax) of Encorafenib and Its Metabolite LHY746
Cmax was observed directly from data. LHY746 is a metabolite of Encorafenib.
Time frame: 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
SLI: Area Under the Concentration Time Profile From Time Zero to 6 Hours (AUC6) for Encorafenib and Its Metabolite LHY746
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.
Time frame: 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
SLI: Area Under the Concentration-time Profile From Time Zero to the Time Tau (AUCtau) of Encorafenib and Its Metabolite LHY746
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.
Time frame: 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
SLI: Time to Maximum Plasma Concentration (Tmax) of Encorafenib and Its Metabolite LHY746
Tmax: time (hours) to Cmax. LHY746 is a metabolite of Encorafenib.
Time frame: 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
SLI: Apparent Total Clearance (CL/F) 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.
Time frame: 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
SLI, Cohort 1: Cmax of Irinotecan and Its Metabolite SN-38
Cmax was observed directly from data. SN-38 is a metabolite of Irinotecan.
Time frame: 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
SLI, Cohort 1: AUClast of Irinotecan and Its Metabolite SN-38
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.
Time frame: 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
SLI, Cohort 1: Apparent Terminal Elimination Half-Life (t1/2) of Irinotecan and Its Metabolite SN-38
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.
Time frame: 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
SLI, Cohort 1: CL/F 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.
Time frame: 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
SLI, Cohort 2: Cmax of Oxaliplatin
Cmax was observed directly from data. Oxaliplatin was evaluated as total platinum in plasma and platinum in plasma ultrafiltrate.
Time frame: 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
SLI, Cohort 2: AUClast of Oxaliplatin
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.
Time frame: 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
SLI, Cohort 2: CL/F of Oxaliplatin
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.
Time frame: 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
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
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".
Time frame: 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
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
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".
Time frame: 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
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
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".
Time frame: 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
SLI, Cohort 2: Ratio of AUClast on Cycle 1 Day 15 as Compared to Cycle 1 Day 1 for Oxaliplatin
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".
Time frame: 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
SLI, Cohort 2: Ratio of Cmax on Cycle 1 Day 15 as Compared to Cycle 1 Day 1 for Oxaliplatin
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".
Time frame: 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
Phase 3: OS for Arm B vs Arm C - FAS
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.
Time frame: From date of first dose to death due to any cause or censoring date, whichever occurred first (maximum up to 37.25 months)
Phase 3: ORR by Derived Investigator Assessment for Arm B vs Arm C - FAS ORR Subset
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.
Time frame: From date of randomization until documented PD, or start of subsequent anticancer therapy, or death, whichever occurred first (maximum up to 24.71 months)
Phase 3: ORR as Assessed by BICR - FAS
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.
Time frame: 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)
Phase 3: DOR as Assessed by BICR for Arm B Versus Arm C - FAS ORR Subset
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.
Time frame: 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)
Phase 3: DOR by Derived Investigator Assessment for Arm B Versus Arm C - FAS ORR Subset
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.
Time frame: 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)
Phase 3: PFS as Assessed by BICR - FAS
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.
Time frame: From date of randomization to earliest documentation of PD or death or censoring date, whichever occurred first (maximum up to 37.25 months)
Phase 3: OS - FAS
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.
Time frame: From date of first dose to death due to any cause or censoring date, whichever occurred first (maximum up to 37.25 months)
Phase 3: PFS by Derived Investigator Assessment - FAS
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.
Time frame: From date of first dose to death due to any cause or censoring date, whichever occurred first (maximum up to 37.25 months)
Phase 3: TTR as Assessed by BICR for Arm B vs Arm C - FAS ORR Subset
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.
Time frame: From date of first dose to CR or PR (maximum up to 24.71 months [107.37 weeks])
Phase 3: TTR by Derived Investigator Assessment for Arm B vs Arm C - FAS ORR Subset
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.
Time frame: From date of first dose to CR or PR (maximum up to 24.71 months [107.37 weeks])
Phase 3: Progression After Next Line of Treatment (PFS2) - FAS
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.
Time frame: 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)
Phase 3: Number of Participants With AEs
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.
Time frame: Through end of the study
Phase 3: Number of Participants With Grade 3 or 4 AEs and Grade 5 AEs
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.
Time frame: Through end of the study
Phase 3: Number of Participants With Shift From Grade <=2 at Baseline to Grade >=3 Post-Baseline in Hematology and Coagulation Parameters
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.
Time frame: Through end of the study
Phase 3: Number of Participants With Shift From Grade <=2 at Baseline to Grade >=3 Post-Baseline in Chemistry Parameters
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.
Time frame: Through end of the study
Phase 3: Number of Participants According to Categorization of Vital Signs Data
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.
Time frame: Through end of the study
Phase 3: Number of Participants According to Categorization of ECGs Findings
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.
Time frame: Through end of the study
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
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.
Time frame: Baseline and Week 72
Phase 3: EuroQol Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L) Visual Analogue Score (VAS) at 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.
Time frame: Baseline and Week 72
Phase 3: Number of Participants According to Response to Patient Global Impression of Severity (PGIS) Assessment at Baseline and at 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.
Time frame: Baseline and Week 30
Phase 3: Number of Participants According to Response to Patient Global Impression of Change (PGIC) Assessment at 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.
Time frame: Week 30
Phase 3: Trough Plasma Concentration of Encorafenib and Its Metabolite LHY746
Trough plasma concentration of encorafenib and its metabolite LHY746 was measured in this outcome measure.
Time frame: 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
Phase 3: Cmax of Encorafenib and Its Metabolite LHY746 in Mainland China Participants
Cmax was observed directly from data. LHY746 is a metabolite of Encorafenib.
Time frame: 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
Phase 3: AUC6 of Encorafenib and Its Metabolite LHY746 in Mainland China Participants
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.
