TriangleNCT04607421 · CITED IN SOURCE DOCUMENTS
A Study of Encorafenib Plus Cetuximab With or Without Chemotherapy in People With Previously Untreated Metastatic Colorectal Cancer
An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.
- Phase
- PHASE3
- Status at capture
- ACTIVE NOT RECRUITING
- Registry last update
- 2026-06-11
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: * has spread to other parts of the body (metastatic); * has a certain type of abnormal gene called "BRAF"; and * has not received prior treatment. Participants in this study will receive one of the following study treatments: * Encorafenib plus cetuximab: These participants will receive encorafenib by mouth at home every day and cetuximab once every two weeks by intravenous (IV) infusion (an injection into the vein) at the study clinic. * Encorafenib plus cetuximab with chemotherapy: These participants will receive encorafenib and cetuximab in the way described in the bullet above. Additionally, they will receive standard chemotherapy by IV infusion and oral treatment at home. * Chemotherapy alone: These participants will receive chemotherapy, the standard treatment for this condition, by IV infusion at the study clinics and oral treatment at home. 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.
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What did the study report?
Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.
Participant flow
Baseline characteristics
SLI: Number of Participants With Dose Limiting Toxicity (DLTs)
Phase 3: Progression Free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR) for Arm B vs Arm C - FAS
Phase 3: Objective Response Rate (ORR) as Assessed by BICR for Arm B vs Arm C - FAS ORR Subset
Cohort 3: ORR as Assessed by BICR for Arm D vs Arm E - FAS
SLI: Number of Participants With Adverse Events (AEs)
SLI: Number of Participants With Grade 3 or 4 AEs and Grade 5 AEs
SLI: Number of Participants With Shift From Grade <=2 at Baseline to Grade >=3 Post-Baseline in Hematology and Coagulation Parameters
SLI: Number of Participants With Shift From Grade <=2 at Baseline to Grade >=3 Post-Baseline in Chemistry Parameters
SLI: Number of Participants According to Categorization of Vital Signs Data
SLI: Number of Participants According to Categorization of Electrocardiogram (ECGs) Findings
SLI: Number of Participants With Dose Modification of Any Study Intervention Due to AEs
SLI: Number of Participants With Dose Discontinuation of Any Study Intervention Due to AEs
SLI: ORR as Assessed by Investigator According to Line of Therapy - FAS
SLI: Duration of Response (DOR) as Assessed by Investigator According to Line of Therapy - FAS
SLI: PFS as Assessed by Investigator According to Line of Therapy - FAS
SLI: Time to Response (TTR) as Assessed by Investigator According to Line of Therapy - FAS
SLI: Overall Survival (OS) According to Line of Therapy - FAS
SLI: Maximum Plasma Concentration (Cmax) of Encorafenib and Its Metabolite LHY746
SLI: Area Under the Concentration Time Profile From Time Zero to 6 Hours (AUC6) for Encorafenib and Its Metabolite LHY746
SLI: Area Under the Concentration-time Profile From Time Zero to the Time Tau (AUCtau) of Encorafenib and Its Metabolite LHY746
SLI: Time to Maximum Plasma Concentration (Tmax) of Encorafenib and Its Metabolite LHY746
SLI: Apparent Total Clearance (CL/F) of Encorafenib
SLI, Cohort 1: Cmax of Irinotecan and Its Metabolite SN-38
SLI, Cohort 1: AUClast of Irinotecan and Its Metabolite SN-38
SLI, Cohort 1: Apparent Terminal Elimination Half-Life (t1/2) of Irinotecan and Its Metabolite SN-38
SLI, Cohort 1: CL/F of Irinotecan
SLI, Cohort 2: Cmax of Oxaliplatin
SLI, Cohort 2: AUClast of Oxaliplatin
SLI, Cohort 2: CL/F of Oxaliplatin
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
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
