Inclusion Criteria:

• Provide a signed and dated Screening informed consent document.
• Age ≥ 18 years at time of informed consent.
• Histologically- or cytologically-confirmed CRC that is metastatic.
• Presence of BRAFV600E in tumor tissue previously determined by a local assay at any time prior to Screening or by the central laboratory. Notes:
  • Only PCR and NGS-based local assays results will be acceptable;
  • Central testing cannot be repeated to resolve discordances with a local result once the central laboratory delivers a definitive result (positive or negative);
  • If the result from the central laboratory is indeterminate or the sample is deemed is inadequate for testing, additional samples may be submitted;
  • If at any time in the Phase 3 portion of the study there is lack of BRAFV600E confirmation by the central laboratory (for any reason including discordance and inadequate available tissue) in 37 total patients or discordance (a valid result of “no BRAFV600E mutation” as determined by the central laboratory) between the local assay and the central laboratory in 18 patients, all subsequent patients will be required to have BRAFV600E determined by the central laboratory prior to enrollment ;
  • Results from local laboratories with more than 1 discordant result leading to patient enrollment will not be accepted for further patient enrollment;
  • Sites with more than 2 randomized patients having indeterminate results after initiation of protocol version 6 will be required to enroll all subsequent patients based only on central laboratory assay results.
• Able to provide a sufficient amount of representative tumor specimen (primary or metastatic, archival or newly obtained) for confirmatory central laboratory testing of BRAF and KRAS mutation status (minimum of 6 slides; optimally up to 15 slides).
  • Note: Tumor samples must be submitted to the central laboratory for BRAF testing as soon as possible following the signing of the Molecular Prescreening informed consent. The BRAF status must be confirmed no later than 30 days following first dose of study drug.
• Eligible to receive cetuximab per locally approved label with regard to tumor RAS status.
• Progression of disease after 1 or 2 prior regimens in the metastatic setting. Notes:
  • Disease relapse during treatment or within 6 months following adjuvant therapy will be considered metastatic disease;
  • Patients who have received 2 prior regimens (i.e., those entering the study in the 3rd line setting), must have received or have been offered and refused prior oxaliplatin unless it was contraindicated due to underlying conditions;
  • Maintenance therapy given in the metastatic setting will not be considered a separate regimen;
  • In the Phase 3 portion of study, the number of patients having received 2 prior regimens will be limited to 215 (35% of the total randomized). Patients with 2 prior regimens who have entered Screening at the time that the limit has been reached will be permitted to continue into the study if they are otherwise determined to be eligible.
• Evidence of measurable or evaluable non-measurable disease per RECIST, v1.1.
• ECOG PS of 0 or 1 10.
• Adequate bone marrow function characterized by the following at screening:
  • Absolute neutrophil count (ANC) ≥ 1.5 × 109 /L;
  • Platelets ≥ 100 × 109 /L;
  • Hemoglobin ≥ 9.0 g/dL
    • Note: Transfusions will be allowed to achieve this. Transfusions will be permitted provided the patient has not received more than 2 units red blood cells in the prior 4 weeks to achieve this criteria.
• Adequate renal function characterized by serum creatinine ≤ 1.5 × upper limit of normal (ULN), or calculated by Cockroft-Gault formula or directly measured creatinine clearance ≥ 50 mL/min at screening.
• Adequate electrolytes at Baseline, defined as serum potassium and magnesium levels within institutional normal limits.
  • Note: replacement treatment to achieve adequate electrolytes will be allowed. 
• Adequate hepatic function characterized by the following at screening:
  • Serum total bilirubin ≤ 1.5 × ULN and < 2 mg/dL;
    • Note: Patients who have a total bilirubin level > 1.5 × ULN will be allowed if their indirect bilirubin level is ≤ 1.5 × ULN.
  • Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 × ULN, or ≤ 5 × ULN in presence of liver metastases.
• Adequate cardiac function characterized by the following at screening:
  • Left ventricular ejection fraction (LVEF) ≥ 50% as determined by a MUGA scan or ECHO;
  • Mean triplicate QT interval corrected for heart rate using Fridericia's formula (QTcF) value ≤480 msec. 
• Able to take oral medications.
• Willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
• Female patients are either postmenopausal for at least 1 year, are surgically sterile for at least 6 weeks, or must agree to take appropriate precautions to avoid pregnancy from screening through follow-up if of childbearing potential.
• For all females, the pregnancy test result must be negative at screening.
• Males must agree to take appropriate precautions to avoid fathering a child from screening through 90 days following end of therapy. 
• Patients under guardianship or partial guardianship will be eligible unless prohibited by local laws or by local/central ethic committees (e.g., France, Germany). Where allowed, all procedures prescribed by law must be followed.

Exclusion Criteria:

• Prior treatment with any RAF inhibitor, MEK inhibitor, cetuximab, panitumumab or other EGFR inhibitors.
• Prior irinotecan hypersensitivity or toxicity that would suggest an inability to tolerate irinotecan 180 mg/m^2 every 2 weeks.
• Symptomatic brain metastasis.
  • Notes: Patients previously treated or untreated for this condition who are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed. Brain metastases must be stable for ≥ 4 weeks, with imaging (e.g., magnetic resonance imaging [MRI] or computed tomography [CT]) demonstrating no current evidence of progressive brain metastases at screening.
• Leptomeningeal disease.
• History or current evidence of RVO or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes) at the time of screening.
• Use of any herbal medications/supplements or any medications or foods that are strong inhibitors or inducers of cytochrome P450 (CYP) 3A4/5 ≤ 1 week prior to the start of study treatment.
• Known history of acute or chronic pancreatitis
• History of chronic inflammatory bowel disease or Crohn’s disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤ 12 months prior to randomization. 
• Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
  • 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;
  • 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.
• Impaired gastrointestinal (GI) function or disease that may significantly alter the absorption of encorafenib or binimetinib (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, 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 without Sponsor approval.
• History of thromboembolic or cerebrovascular events ≤ 6 months prior to starting study treatment, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli.
• Concurrent neuromuscular disorder that is associated with the potential of elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
• Treatment with any of the following:
  • Cyclical chemotherapy within a period of time that was shorter than the cycle length used for that treatment (e.g., 6 weeks for nitrosourea, mitomycin-C) prior to starting study treatment;
  • Biologic therapy (e.g., antibodies) except bevacizumab or aflibercept, continuous or intermittent small molecule therapeutics, or any other investigational agents within a period of time that is ≤ 5 half-lives (t1/2) or ≤ 4 weeks (whichever is shorter) prior to starting study treatment Bevacizumab or aflibercept therapy ≤ 3 weeks prior to starting study treatment;
  • Radiation therapy that included > 30% of the bone marrow.
• Residual CTCAE ≥ Grade 2 toxicity from any prior anticancer therapy, with the exception of Grade 2 alopecia or Grade 2 neuropathy.
• Known history of HIV infection.
• Active hepatitis B or hepatitis C infection.
• Known history of Gilbert's syndrome or is known to have any of the following genotypes: UGT1A1*6/*6, UGT1A1*28/*28, or UGT1A1*6/*28.
• Known contraindication to receive cetuximab or irinotecan at the planned doses; refer to the most recent cetuximab and irinotecan SPC or local label as applicable.
• Current treatment with a non-topical medication known to be a strong inhibitor of CYP3A4. However, patients who either discontinue this treatment or switch to another medication at least 7 days prior to starting study treatment are eligible.
• Concomitant use of St. John’s Wort (hypericum perforatum).
• Other severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient an inappropriate candidate for the study.
• Pregnant, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test result, or nursing (lactating).
• Prior enrollment into this clinical study.