Time frame: Pre-dose (0 hr), 0.5, 1, 2, 3, 4, 5 and 6 hrs post-dose on Days 1 and 15 of Cycle 1
Phase 3: AUCtau of Encorafenib and Its Metabolite LHY746 in Mainland China Participants
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.
Time frame: 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
Phase 3: Tmax of Encorafenib and Its Metabolite LHY746 in Mainland China Participants
Tmax: time (hours) to Cmax. LHY746 is a metabolite of Encorafenib.
Time frame: 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
Phase 3: CL/F of Encorafenib in Mainland China Participants
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.
Time frame: 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
Phase 3: Number of Participants Classified According to Microsatellite Instability (MSI) Status as Determined by Retrospective Central Testing of Baseline Tumor Tissue
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.
Time frame: Baseline
Phase 3: Number of Participants According to Circulating Tumor Deoxyribonucleic Acid (ctDNA) Status
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.
Time frame: 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)
Phase 3: Number of Participants According to B-Raf Serine/Threonine-Protein Kinase (BRAF) Valine 600 (V600) Status From ctDNA
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.
Time frame: 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)
Cohort 3: PFS as Assessed by BICR - FAS
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.
Time frame: From date of randomization to earliest documentation of PD by BICR or death or censoring date, whichever occurred first
Cohort 3: ORR by Derived Investigator Assessment - FAS
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.
Time frame: From date of randomization until documented PD, or start of subsequent anticancer therapy, or death, whichever occurred first (maximum up to 14.1 months)
Cohort 3: DOR as Assessed by BICR - FAS
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.
Time frame: 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)
Cohort 3: DOR by Derived Investigator Assessment - FAS
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.
Time frame: 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)
Cohort 3: PFS by Derived Investigator Assessment - FAS
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.
Time frame: From date of randomization to earliest documentation of PD or death or censoring date, whichever occurred first
Cohort 3: OS - FAS
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.
Time frame: From date of first dose to death due to any cause or censoring date, whichever occurred first
Cohort 3: TTR as Assessed by BICR - FAS
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.
Time frame: From date of first dose to CR or PR (maximum up to 14.1 months [61.29 weeks])
Cohort 3: TTR by Derived Investigator Assessment - FAS
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.
Time frame: From date of first dose to CR or PR (maximum up to 14.1 months [61.29 weeks])
Cohort 3: Number of Participants With AEs
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.
Time frame: Through end of the study
Cohort 3: Number of Participants With Grade 3 or 4 AEs and Grade 5 AEs
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.
Time frame: Through end of the study
Cohort 3: Number of Participants With Shift From Grade <=2 at Baseline to Grade >=3 Post-Baseline in Hematology and Coagulation Parameters
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.
Time frame: Through end of the study
Cohort 3: Number of Participants With Shift From Grade <=2 at Baseline to Grade >=3 Post-Baseline in Chemistry Parameters
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.
Time frame: Through end of the study
Cohort 3: Number of Participants According to Categorization of Vital Signs Data
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.
Time frame: Through end of the study
Cohort 3: Number of Participants According to Categorization of ECGs Findings
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.
Time frame: Through end of the study
Cohort 3: EORTC QLQC30 Global Health Status/QoL
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.
Time frame: Through end of the study
Cohort 3: EQ-5D-5L VAS
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.
Time frame: Through end of the study
Cohort 3: Number of Participants According to Response to PGIS Assessment
PGIS is a single-item scale where participants rated the severity of colorectal cancer as follows: none, mild, moderate, severe and very severe.
Time frame: Through end of the study
Cohort 3: Number of Participants According to Response to PGIC Assessment
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.
Time frame: Through end of the study
Cohort 3: Trough Plasma Concentration of Encorafenib and Its Metabolite LHY746
Trough plasma concentration of encorafenib and its metabolite LHY746 was measured in this outcome measure.
Time frame: 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
Cohort 3: Number of Participants Classified According to MSI Status as Determined by Retrospective Central Testing
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.
Time frame: Through end of the study
Cohort 3: Number of Participants According to ctDNA Status
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.
Time frame: Through end of the study
Cohort 3: Number of Participants According to BRAF V600 Status From ctDNA
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.
Time frame: Through end of the study
Study had following parts: Safety lead-in (SLI), Phase 3 and Cohort 3. A total of 841 participants (57 participants in SLI, 637 participants in Phase 3 and 147 participants in Cohort 3) were enrolled in the study. Results are reported at Primary Completion Date, and data is disclosed for only those outcome measures whose analysis were final. Remaining outcome measures data would be reported upon their complete analyses at study completion date.
| Milestone | SLI: Cohort 1 [EC + FOLFIRI] | SLI: Cohort 2 [EC + mFOLFOX6] | Phase 3: Arm A [EC] | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] | Cohort 3: Arm D [EC + FOLFIRI] | Cohort 3: Arm E [FOLFIRI With or Without Bevacizumab] |
|---|---|---|---|---|---|---|---|
| Started | 30 | 27 | 0 | 0 | 0 | 0 | 0 |
| Completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Not completed | 30 | 27 | 0 | 0 | 0 | 0 | 0 |
| Withdrew: Death | 18 | 16 | 0 | 0 | 0 | 0 | 0 |
| Withdrew: Lost to follow-up | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Withdrew: Withdrawal by subject | 0 | 2 | 0 | 0 | 0 | 0 | 0 |
| Withdrew: Ongoing | 11 | 9 | 0 | 0 | 0 | 0 | 0 |
| Milestone | SLI: Cohort 1 [EC + FOLFIRI] | SLI: Cohort 2 [EC + mFOLFOX6] | Phase 3: Arm A [EC] | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] | Cohort 3: Arm D [EC + FOLFIRI] | Cohort 3: Arm E [FOLFIRI With or Without Bevacizumab] |
|---|---|---|---|---|---|---|---|
| Started | 0 | 0 | 158 | 236 | 243 | 0 | 0 |
| Completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Not completed | 0 | 0 | 158 | 236 | 243 | 0 | 0 |
| Withdrew: Death | 0 | 0 | 91 | 94 | 143 | 0 | 0 |
| Withdrew: Lost to follow-up | 0 | 0 | 2 | 2 | 2 | 0 | 0 |
| Withdrew: Withdrawal by subject | 0 | 0 | 12 | 8 | 19 | 0 | 0 |
| Withdrew: Ongoing | 0 | 0 | 53 | 132 | 79 | 0 | 0 |
| Milestone | SLI: Cohort 1 [EC + FOLFIRI] | SLI: Cohort 2 [EC + mFOLFOX6] | Phase 3: Arm A [EC] | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] | Cohort 3: Arm D [EC + FOLFIRI] | Cohort 3: Arm E [FOLFIRI With or Without Bevacizumab] |
|---|---|---|---|---|---|---|---|
| Started | 0 | 0 | 0 | 0 | 0 | 73 | 74 |
| Completed | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Not completed | 0 | 0 | 0 | 0 | 0 | 73 | 74 |
| Withdrew: Death | 0 | 0 | 0 | 0 | 0 | 11 | 20 |
| Withdrew: Lost to follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Withdrew: Withdrawal by subject | 0 | 0 | 0 | 0 | 0 | 2 | 6 |
| Withdrew: Ongoing | 0 | 0 | 0 | 0 | 0 | 60 | 47 |
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.