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
SLI, Cohort 2: Ratio of AUClast on Cycle 1 Day 15 as Compared to Cycle 1 Day 1 for Oxaliplatin
SLI, Cohort 2: Ratio of Cmax on Cycle 1 Day 15 as Compared to Cycle 1 Day 1 for Oxaliplatin
Phase 3: OS for Arm B vs Arm C - FAS
Phase 3: ORR by Derived Investigator Assessment for Arm B vs Arm C - FAS ORR Subset
Phase 3: ORR as Assessed by BICR - FAS
Phase 3: DOR as Assessed by BICR for Arm B Versus Arm C - FAS ORR Subset
Phase 3: DOR by Derived Investigator Assessment for Arm B Versus Arm C - FAS ORR Subset
Phase 3: PFS as Assessed by BICR - FAS
Phase 3: OS - FAS
Phase 3: PFS by Derived Investigator Assessment - FAS
Phase 3: TTR as Assessed by BICR for Arm B vs Arm C - FAS ORR Subset
Phase 3: TTR by Derived Investigator Assessment for Arm B vs Arm C - FAS ORR Subset
Phase 3: Progression After Next Line of Treatment (PFS2) - FAS
Phase 3: Number of Participants With AEs
Phase 3: Number of Participants With Grade 3 or 4 AEs and Grade 5 AEs
Phase 3: Number of Participants With Shift From Grade <=2 at Baseline to Grade >=3 Post-Baseline in Hematology and Coagulation Parameters
Phase 3: Number of Participants With Shift From Grade <=2 at Baseline to Grade >=3 Post-Baseline in Chemistry Parameters
Phase 3: Number of Participants According to Categorization of Vital Signs Data
Phase 3: Number of Participants According to Categorization of ECGs Findings
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
Phase 3: EuroQol Quality of Life 5-Dimension 5-Level Scale (EQ-5D-5L) Visual Analogue Score (VAS) at 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
Phase 3: Number of Participants According to Response to Patient Global Impression of Change (PGIC) Assessment at Week 30
Phase 3: Trough Plasma Concentration of Encorafenib and Its Metabolite LHY746
Phase 3: Cmax of Encorafenib and Its Metabolite LHY746 in Mainland China Participants
Phase 3: AUC6 of Encorafenib and Its Metabolite LHY746 in Mainland China Participants
Phase 3: AUCtau of Encorafenib and Its Metabolite LHY746 in Mainland China Participants
Phase 3: Tmax of Encorafenib and Its Metabolite LHY746 in Mainland China Participants
Phase 3: CL/F of Encorafenib in Mainland China Participants
Phase 3: Number of Participants Classified According to Microsatellite Instability (MSI) Status as Determined by Retrospective Central Testing of Baseline Tumor Tissue
Phase 3: Number of Participants According to Circulating Tumor Deoxyribonucleic Acid (ctDNA) Status
Phase 3: Number of Participants According to B-Raf Serine/Threonine-Protein Kinase (BRAF) Valine 600 (V600) Status From ctDNA
Cohort 3: PFS as Assessed by BICR - FAS
Cohort 3: ORR by Derived Investigator Assessment - FAS
Cohort 3: DOR as Assessed by BICR - FAS
Cohort 3: DOR by Derived Investigator Assessment - FAS
Cohort 3: PFS by Derived Investigator Assessment - FAS
Cohort 3: OS - FAS
Cohort 3: TTR as Assessed by BICR - FAS
Cohort 3: TTR by Derived Investigator Assessment - FAS
Cohort 3: Number of Participants With AEs
Cohort 3: Number of Participants With Grade 3 or 4 AEs and Grade 5 AEs
Cohort 3: Number of Participants With Shift From Grade <=2 at Baseline to Grade >=3 Post-Baseline in Hematology and Coagulation Parameters
Cohort 3: Number of Participants With Shift From Grade <=2 at Baseline to Grade >=3 Post-Baseline in Chemistry Parameters
Cohort 3: Number of Participants According to Categorization of Vital Signs Data
Cohort 3: Number of Participants According to Categorization of ECGs Findings
Cohort 3: EORTC QLQC30 Global Health Status/QoL
Cohort 3: EQ-5D-5L VAS
Cohort 3: Number of Participants According to Response to PGIS Assessment
Cohort 3: Number of Participants According to Response to PGIC Assessment
Cohort 3: Trough Plasma Concentration of Encorafenib and Its Metabolite LHY746
