Testing the Use of BRAF-Targeted Therapy After Surgery and Usual Chemotherapy for BRAF-Mutated Colon Cancer

This phase II/III trial compares treatment with encorafenib and cetuximab to usual care (patient observation) for reducing the chance of cancer recurrence after standard surgery and chemotherapy in patients with BRAF-mutated stage IIB-III colon cancer. Encorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of tumor cells. This may help keep tumor cells from growing. Giving encorafenib and cetuximab after standard surgery and chemotherapy may be more effective at reducing the chance of cancer recurrence compared to the usual patient observation.

Inclusion Criteria:PRE-REGISTRATION (STEP 0) ELIGIBILITY CRITERIA:BRAF V600 mutational status may be determined either locally or by central testing. This testing is mandatory prior to registration to determine eligibility. Tissue submission should be initiated as soon after surgery as possible. For tumors evaluated at local laboratories, formalin-fixed paraffin-embedded (FFPE) tumor tissue must still be submitted for central confirmation of BRAF statusREGISTRATION (STEP 1) ELIGIBILITY CRITERIA:Histologically-proven stage III (any T [Tx, T1, T2, T3, or T4], N1-2M0; includes N1C) or high-risk (pT4) stage II colon adenocarcinoma. Tumors must be deemed to originate in the colon including tumors that extend into/involve the small bowel (e.g. those at the ileocecal valve) and must have been completely resectedBRAF V600E mutationMMR proficient (pMMR) or microsatellite stable (MSS) tumorHistologic documentation: adenocarcinomaStage: III (any T [Tx, T1, T2, T3, or T4], N1-2M0; includes N1C) or high-risk II (pT4)Tumor site: colonPatients must have received at least 3 months of adjuvant chemotherapy with either leucovorin calcium, fluorouracil, and oxaliplatin (FOLFOX) (minimum of 5 cycles) or capecitabine and oxaliplatin (CAPOX) (minimum of 3 cycles)Adjuvant therapy must be completed at most 8 weeks prior to registrationNo other prior medical therapy (chemotherapy, immunotherapy, biologic, or targeted therapy) or radiation therapy for the current colon cancer is permittedNot pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is requiredAge >= 18 yearsEastern Cooperative Oncology Group (ECOG) performance status: 0-2Absolute neutrophil count (ANC) >= 1.0 x 10^9/LPlatelet count >= 75 x 10^9/LHemoglobin > 9.0 g/dLTotal bilirubin =< 1.5 x upper limit of normal (ULN)Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x ULNCorrected QT (QTc) Interval =< 480 msecCreatinine = calculated (calc.) creatinine clearance >= 40 mL/minHuman immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trialNo medical condition such as uncontrolled infection, uncontrolled diabetes mellitus, or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patientPatients with known history or current symptoms of cardiac disease or history of treatment with cardiotoxic agents in the last 12 months, 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 betterNo uncontrolled or poorly-controlled hypertension (> 180 mmHg systolic or > 130 mmHg diastolic)No history of allergic reactions attributed to compounds of chemical or biologic composition similar to those of cetuximabNo "currently active" second malignancy other than non-melanoma skin cancers or cervical carcinoma in situ. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for >= 3 yearsPatients are not considered to have a "currently active" malignancy if they had a gastric or bowel carcinoid < 1 cm, ductal carcinoma in situ (DCIS)/lobular carcinoma in situ (LCIS) of the breast without invasive cancer, or endometrial dysplasia/carcinoma in situPatients are not considered to have a "currently active" malignancy if they had a sebaceous neoplasm (sebaceous adenoma, sebaceous epithelioma, sebaceous adenocarcinoma, keratoacanthoma, and squamous cell carcinoma) that was noninvasiveNo known medical condition causing an inability to swallow oral formulations of agentsNo residual Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 grade >= 2 toxicity from prior chemotherapy, with the exception of grade 2 alopecia or neuropathyDrugs that prolong the QTc interval should be avoided if possible, as encorafenib can prolong the QTc interval. Drugs that are generally accepted to have a risk of causing Torsades de Pointes should be discontinued or replaced with drugs that do not carry this risk if at all possible. Patients who receive potential QTc-prolonging medications should be monitored closelyChronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed during treatment on this study. Patients on strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration on the studyChronic concomitant treatment with strong CYP3A4 inducers is not allowed during treatment on this study. Patients must discontinue the drug 14 days prior to registration on the studyExclusion Criteria: N/A