| Participants | SLI: Cohort 1 [EC + FOLFIRI] | SLI: Cohort 2 [EC + mFOLFOX6] |
|---|---|---|
| SLI: Number of Participants With Dose Limiting Toxicity (DLTs) | 1 | 0 |
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.
| Months | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] |
|---|---|---|
| Phase 3: Progression Free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR) for Arm B vs Arm C - FAS | 12.8 (11.2 to 15.9) | 7.1 (6.8 to 8.5) |
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.
| Percentage of participants | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] |
|---|---|---|
| Phase 3: Objective Response Rate (ORR) as Assessed by BICR for Arm B vs Arm C - FAS ORR Subset | 60.9 (51.6 to 69.5) | 40.0 (31.3 to 49.3) |
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.
| Percentage of participants | Cohort 3: Arm D [EC + FOLFIRI] | Cohort 3: Arm E [FOLFIRI With or Without Bevacizumab] |
|---|---|---|
| Cohort 3: ORR as Assessed by BICR for Arm D vs Arm E - FAS | 64.4 (52.9 to 74.4) | 39.2 (28.9 to 50.6) |
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.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
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.
| Percentage of participants | SLI: Cohort 1 [EC + FOLFIRI] | SLI: Cohort 2 [EC + mFOLFOX6] |
|---|---|---|
| First Line Treatment | 75.0 (46.8 to 91.1) | 68.4 (46.0 to 84.6) |
| Second Line Treatment | 61.1 (38.6 to 79.7) | 50.0 (21.5 to 78.5) |
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.
| Months | SLI: Cohort 1 [EC + FOLFIRI] | SLI: Cohort 2 [EC + mFOLFOX6] |
|---|---|---|
| First Line Treatment | 15.2 (10.6 to NA) | 6.9 (3.7 to NA) |
| Second Line Treatment | 12.5 (3.4 to 18.7) | 5.6 (2.7 to NA) |
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.
| Months | SLI: Cohort 1 [EC + FOLFIRI] | SLI: Cohort 2 [EC + mFOLFOX6] |
|---|---|---|
| First Line Treatment | NA (15.3 to NA) | 9.9 (6.4 to 21.9) |
| Second Line Treatment | 13.8 (4.9 to 15.9) | 9.0 (6.9 to 12.4) |
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.
| Weeks | SLI: Cohort 1 [EC + FOLFIRI] | SLI: Cohort 2 [EC + mFOLFOX6] |
|---|---|---|
| First Line Treatment | 6.6 (6.1 to 94.1) | 6.9 (5.9 to 25.9) |
| Second Line Treatment | 12.9 (6.1 to 37.0) | 9.4 (6.4 to 18.9) |
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.
| Months | SLI: Cohort 1 [EC + FOLFIRI] | SLI: Cohort 2 [EC + mFOLFOX6] |
|---|---|---|
| First Line Treatment | NA (23.7 to NA) | 17.6 (9.1 to NA) |
| Second Line Treatment | 19.7 (13.9 to 25.1) | 16.6 (10.4 to 18.7) |
Cmax was observed directly from data. LHY746 is a metabolite of Encorafenib.
| Nanograms per milliliter | SLI: Cohort 1 [EC + FOLFIRI] | SLI: Cohort 2 [EC + mFOLFOX6] |
|---|---|---|
| Encorafenib: Cycle 1 Day 1 | — | 2870 ± 95.4 |
| LHY746: Cycle 1 Day 1 | — | 582 ± 84.2 |
| Encorafenib: Cycle 1 Day 15 | 2970 ± 45.8 | 2320 ± 59.8 |
| LHY746: Cycle 1 Day 15 | 864 ± 68.8 | 873 ± 82.3 |
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.
| Nanogram*hour per milliliter | SLI: Cohort 1 [EC + FOLFIRI] | SLI: Cohort 2 [EC + mFOLFOX6] |
|---|---|---|
| Encorafenib: Cycle 1 Day 1 | — | 9380 ± 97.4 |
| LHY746: Cycle 1 Day 1 | — | 1640 ± 109 |
| Encorafenib: Cycle 1 Day 15 | 8910 ± 36.2 | 6130 ± 49.4 |
| LHY746: Cycle 1 Day 15 | 3400 ± 67.9 | 2820 ± 123 |
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.
| Nanogram*hour per milliliter | SLI: Cohort 1 [EC + FOLFIRI] | SLI: Cohort 2 [EC + mFOLFOX6] |
|---|---|---|
| Encorafenib: Cycle 1 Day 15 | 13000 ± 37 | 9170 ± 28.1 |
| LHY746: Cycle 1 Day 15 | 8460 ± 78.2 | 7740 ± 115 |
Tmax: time (hours) to Cmax. LHY746 is a metabolite of Encorafenib.
