• Patients must have histologically confirmed stage IV colorectal cancer positive for BRAF V600E mutation and on at least 1 prior line of systemic therapy and have not had any previous BRAF inhibitor therapy Patients must have measurable disease as defined by RECIST 1.1 See Section 7 for the evaluation of measurable disease. Baseline imaging scan will be used.

• Patients must have discontinued prior chemotherapy or targeted therapy at least 14 days prior to D1 of starting study treatment (E+C). Note: patients are allowed to start standard of care treatment with Encorafenib and Cetuximab/panitumumab (prior to registration for up to 14 days).

• Patients must be at least 18 years of age.

• Patients must exhibit an ECOG performance status of 0 or 1.\[Refer Appendix 1\]

• Patients must have adequate organ and bone marrow function as defined below. If laboratory values are outside these thresholds at screening, repeat labs can be done within a 14 day window. If lab values meet criteria at screening as delineated below, they do not need to be repeated:

• Leukocytes (WBC) ≥ 3,000/mcL

• Absolute neutrophil count (ANC) ≥ 1,500/mcL

• Hemoglobin (Hgb) ≥ 9 g/dL NOTE: Transfusions will be allowed to achieve this, but no more than 2 units of pRBC in the prior 4 weeks.

• Platelets (PLT) ≥ 100,000/mcL Transfusions will be allowed to achieve this, but no more than 2 units of platelet transfusion in the prior 2 weeks

• Total bilirubin ≤ 1.5 x Institutional upper limit of normal (ULN)

• AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional ULN, or \< 5x ULN in presence of liver metastases.

• Creatinine, OR 1.5x ULN OR Glomerular filtration rate (GFR) eGFR is estimated GFR calculated by the C-G formula \> 50 mL/min/1.73 m2 Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; ULN = upper limit of normal.

• For patients with a known history of Human immunodeficiency virus (HIV), infected patients on effective anti-retroviral therapy must have an undetectable viral load.

• For patients with a known history of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

• Patients with a known history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

• Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression.

• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen.

• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better. Note: Patients with clinically significant cardiac disease, including New York Heart Association Class III or IV heart failure are not eligible.

• Females of child-bearing potential (FOCBP) are required to have a negative urine or serum pregnancy test within 7 days prior to commencement of dosing .Note: The test will have to be repeated if Cycle 1 Day1 is more than 3 days from registration. Females of non-childbearing potential may be included without serum pregnancy test if they are either surgically sterile or have been postmenopausal for ≥ 1 year.

• The effects of Encorafenib and Cetuximab on the developing human fetus are unknown.

∙ For this reason and because Encorafenib, Cettuximab \[Class C\] agents as well as other therapeutic agents used in this trial may be teratogenic, females of child-bearing potential (FOCBP) and men must agree to use adequate contraception ( only effective non-hormonal methods of contraception are allowed e.g. barrier method; abstinence from time of informed consent (atleast 14 days prior to C1D1), for the duration of study participation, and for 4 months following completion of therapy.

∙ Should a female patient become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception from time of informed consent, for the duration of study participation, and 4 months after completion of administration. NOTE: At the discretion of the investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance.

∙ (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable methods of contraception.) NOTE: Hormonal-based methods (e.g., oral contraceptives) are NOT permitted as contraception Since encorafenib can increase the serum concentration of oral contraceptive pills. Note: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

• Has not undergone a hysterectomy or bilateral oophorectomy

• Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for \> 12 months).

‣ Patients taking any type and number of prior anticancer therapies. Exception: BRAF or MEK inhibitors.

⁃ All prior anti-cancer treatment-related toxicities (except alopecia ,neuropathy and laboratory values as listed in Eligibility Criteria 3.1.6) must be Grade 1 or less according to the Common Terminology Criteria for Adverse Events version 5 (CTCAE version5) at the time of starting treatment (C1D1). Note: If patient is receiving the 14 days of SOC treatment and has a toxicity attributed to that they would be permitted to register if the toxicity is clearly attributed to standard of care treatment and corresponding documentation is provided.

⁃ If patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy

⁃ Patients should have a QTc interval of ≤480 ms on the EKG Note: A single 12-lead EKG is acceptable.

⁃ Patients must be able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, stomach resection, small bowel resection with decreased intestinal absorption) that may alter absorption.

⁃ Patients must have the ability to understand and the willingness to sign a written informed consent document.