A Study of Encorafenib Plus Cetuximab With or Without Chemotherapy in People With Previously Untreated Metastatic Colorectal Cancer

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.

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.

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