| Hours | SLI: Cohort 1 [EC + FOLFIRI] | SLI: Cohort 2 [EC + mFOLFOX6] |
|---|---|---|
| Encorafenib: Cycle 1 Day 1 | — | 2.77 (1.08 to 6) |
| LHY746: Cycle 1 Day 1 | — | 7.28 (3 to 8.15) |
| Encorafenib: Cycle 1 Day 15 | 2.32 (1.43 to 5.33) | 2.16 (0.983 to 6) |
| LHY746: Cycle 1 Day 15 | 5.25 (1.5 to 6.87) | 3.98 (1 to 8) |
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.
| Liters per hour | SLI: Cohort 1 [EC + FOLFIRI] | SLI: Cohort 2 [EC + mFOLFOX6] |
|---|---|---|
| Cycle 1 Day 15 | 23 ± 37.1 | 32.7 ± 28.1 |
Cmax was observed directly from data. SN-38 is a metabolite of Irinotecan.
| Nanograms per milliliter | SLI: Cohort 1 [EC + FOLFIRI] |
|---|---|
| Irinotecan: Cycle 1 Day 1 | 1820 ± 18.9 |
| SN-38: Cycle 1 Day 1 | 21.9 ± 49.3 |
| Irinotecan: Cycle 1 Day 15 | 1650 ± 26 |
| SN-38: Cycle 1 Day 15 | 23.9 ± 60.6 |
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.
| Nanogram*hour per milliliter | SLI: Cohort 1 [EC + FOLFIRI] |
|---|---|
| Irinotecan: Cycle 1 Day 1 | 11000 ± 35.4 |
| SN-38: Cycle 1 Day 1 | 225 ± 119 |
| Irinotecan: Cycle 1 Day 15 | 8180 ± 45.6 |
| SN-38: Cycle 1 Day 15 | 145 ± 98.3 |
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.
| Hours | SLI: Cohort 1 [EC + FOLFIRI] |
|---|---|
| Irinotecan: Cycle 1 Day 1 | 7.69 ± 17.2 |
| SN-38: Cycle 1 Day 1 | 13.9 ± 21 |
| Irinotecan: Cycle 1 Day 15 | 5.04 ± 66.8 |
| SN-38: Cycle 1 Day 15 | 7.05 ± 138 |
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.
| Liters per hour | SLI: Cohort 1 [EC + FOLFIRI] |
|---|---|
| Cycle 1 Day 1 | 28 ± 27.2 |
| Cycle 1 Day 15 | 37.1 ± 39 |
Cmax was observed directly from data. Oxaliplatin was evaluated as total platinum in plasma and platinum in plasma ultrafiltrate.
| Nanograms per milliliter | SLI: Cohort 2 [EC + mFOLFOX6] |
|---|---|
| Platinum in plasma: Cycle 1 Day 1 | 2400 ± 17.1 |
| Platinum in plasma-ultrafiltrate: Cycle 1 Day 1 | 636 ± 40.7 |
| Platinum in plasma: Cycle 1 Day 15 | 2420 ± 16.3 |
| Platinum in plasma-ultrafiltrate: Cycle 1 Day 15 | 697 ± 32.5 |
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.
| Nanogram*hour per milliliter | SLI: Cohort 2 [EC + mFOLFOX6] |
|---|---|
| Platinum in plasma: Cycle 1 Day 1 | 47500 ± 49.9 |
| Platinum in plasma-ultrafiltrate: Cycle 1 Day 1 | 6060 ± 60.7 |
| Platinum in plasma: Cycle 1 Day 15 | 53000 ± 18 |
| Platinum in plasma-ultrafiltrate: Cycle 1 Day 15 | 5910 ± 19.8 |
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.
| Liters per hour | SLI: Cohort 2 [EC + mFOLFOX6] |
|---|---|
| Cycle 1 Day 1 | 21.3 ± 28.2 |
| Cycle 1 Day 15 | 21.3 ± 25.8 |
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".
| Ratio | SLI: Cohort 1 [EC + FOLFIRI] |
|---|---|
| Irinotecan | 0.746 (0.697 to 0.798) |
| SN-38 | 0.581 (0.453 to 0.745) |
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".
| Ratio | SLI: Cohort 1 [EC + FOLFIRI] |
|---|---|
| Irinotecan | 0.76 (0.675 to 0.856) |
| SN-38 | 0.723 (0.565 to 0.926) |
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".
| Ratio | SLI: Cohort 1 [EC + FOLFIRI] |
|---|---|
| Irinotecan | 0.912 (0.840 to 0.990) |
| SN-38 | 1.13 (0.997 to 1.28) |
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".
| Ratio | SLI: Cohort 2 [EC + mFOLFOX6] |
|---|---|
| Platinum in plasma | 1.12 (1.04 to 1.2) |
| Platinum in ultrafiltrate | 1.04 (0.985 to 1.11) |
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".
| Ratio | SLI: Cohort 2 [EC + mFOLFOX6] |
|---|---|
| Platinum in plasma | 0.984 (0.904 to 1.07) |
| Platinum in ultrafiltrate | 1.11 (0.940 to 1.32) |
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.
| Months | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] |
|---|---|---|
| Phase 3: OS for Arm B vs Arm C - FAS | 30.3 (21.7 to NA) | 15.1 (13.7 to 17.7) |
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.
| Percentage of participants | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] |
|---|---|---|
| Phase 3: ORR by Derived Investigator Assessment for Arm B vs Arm C - FAS ORR Subset | 64.5 (55.3 to 72.9) | 40.0 (31.3 to 49.3) |
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.