Cohort 3: Number of Participants Classified According to MSI Status as Determined by Retrospective Central Testing
Cohort 3: Number of Participants According to ctDNA Status
Cohort 3: Number of Participants According to BRAF V600 Status From ctDNA
Adverse events
Limitations, agreements, and source contact
Who could take part
- eligibility Criteria
- Inclusion Criteria: * Safety Lead-In = Male/female ≥ 18 years old * Phase 3 and Cohort 3: Male/female ≥ 16 years old (where permitted locally) * Histologically or cytologically confirmed Stage IV CRC that contains BRAF V600E mutation * Prior systemic treatment in metastatic setting: 0-1 regimens for Safety Lead In; none for Phase 3 and Cohort 3. (Note: Prior adjuvant or neoadjuvant therapy considered metastatic treatment if relapse/metastasis \< 6 month from end of adj/neoadjuvant treatment ) * Measurable disease (Phase 3 and Cohort 3)/ Measurable or evaluable disease (Safety Lead-in) * ECOG PS 0-1 * Adequate organ function Exclusion Criteria: * Tumors that are locally confirmed or unknown MSI-H or dMMR unless participant is ineligible to receive immune checkpoint inhibitors due to a pre-existing medical condition * Active bacterial or viral infections in 2 weeks prior to starting dosing * Symptomatic brain metastases
- healthy Volunteers
- false
- minimum Age
- 16 Years
- sex
- ALL
- std Ages
- CHILD
- ADULT
- OLDER_ADULT
Treatment arms and interventions
- arm Groups
- description
- 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
- intervention Names
- Drug: Encorafenib
- Drug: Cetuximab
- Drug: Irinotecan
- Drug: Leucovorin
- Drug: 5-FU
- label
- Safety Lead-in Cohort 1
- type
- EXPERIMENTAL
- description
- 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
- intervention Names
- Drug: Encorafenib
- Drug: Cetuximab
- Drug: Oxaliplatin
- Drug: Leucovorin
- Drug: 5-FU
- label
- Safety Lead-in Cohort 2
- type
- EXPERIMENTAL
- description
- Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120-minute IV infusion) every two weeks
- intervention Names
- Drug: Encorafenib
- Drug: Cetuximab
- label
- Phase 3 Arm A
- type
- EXPERIMENTAL
- description
- 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
- intervention Names
- Drug: Encorafenib
- Drug: Cetuximab
- Drug: Oxaliplatin
- Drug: Leucovorin
- Drug: 5-FU
- label
- Phase 3 Arm B
- type
- EXPERIMENTAL
- description
- 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)
- intervention Names
- Drug: Oxaliplatin
- Drug: Irinotecan
- Drug: Leucovorin
- Drug: 5-FU
- Drug: Capecitabine
- Drug: Bevacizumab
- label
- Phase 3 Arm C
- type
- ACTIVE_COMPARATOR
- description
- 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
- intervention Names
- Drug: Encorafenib
- Drug: Cetuximab
- Drug: Irinotecan
- Drug: Leucovorin
- Drug: 5-FU
- label
- Cohort 3 Arm D
- type
- EXPERIMENTAL
- description
- 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)
- intervention Names
- Drug: Irinotecan
- Drug: Leucovorin
- Drug: 5-FU
- Drug: Bevacizumab
- label
- Cohort 3 Arm E
- type
- ACTIVE_COMPARATOR
- interventions
- arm Group Labels
- Cohort 3 Arm D
- Phase 3 Arm A
- Phase 3 Arm B
- Safety Lead-in Cohort 1
- Safety Lead-in Cohort 2
- description
- 75 mg capsules
- name
- Encorafenib
- other Names
- Braftovi, PF-07263896, LGX818, ONO-7702
- type
- DRUG
- arm Group Labels
- Cohort 3 Arm D
- Phase 3 Arm A
- Phase 3 Arm B
- Safety Lead-in Cohort 1
- Safety Lead-in Cohort 2
- description
- Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vial
- name
- Cetuximab
- other Names
- Erbitux
- type
- DRUG
- arm Group Labels
- Phase 3 Arm B
- Phase 3 Arm C
- Safety Lead-in Cohort 2
- description
- Powder for solution for intravenous use 50 mg/vial, 100 mg/vial, or 200 mg/vial
- name
- Oxaliplatin
- other Names
- Eloxatin
- type
- DRUG
- arm Group Labels
- Cohort 3 Arm D
- Cohort 3 Arm E
- Phase 3 Arm C
- Safety Lead-in Cohort 1
- description
- Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vial
- name
- Irinotecan
- other Names
- Campostar
- type
- DRUG
- arm Group Labels
- Cohort 3 Arm D
- Cohort 3 Arm E
- Phase 3 Arm B
- Phase 3 Arm C
- Safety Lead-in Cohort 1
- Safety Lead-in Cohort 2
- description
- Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial
- name
- Leucovorin
- other Names
- Wellcovorin, Fusilev, Khapzory
- type
- DRUG
- arm Group Labels
- Cohort 3 Arm D
- Cohort 3 Arm E
- Phase 3 Arm B
- Phase 3 Arm C
- Safety Lead-in Cohort 1
- Safety Lead-in Cohort 2
- description
- Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial
- name
- 5-FU
- other Names
- Fluorouracil
- type
- DRUG
- arm Group Labels
- Phase 3 Arm C
- description
- 150 mg or 500 mg Tablet
- name
- Capecitabine
- other Names
- Xeloda
- type
- DRUG
- arm Group Labels
- Cohort 3 Arm E
- Phase 3 Arm C
- description
- Optional Injection for intravenous use 100 mg/vial or 400 mg/vial
- name
- Bevacizumab
- other Names
- Zirabev
- type
- DRUG
Study design
- allocation
- RANDOMIZED
- intervention Model
- PARALLEL
- masking Info
- masking
- NONE
- primary Purpose
- TREATMENT
Enrollment
- count
- 841
- type
- ACTUAL
Registered outcome plans (not posted results)
- primary Outcomes
- description
- 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.
- measure
- SLI: Number of Participants With Dose Limiting Toxicity (DLTs)
- time Frame
- Cycle 1 (28 days)
- description
- 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.
- measure
- Phase 3: Progression Free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR) for Arm B vs Arm C - FAS
- 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)
- description
- 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.
- measure
- Phase 3: Objective Response Rate (ORR) as Assessed by BICR for Arm B vs Arm C - FAS ORR Subset
- 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)
- description
- 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.
- measure
- Cohort 3: ORR as Assessed by BICR for Arm D vs Arm E - FAS
- 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)
- secondary Outcomes
- description
- 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.
- measure
- SLI: Number of Participants With Adverse Events (AEs)
- time Frame
- Through end of the study
- description
- 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.
- measure
- SLI: Number of Participants With Grade 3 or 4 AEs and Grade 5 AEs
- time Frame
- Through end of the study
- description
- 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.
- measure
- SLI: Number of Participants With Shift From Grade <=2 at Baseline to Grade >=3 Post-Baseline in Hematology and Coagulation Parameters
- time Frame
- Through end of the study
- description
- 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.
- measure
- SLI: Number of Participants With Shift From Grade <=2 at Baseline to Grade >=3 Post-Baseline in Chemistry Parameters
- time Frame
- Through end of the study
- description
- 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.
- measure
- SLI: Number of Participants According to Categorization of Vital Signs Data
- time Frame
- Through end of the study
- description
- 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.
- measure
- SLI: Number of Participants According to Categorization of Electrocardiogram (ECGs) Findings
- time Frame
- Through end of the study
- description
- 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.
- measure
- SLI: Number of Participants With Dose Modification of Any Study Intervention Due to AEs
- time Frame
- Through end of the study
- description
- 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.
- measure
- SLI: Number of Participants With Dose Discontinuation of Any Study Intervention Due to AEs
- time Frame
- Through end of the study
- description
- 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.
