Inclusion Criteria:
* Provision of signed and dated informed consent form.
* Age ≥18 years at time of informed consent.
* Histologically- or cytologically-confirmed mCRC that is metastatic.
* Presence of BRAF V600E mutation in tumor tissue previously determined according to the guidelines of each center, any time point before the enrollment in the study.
* Microsatellite stability must be confirmed according to the guidelines of each center, any time point before the enrollment in the study.
* Eligible to receive cetuximab per locally approved label with regard to tumor RAS status, any time point before the enrollment in the study.
* Progression of disease after 1 or 2 prior regimens in the metastatic setting.
* Evidence of measurable or evaluable non-measurable disease per RECIST, v1.1.
* ECOG PS of 0 or 1.
* Adequate bone marrow function characterized by the following at screening:
1. Absolute neutrophil count (ANC) ≥1.5 x 109/L
2. Platelets ≥100 x 109/L
3. Hemoglobin ≥9.0 g/dL (with or without blood transfusions).
* Adequate hepatic and renal function characterized by the following at screening:
1. Serum total bilirubin ≤1.5 x upper limit of normal (ULN) and \<2 mg/dL. Note: Total bilirubin \>1.5 x ULN is allowed if direct (conjugated) ≤1.5 x ULN and indirect (unconjugated) bilirubin is ≤4.25 x ULN. Note: Participants with hyperbilirubinemia due to non-hepatic cause (e.g., hemolysis, hematoma) may be enrolled following discussion and agreement with the Sponsor medical monitor.
2. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤2.5 x ULN, or ≤5 x ULN in the presence of liver metastases.
3. Adequate renal function defined by an estimated creatinine clearance ≥50 mL/min according to the Cockcroft Gault formula or by 24-hour urine collection for creatinine clearance, or according to local institutional standard method.
4. Protein \< 2+ on dipstick urinalysis or ≤ 1.0 g in a 24-hour urine collection. All patients with ≥2+ protein on dipstick urinalysis at baseline must undergo a 24-hour urine collection for protein.
5. Adequate electrolytes, defined as serum potassium and magnesium levels within institutional normal limits.
Note: Replacement treatment to achieve adequate electrolytes will be allowed.
* Adequate cardiac function characterized by the following at screening:
a.Mean triplicate QT interval corrected for heart rate using Fridericia's formula (QTcF) value ≤480 msec.
* Able to take oral medications.
* Highly effective contraception for both male and female subjects if the risk of conceptions exists during and at least up to 6 months after the last medication. See 10.4. Appendix 4.
Exclusion Criteria:
* Treatment with another investigational drug or participation in another investigational study at enrolment or within 30 days prior to enrolment.
* Patient unable to comply with the study protocol owing to psychological, social (lack of social support or social exclusion) or geographical reasons.
* Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study.
* Prior history of hypertensive crisis or hypertensive encephalopathy.
* Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Cycle 1, Day 1.
* Evidence of bleeding diathesis or clinically significant coagulopathy (in the absence of therapeutic anticoagulation).
* Patients with history of pulmonary hemorrhage/hemoptysis (\>1/2 teaspoon red blood) within 6 months prior to Cycle 1, Day 1.
* Known history of acute or chronic pancreatitis.
* Tumors with microsatellite instability or mismatch repair deficiency.
* History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention. (immunomodulatory or immunosuppressive medications or surgery) ≤ 12 months before the enrollment in the study.
* Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
1. History of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft \[CABG\], coronary angioplasty or stenting) ≤ 6 months prior to start of study treatment.
2. Symptomatic congestive heart failure (i.e., Grade 2 or higher), history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality ≤ 6 months prior to start of study treatment, except atrial fibrillation and paroxysmal supraventricular tachycardia.
* Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy.
* Impaired hepatic function, defined as Child-Pugh class B or C.
* Known history of human immunodeficiency virus (HIV), active hepatitis B virus (HBV) infection or active hepatitis C virus (HCV) infection. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Patients with past exposure to HBV are also eligible for the study provided they are negative for HBV DNA.
* Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and the enrollment in the study.
* Subjects with leptomeningeal carcinomatosis.
* Impaired gastrointestinal (GI) function or disease that may significantly alter the absorption of encorafenib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption).
* Concurrent or previous other malignancy within 5 years of study entry without Sponsor approval, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other noninvasive or indolent malignancy.
* History of thromboembolic or cerebrovascular events ≤ 6 months prior to starting study treatment, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary embolism.
* Knowledge of any other disease or medication that may interfere with study treatment.
* Known severe hypersensitivity reactions to monoclonal anti-bodies or BRAF inhibitors.
* Known hypersensitivity to any of encorafenib, cetuximab or bevacizumab-bvzr active ingredients or their excipients.