| Percentage of participants | Phase 3: Arm A [EC] | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] |
|---|---|---|---|
| Phase 3: ORR as Assessed by BICR - FAS | 45.6 (38.0 to 53.3) | 65.7 (59.4 to 71.4) | 37.4 (31.6 to 43.7) |
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.
| Months | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] |
|---|---|---|
| Phase 3: DOR as Assessed by BICR for Arm B Versus Arm C - FAS ORR Subset | 13.9 (8.5 to NA) | 11.1 (6.7 to 12.7) |
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.
| Months | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] |
|---|---|---|
| Phase 3: DOR by Derived Investigator Assessment for Arm B Versus Arm C - FAS ORR Subset | 12.5 (9.4 to NA) | 8.3 (5.5 to 11.3) |
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.
| Months | Phase 3: Arm A [EC] | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] |
|---|---|---|---|
| Phase 3: PFS as Assessed by BICR - FAS | 6.8 (5.7 to 8.3) | 12.8 (11.2 to 15.9) | 7.1 (6.8 to 8.5) |
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.
| Months | Phase 3: Arm A [EC] | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] |
|---|---|---|---|
| Phase 3: OS - FAS | 19.5 (17.6 to 22.5) | 30.3 (21.7 to NA) | 15.1 (13.7 to 17.7) |
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.
| Months | Phase 3: Arm A [EC] | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] |
|---|---|---|---|
| Phase 3: PFS by Derived Investigator Assessment - FAS | 6.2 (5.6 to 7.1) | 13.6 (12.1 to 16.1) | 7.0 (6.0 to 8.3) |
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.
| Weeks | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] |
|---|---|---|
| Phase 3: TTR as Assessed by BICR for Arm B vs Arm C - FAS ORR Subset | 7.1 (5.7 to 53.7) | 7.3 (5.4 to 48.0) |
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.
| Weeks | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] |
|---|---|---|
| Phase 3: TTR by Derived Investigator Assessment for Arm B vs Arm C - FAS ORR Subset | 6.9 (5.6 to 93.1) | 7.1 (5.4 to 24.6) |
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.
| Months | Phase 3: Arm A [EC] | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] |
|---|---|---|---|
| Phase 3: Progression After Next Line of Treatment (PFS2) - FAS | 14.3 (12.7 to 16.6) | 20.7 (19.0 to 23.9) | 12.7 (11.2 to 13.7) |
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.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
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.
| Units on a scale | Phase 3: Arm A [EC] | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] |
|---|---|---|---|
| Baseline | 63.0 ± 21.64 | 67.1 ± 21.65 | 66.8 ± 21.43 |
| Week 72 | 75.3 ± 14.64 | 71.3 ± 18.52 | 73.3 ± 16.57 |
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.
| Units on a scale | Phase 3: Arm A [EC] | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] |
|---|---|---|---|
| Baseline | 70.4 ± 19.76 | 70.9 ± 17.67 | 73.4 ± 18.28 |
| Week 72 | 78.7 ± 16.19 | 74.1 ± 18.67 | 79.3 ± 15.62 |
PGIS is a single-item scale where participants rated the severity of colorectal cancer as follows: none, mild, moderate, severe and very severe.
| Participants | Phase 3: Arm A [EC] | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] |
|---|---|---|---|
| Baseline — None | 27 | 50 | 48 |
| Baseline — Mild | 44 | 67 | 64 |
| Baseline — Moderate | 37 | 56 | 47 |
| Baseline — Severe | 26 | 28 | 23 |
| Baseline — Very Severe | 0 | 0 | 0 |
| Week 30 — None | 27 | 48 | 34 |
| Week 30 — Mild | 25 | 53 | 35 |
| Week 30 — Moderate | 13 | 30 | 14 |
| Week 30 — Severe | 3 | 9 | 6 |
| Week 30 — Very Severe | 0 | 0 | 0 |
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.
| Participants | Phase 3: Arm A [EC] | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] |
|---|---|---|---|
| Much better | 0 | 0 | 0 |
| A little better | 23 | 54 | 39 |
| No change | 27 | 54 | 30 |
| A little worse | 16 | 26 | 15 |
| Much worse | 2 | 6 | 5 |
Trough plasma concentration of encorafenib and its metabolite LHY746 was measured in this outcome measure.
| Nanograms per milliliter | Phase 3: Arm A [EC] | Phase 3: Arm B [EC + mFOLFOX6] |
|---|---|---|
| Encorafenib: Cycle 1 Day 1 | 116.2 ± 3892 | NA ± NA |
| Encorafenib: Cycle 2 Day 1 | 10.44 ± 180 | 15.69 ± 229 |
| Encorafenib: Cycle 3 Day 1 | 10.60 ± 137 | 13.07 ± 179 |
| Encorafenib: Cycle 4 Day 1 | 9.926 ± 193 | 17.37 ± 169 |
| Encorafenib: Cycle 5 Day 1 | 10.02 ± 217 | 17.13 ± 201 |
| Encorafenib: Cycle 6 Day 1 | 11.74 ± 169 | 15.03 ± 143 |
| LHY746: Cycle 1 Day 1 | 35.54 ± 549 | NA ± NA |
| LHY746: Cycle 2 Day 1 | 44.71 ± 251 | 62.90 ± 213 |
| LHY746: Cycle 3 Day 1 | 50.36 ± 178 | 61.88 ± 220 |
| LHY746: Cycle 4 Day 1 | 41.61 ± 224 | 76.79 ± 205 |
| LHY746: Cycle 5 Day 1 | 37.87 ± 242 | 66.29 ± 192 |
| LHY746: Cycle 6 Day 1 | 58.59 ± 250 | 72.39 ± 212 |
Cmax was observed directly from data. LHY746 is a metabolite of Encorafenib.