- measure
- SLI: ORR as Assessed by Investigator According to Line of Therapy - FAS
- 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)
- description
- 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.
- measure
- SLI: Duration of Response (DOR) as Assessed by Investigator According to Line of Therapy - FAS
- 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)
- description
- 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.
- measure
- SLI: PFS as Assessed by Investigator According to Line of Therapy - FAS
- 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)
- description
- 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.
- measure
- SLI: Time to Response (TTR) as Assessed by Investigator According to Line of Therapy - FAS
- 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])
Full study description
- brief Summary
- 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: * has spread to other parts of the body (metastatic); * has a certain type of abnormal gene called "BRAF"; and * has not received prior treatment. Participants in this study will receive one of the following study treatments: * Encorafenib plus cetuximab: These participants will receive encorafenib by mouth at home every day and cetuximab once every two weeks by intravenous (IV) infusion (an injection into the vein) at the study clinic. * Encorafenib plus cetuximab with chemotherapy: These participants will receive encorafenib and cetuximab in the way described in the bullet above. Additionally, they will receive standard chemotherapy by IV infusion and oral treatment at home. * Chemotherapy alone: These participants will receive chemotherapy, the standard treatment for this condition, by IV infusion at the study clinics and oral treatment at home. 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.
- detailed Description
- 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.
Source references
- references
- citation
- Kopetz S, Tabernero J, Elez E. BREAKWATER Phase III: results for encorafenib and cetuximab plus mFOLFOX6 in first-line BRAF V600E-mutant metastatic colorectal cancer. Future Oncol. 2025 Dec;21(28):3585-3588. doi: 10.1080/14796694.2025.2579882. Epub 2025 Nov 13.
- pmid
- 41230651
- type
- DERIVED
- citation
- Elez E, Yoshino T, Shen L, Lonardi S, Van Cutsem E, Eng C, Kim TW, Wasan HS, Desai J, Ciardiello F, Yaeger R, Maughan TS, Morris VK, Wu C, Usari T, Laliberte R, Dychter SS, Zhang X, Tabernero J, Kopetz S; BREAKWATER Trial Investigators. Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer. N Engl J Med. 2025 Jun 26;392(24):2425-2437. doi: 10.1056/NEJMoa2501912. Epub 2025 May 30.
- pmid
- 40444708
- type
- DERIVED
- citation
- Kopetz S, Yoshino T, Van Cutsem E, Eng C, Kim TW, Wasan HS, Desai J, Ciardiello F, Yaeger R, Maughan TS, Beyzarov E, Zhang X, Ferrier G, Zhang X, Tabernero J. Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial. Nat Med. 2025 Mar;31(3):901-908. doi: 10.1038/s41591-024-03443-3. Epub 2025 Jan 25.
- pmid
- 39863775
- type
- DERIVED
- citation
- Van Cutsem E, Taieb J, Yaeger R, Yoshino T, Grothey A, Maiello E, Elez E, Dekervel J, Ross P, Ruiz-Casado A, Graham J, Kato T, Ruffinelli JC, Andre T, Carriere Roussel E, Klauck I, Groc M, Vedovato JC, Tabernero J. ANCHOR CRC: Results From a Single-Arm, Phase II Study of Encorafenib Plus Binimetinib and Cetuximab in Previously Untreated BRAFV600E-Mutant Metastatic Colorectal Cancer. J Clin Oncol. 2023 May 10;41(14):2628-2637. doi: 10.1200/JCO.22.01693. Epub 2023 Feb 10.
- pmid
- 36763936
- type
- DERIVED
- see Also Links
- label
- To obtain contact information for a study center near you, click here.
Source notices and limitations
Discovery and provenance
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- ef="https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm">Drugs@FDA</a>.</p><h2>Efficacy and Safety</h2><p>Efficacy was evaluated in the BREAKWATER trial (NCT04607421), a randomized, active-controlled, open-label, multicenter trial in patients with treatment-naïve, BRAF V600E mutation–positive, metastatic CRC, as detected us
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Preserved source evidence · Not medical advice