| Nanograms per milliliter | Phase 3: Arm A [EC] |
|---|---|
| Encorafenib: Cycle 1 Day 1 | 5200 ± 41.4 |
| LHY746: Cycle 1 Day 1 | 871 ± 42.2 |
| Encorafenib: Cycle 1 Day 15 | 3020 ± 55.7 |
| LHY746: Cycle 1 Day 15 | 1250 ± 76.7 |
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.
| Nanogram*hour per milliliter | Phase 3: Arm A [EC] |
|---|---|
| Encorafenib: Cycle 1 Day 1 | 15400 ± 61.2 |
| LHY746: Cycle 1 Day 1 | 2890 ± 63 |
| Encorafenib: Cycle 1 Day 15 | 8010 ± 41.6 |
| LHY746: Cycle 1 Day 15 | 5100 ± 83.8 |
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.
| Nanogram*hour per milliliter | Phase 3: Arm A [EC] |
|---|---|
| Encorafenib: Cycle 1 Day 1 | 26800 ± 47 |
| LHY746: Cycle 1 Day 1 | 11900 ± 65.5 |
| Encorafenib: Cycle 1 Day 15 | 11100 ± 32.2 |
| LHY746: Cycle 1 Day 15 | 11300 ± 103 |
Tmax: time (hours) to Cmax. LHY746 is a metabolite of Encorafenib.
| Hours | Phase 3: Arm A [EC] |
|---|---|
| Encorafenib: Cycle 1 Day 1 | 2 (1.02 to 24) |
| LHY746: Cycle 1 Day 1 | 6.07 (2 to 24) |
| Encorafenib: Cycle 1 Day 15 | 2 (0.533 to 24) |
| LHY746: Cycle 1 Day 15 | 3 (1.08 to 5.1) |
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.
| Liters per hour | Phase 3: Arm A [EC] |
|---|---|
| Cycle 1 Day 1 | 11.4 ± 53.3 |
| Cycle 1 Day 15 | 27 ± 32.3 |
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.
| Participants | Phase 3: Arm A [EC] | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] |
|---|---|---|---|
| MSI-H | 1 | 1 | 1 |
| MSS | 147 | 218 | 219 |
| MSI-Unknown | 5 | 13 | 9 |
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.
| Participants | Phase 3: Arm A [EC] | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] |
|---|---|---|---|
| Cycle 1 Day 1 — Detected | 116 | 174 | 170 |
| Cycle 1 Day 1 — Not Detected | 2 | 2 | 0 |
| Cycle 1 Day 1 — Not Evaluable | 5 | 14 | 9 |
| Cycle 1 Day 15 — Detected | 85 | 136 | 122 |
| Cycle 1 Day 15 — Not Detected | 17 | 20 | 6 |
| Cycle 1 Day 15 — Not Evaluable | 4 | 3 | 1 |
| Cycle 2 Day 15 — Detected | 80 | 128 | 105 |
| Cycle 2 Day 15 — Not Detected | 11 | 20 | 6 |
| Cycle 2 Day 15 — Not Evaluable | 12 | 6 | 2 |
| Cycle 7 Day 1 — Detected | 43 | 102 | 59 |
| Cycle 7 Day 1 — Not Detected | 9 | 9 | 2 |
| Cycle 7 Day 1 — Not Evaluable | 3 | 0 | 2 |
| End of Treatment — Detected | 70 | 58 | 99 |
| End of Treatment — Not Detected | 0 | 2 | 2 |
| End of Treatment — Not Evaluable | 5 | 3 | 1 |
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.
| Participants | Phase 3: Arm A [EC] | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] |
|---|---|---|---|
| Outside China: Cycle 1 Day 1 — Measurable | 105 | 149 | 154 |
| Outside China: Cycle 1 Day 1 — Not measurable | 18 | 41 | 25 |
| Outside China: Cycle 1 Day 15 — Measurable | 58 | 81 | 100 |
| Outside China: Cycle 1 Day 15 — Not measurable | 48 | 78 | 29 |
| Outside China: Cycle 2 Day 15 — Measurable | 47 | 45 | 65 |
| Outside China: Cycle 2 Day 15 — Not measurable | 56 | 109 | 48 |
| Outside China: Cycle 7 Day 1 — Measurable | 25 | 28 | 31 |
| Outside China: Cycle 7 Day 1 — Not measurable | 30 | 83 | 32 |
| Outside China: End of Treatment — Measurable | 64 | 40 | 71 |
| Outside China: End of Treatment — Not measurable | 11 | 23 | 31 |
| Mainland China: Cycle 1 Day 1 — Measurable | 19 | 29 | 35 |
| Mainland China: Cycle 1 Day 1 — Not measurable | 5 | 6 | 3 |
| Mainland China: Cycle 1 Day 15 — Measurable | 12 | 13 | 22 |
| Mainland China: Cycle 1 Day 15 — Not measurable | 10 | 19 | 1 |
| Mainland China: Cycle 2 Day 15 — Measurable | 8 | 7 | 11 |
| Mainland China: Cycle 2 Day 15 — Not measurable | 13 | 23 | 10 |
| Mainland China: Cycle 7 Day 1 — Measurable | 6 | 5 | 4 |
| Mainland China: Cycle 7 Day 1 — Not measurable | 10 | 17 | 4 |
| Mainland China: End of Treatment — Measurable | 10 | 11 | 13 |
| Mainland China: End of Treatment — Not measurable | 1 | 2 | 7 |
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.
Results for this outcome have not been posted.
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.
| Percentage of participants | Cohort 3: Arm D [EC + FOLFIRI] | Cohort 3: Arm E [FOLFIRI With or Without Bevacizumab] |
|---|---|---|
| Cohort 3: ORR by Derived Investigator Assessment - FAS | 60.3 (48.8 to 70.7) | 40.5 (30.1 to 51.9) |
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.
| Months | Cohort 3: Arm D [EC + FOLFIRI] | Cohort 3: Arm E [FOLFIRI With or Without Bevacizumab] |
|---|---|---|
| Cohort 3: DOR as Assessed by BICR - FAS | NA (NA to NA) | NA (7.0 to NA) |
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.
| Months | Cohort 3: Arm D [EC + FOLFIRI] | Cohort 3: Arm E [FOLFIRI With or Without Bevacizumab] |
|---|---|---|
| Cohort 3: DOR by Derived Investigator Assessment - FAS | NA (9.5 to NA) | NA (6.9 to NA) |
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.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
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.
| Weeks | Cohort 3: Arm D [EC + FOLFIRI] | Cohort 3: Arm E [FOLFIRI With or Without Bevacizumab] |
|---|---|---|
| Cohort 3: TTR as Assessed by BICR - FAS | 6.9 (5.4 to 36.1) | 7.1 (5.9 to 25.3) |
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.
| Weeks | Cohort 3: Arm D [EC + FOLFIRI] | Cohort 3: Arm E [FOLFIRI With or Without Bevacizumab] |
|---|---|---|
| Cohort 3: TTR by Derived Investigator Assessment - FAS | 6.5 (5.3 to 18.4) | 6.9 (5.9 to 19.1) |
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.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
PGIS is a single-item scale where participants rated the severity of colorectal cancer as follows: none, mild, moderate, severe and very severe.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
Trough plasma concentration of encorafenib and its metabolite LHY746 was measured in this outcome measure.
| Nanograms per milliliter | Cohort 3: Arm D [EC + FOLFIRI] |
|---|---|
| Encorafenib: Cycle 1 Day 1 | NA ± NA |
| Encorafenib: Cycle 2 Day 1 | 10.53 ± 212 |
| Encorafenib: Cycle 3 Day 1 | 11.26 ± 417 |
| Encorafenib: Cycle 4 Day 1 | 9.336 ± 141 |
| Encorafenib: Cycle 5 Day 1 | 9.175 ± 111 |
| Encorafenib: Cycle 6 Day 1 | 13.90 ± 466 |
| LHY746: Cycle 1 Day 1 | NA ± NA |
| LHY746: Cycle 2 Day 1 | 40.80 ± 258 |
| LHY746: Cycle 3 Day 1 | 33.86 ± 250 |
| LHY746: Cycle 4 Day 1 | 25.85 ± 153 |
| LHY746: Cycle 5 Day 1 | 29.49 ± 210 |
| LHY746: Cycle 6 Day 1 | 43.71 ± 271 |
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.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
Collected over AEs: From first dose of study treatment (Day 1) up to 28 days post last dose of study treatment (maximum treatment exposure: SIL = 33.9 months, Phase 3 = 37.25 months and cohort 3 =14.1 months; maximum follow-up: SIL = 34.9 months, Phase 3 = 38.25 and, Cohort 3 =15.1 months); All-cause mortality: From randomization through end of the study at PCD cut-off (maximum of 38.25 months). Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| SLI: Cohort 1 [EC + FOLFIRI] | 18/30 (60%) | 14/30 (46.7%) | 29/30 (96.7%) |
| SLI: Cohort 2 [EC + mFOLFOX6] | 17/27 (63%) | 12/27 (44.4%) | 27/27 (100%) |
| Phase 3: Arm A [EC] | 92/158 (58.2%) | 46/153 (30.1%) | 144/153 (94.1%) |
| Phase 3: Arm B [EC + mFOLFOX6] | 94/236 (39.8%) | 107/232 (46.1%) | 232/232 (100%) |
| Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] | 148/243 (60.9%) | 89/229 (38.9%) | 221/229 (96.5%) |
| Cohort 3: Arm D [EC + FOLFIRI] | 11/73 (15.1%) | 28/71 (39.4%) | 70/71 (98.6%) |
| Cohort 3: Arm E [FOLFIRI With or Without Bevacizumab] | 20/74 (27%) | 25/68 (36.8%) | 67/68 (98.5%) |
| Event | SLI: Cohort 1 [EC + FOLFIRI] | SLI: Cohort 2 [EC + mFOLFOX6] | Phase 3: Arm A [EC] | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] | Cohort 3: Arm D [EC + FOLFIRI] | Cohort 3: Arm E [FOLFIRI With or Without Bevacizumab] |
|---|---|---|---|---|---|---|---|
| PyrexiaGeneral disorders | 3/30 | 3/27 | 0/153 | 9/232 | 3/229 | 2/71 | 0/68 |
| Intestinal obstructionGastrointestinal disorders | 3/30 | 0/27 | 6/153 | 11/232 | 5/229 | 0/71 | 4/68 |
| Disease progressionGeneral disorders | 2/30 | 0/27 | 4/153 | 8/232 | 1/229 | 1/71 | 0/68 |
| DiarrhoeaGastrointestinal disorders | 0/30 | 1/27 | 0/153 | 1/232 | 5/229 | 1/71 | 4/68 |
| Febrile neutropeniaBlood and lymphatic system disorders | 0/30 | 1/27 | 0/153 | 2/232 | 9/229 | 4/71 | 0/68 |
| IleusGastrointestinal disorders | 1/30 | 1/27 | 2/153 | 3/232 | 4/229 | 1/71 | 3/68 |
| Large intestine perforationGastrointestinal disorders | 0/30 | 0/27 | 0/153 | 1/232 | 2/229 | 0/71 | 3/68 |
| Pulmonary embolismRespiratory, thoracic and mediastinal disorders | 1/30 | 0/27 | 0/153 | 3/232 | 1/229 | 2/71 | 3/68 |
| Infusion related reactionInjury, poisoning and procedural complications | 0/30 | 0/27 | 1/153 | 1/232 | 0/229 | 3/71 | 0/68 |
| Urinary tract infectionInfections and infestations | 0/30 | 1/27 | 6/153 | 3/232 | 2/229 | 0/71 | 2/68 |
| Event | SLI: Cohort 1 [EC + FOLFIRI] | SLI: Cohort 2 [EC + mFOLFOX6] | Phase 3: Arm A [EC] | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] | Cohort 3: Arm D [EC + FOLFIRI] | Cohort 3: Arm E [FOLFIRI With or Without Bevacizumab] |
|---|---|---|---|---|---|---|---|
| NauseaGastrointestinal disorders | 15/30 | 20/27 | 30/153 | 124/232 | 114/229 | 43/71 | 39/68 |
| DiarrhoeaGastrointestinal disorders | 14/30 | 10/27 | 28/153 | 97/232 | 114/229 | 38/71 | 31/68 |
| AnaemiaBlood and lymphatic system disorders | 6/30 | 6/27 | 32/153 | 106/232 | 57/229 | 29/71 | 16/68 |
| VomitingGastrointestinal disorders | 8/30 | 11/27 | 21/153 | 82/232 | 51/229 | 32/71 | 21/68 |
| ConstipationGastrointestinal disorders | 13/30 | 7/27 | 22/153 | 63/232 | 52/229 | 21/71 | 20/68 |
| FatigueGeneral disorders | 13/30 | 9/27 | 32/153 | 60/232 | 64/229 | 23/71 | 27/68 |
| PyrexiaGeneral disorders | 5/30 | 11/27 | 26/153 | 61/232 | 33/229 | 10/71 | 3/68 |
| Dermatitis acneiformSkin and subcutaneous tissue disorders | 12/30 | 7/27 | 30/153 | 43/232 | 2/229 | 8/71 | 0/68 |
| Decreased appetiteMetabolism and nutrition disorders | 8/30 | 8/27 | 25/153 | 87/232 | 62/229 | 21/71 | 22/68 |
| AlopeciaSkin and subcutaneous tissue disorders | 7/30 | 2/27 | 13/153 | 53/232 | 26/229 | 25/71 | 15/68 |
| Age, Categorical(Participants) | SLI: Cohort 1 [EC + FOLFIRI] | SLI: Cohort 2 [EC + mFOLFOX6] | Phase 3: Arm A [EC] | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] | Cohort 3: Arm D [EC + FOLFIRI] | Cohort 3: Arm E [FOLFIRI With or Without Bevacizumab] | Total |
|---|---|---|---|---|---|---|---|---|
| <=18 years | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Between 18 and 65 years | 20 | 18 | 105 | 150 | 139 | 37 | 46 | 515 |
| >=65 years | 10 | 9 | 53 | 86 | 104 | 36 | 28 | 326 |
| Sex: Female, Male(Participants) | SLI: Cohort 1 [EC + FOLFIRI] | SLI: Cohort 2 [EC + mFOLFOX6] | Phase 3: Arm A [EC] | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] | Cohort 3: Arm D [EC + FOLFIRI] | Cohort 3: Arm E [FOLFIRI With or Without Bevacizumab] | Total |
|---|---|---|---|---|---|---|---|---|
| Female | 10 | 16 | 79 | 113 | 124 | 40 | 39 | 421 |
| Male | 20 | 11 | 79 | 123 | 119 | 33 | 35 | 420 |
| Ethnicity (NIH/OMB)(Participants) | SLI: Cohort 1 [EC + FOLFIRI] | SLI: Cohort 2 [EC + mFOLFOX6] | Phase 3: Arm A [EC] | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] | Cohort 3: Arm D [EC + FOLFIRI] | Cohort 3: Arm E [FOLFIRI With or Without Bevacizumab] | Total |
|---|---|---|---|---|---|---|---|---|
| Hispanic or Latino | 4 | 5 | 16 | 28 | 30 | 10 | 5 | 98 |
| Not Hispanic or Latino | 24 | 21 | 131 | 187 | 201 | 58 | 64 | 686 |
| Unknown or Not Reported | 2 | 1 | 11 | 21 | 12 | 5 | 5 | 57 |
| Race (NIH/OMB)(Participants) | SLI: Cohort 1 [EC + FOLFIRI] | SLI: Cohort 2 [EC + mFOLFOX6] | Phase 3: Arm A [EC] | Phase 3: Arm B [EC + mFOLFOX6] | Phase 3: Arm C [Standard of Care Chemotherapy, Control Arm] | Cohort 3: Arm D [EC + FOLFIRI] | Cohort 3: Arm E [FOLFIRI With or Without Bevacizumab] | Total |
|---|---|---|---|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 1 |
| Asian | 6 | 8 | 64 | 88 | 91 | 29 | 20 | 306 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 2 |
| Black or African American | 1 | 0 | 1 | 0 | 1 | 0 | 0 | 3 |
| White | 23 | 19 | 88 | 141 | 144 | 41 | 49 | 505 |
| More than one race | 0 | 0 | 0 | 0 | 2 | 0 | 1 | 3 |
| Unknown or Not Reported | 0 | 0 | 4 | 7 | 5 | 2 | 3 | 21 |
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PDFs hosted by the registry, ClinicalTrials.gov.
Plan to share: Yes — Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
Data sharing details ↗ · www.pfizer.com
Ran from Dec 2020 to primary completion in Mar 2025, 50 months.
Results were first posted in Jun 2026, 1 year 3 months after primary completion.
Of 69 industry-sponsored phase 3 interventional studies under Colorectal Neoplasms, half reached primary completion within 43 months of starting (the median), counting those still running; a quarter within 26 and three quarters within 54. This study's 50 months is above that.
Counting every sponsor, half of 175 studies reached it within 50 months; a quarter within 35 and three quarters within 79.
Completion moved once since we started tracking on Sep 25, 2026: Dec 2027 → Jul 2027, on Nov 5, 2026.
Earlier changes are on the record history on ClinicalTrials.gov ↗
How these figures are worked out, and which studies are left out of them.
From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗
This study is active, not recruiting, as verified in Oct 2026. You cannot join it, but the record below documents what was studied.
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Studies of the drugs tested here: Encorafenib · Cetuximab · Oxaliplatin · Irinotecan · Leucovorin · Fluorouracil