Testing the Addition of Nivolumab to Standard Treatment for Patients With Metastatic or Unresectable Colorectal Cancer That Have a BRAF Mutation

Inclusion Criteria:

• Participants must have a histologically or cytologically confirmed diagnosis ofadenocarcinoma of the colon or rectum. The date of diagnosis will be determinedaccording to the pathologic date of diagnosis

• Participants must have measurable disease according to RECIST1.1 criteria. Computedtomography (CT) scans or magnetic resonance imaging (MRIs) used to assess measurabledisease must have been completed within 28 days prior to registration. CT scans orMRIs used to assess non-measurable disease must have been completed within 42 daysprior to registration. All disease must be assessed and documented on the BaselineTumor Assessment Form

• Participants must have documented unresectable and/or metastatic disease on CT orMRI imaging. All disease must be assessed and documented on the Baseline TumorAssessment Form

• Participants must have BRAF^V600E mutated colorectal cancer as tested in a ClinicalLaboratory Improvement Act (CLIA)-certified laboratory

• Participants must have proficient mismatch repair (pMMR) or microsatellite stable (MSS) status as tested in a CLIA-certified laboratory and documented by the treatingclinician. Proficient mismatch repair status can be determined by intact expressionby immunohistochemistry of all 4 mismatch repair proteins (MLH1, MSH2, MSH6, andPMS2). Microsatellite instability can be determined by polymerase chain reaction (PCR)

• Participants with brain metastases must have completed surgery or radiation therapy >= 28 days prior to registration. These participants must have a CT or MRI of thebrain showing no new or enlarging lesions within 42 days prior to registration.These participants must also be neurologically asymptomatic and withoutcorticosteroid treatment for at least 7 days prior to registration. Metastatic brainparenchymal disease must have been treated and participant must be off steroids for 7 days prior to registration. The presence of leptomeningeal disease (LMD) is notconsidered stable disease, and participants with LMD are not eligible for this study

• Participants with known evidence of chronic hepatitis B virus (HBV) infection musthave undetectable HBV viral load on suppressive therapy within 28 days prior toregistration

• Participants with a history of hepatitis C virus (HCV) infection must have beentreated and cured. Participants with HCV infection who are currently on treatmentmust have an undetectable HCV viral load within 28 days prior to registration

• Participants must have had one or two prior regimens of systemic chemotherapy formetastatic or locally advanced, unresectable disease. (A maintenance regimen of 5-fluorouracil or capecitabine, with or without bevacizumab, should not be countedas a separate line of treatment. The re-introduction of an initially successfulinduction regimen will not be counted as one additional line of treatment). Priortreatment for metastatic disease is not required for patients who experienceddisease recurrence during or within 6 months of completion of adjuvant chemotherapy

• Participants must be of age >= 18 years at the time of informed consent

• Participants must have a Zubrod performance status of 0 or 1

• Participants must have a complete medical history and physical exam within 28 daysprior to registration

• Absolute neutrophil count >= 1.0 x 10^3/uL (within 28 days prior to registration)

• Hemoglobin >= 9 g/dL (within 28 days prior to registration)

• Platelets >= 75 x 10^3/uL (within 28 days prior to registration)

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (within 28 daysprior to registration)

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x institutionalULN (within 28 days prior to registration)

• If liver metastases are present, then it is acceptable for AST level =< 5.0 x ULN,and/or an ALT level =< 5.0 x ULN (within 28 days prior to registration)

• Participants must have serum creatinine =< the IULN OR measured OR calculatedcreatinine clearance >= 50 mL/min using the Cockroft-Gault Formula. This specimenmust have been drawn and processed within 28 days prior to registration

• Participants must be able to swallow and retain pills

• Participants must have adequate cardiac function. Participants with known history orcurrent symptoms of cardiac disease, or history of treatment with cardiotoxicagents, must have a clinical risk assessment of cardiac function using the New YorkHeart Association Functional Classification. To be eligible for this trial,participants must be class 2 or better

• Participants must be offered the opportunity to participate in specimen banking.With participant consent, specimens must be collected and submitted via theSouthwest Oncology Group (SWOG) Specimen Tracking System

• Participants must be informed of the investigational nature of this study and mustsign and give informed consent in accordance with institutional and federalguidelines.

• Note: As a part of the OPEN registration process, the treating institution'sidentity is provided in order to ensure that the current (within 365 days) dateof institutional review board approval for this study has been entered in thesystem

Exclusion Criteria:

• Participants must not have a known positive serology for human immunodeficiencyvirus (HIV). Encorafenib is contraindicated with concomitant use of non-nucleosideanalog reverse transcriptase inhibitors like efavirenz and etravirine. In addition,it is recommended in the investigator brochure of encorafenib to avoid usingencorafenib with protease inhibitors. Therefore, because all participants on thisstudy would receive encorafenib for either randomized arm of treatment, participantswith HIV who receive these components of highly active antiretroviral therapy (HAART) would be at high risk for complications of drug-drug interaction

• Participants must not have had prior treatment with a BRAF inhibitor (including, butnot limited to, encorafenib, dabrafenib, or vemurafenib), MEK inhibitor (including,but not limited to, trametinib, selumetinib, or binimetinib), or ERK inhibitor (ofnote, regorafenib is not considered a BRAF inhibitor for the context of eligibilitycriteria)

• Participants must not have had prior treatment with anti-EGFR therapies

• Participants must not have had prior treatment with an anti-PD-1, anti-PD-L1,anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specificallytargeting T-cell co-stimulation or immune checkpoint pathways

• Participants must not have a condition requiring systemic treatment with eithercorticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressivemedications within 14 days of registration. Inhaled or topical steroids and adrenalreplacement doses < 10 mg daily prednisone equivalents are permitted in the absenceof active autoimmune disease. Patients are permitted to use topical, ocular,intra-articular, intranasal, and inhalational corticosteroids (with minimal systemicabsorption). Physiologic replacement doses of systemic corticosteroids arepermitted, even if < 10 mg/day prednisone equivalents. A brief course ofcorticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment ofnon-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused bycontact allergen) is permitted, as long as there has been a washout period forcorticosteroids of >= 7 days prior to registration

• Participants must not have received a live vaccine within 30 days prior to studyregistration. Seasonal flu and COVID vaccines that do not contain a live virus arepermitted

• Participants must not be receiving any other investigational agents

• Participants must not have impaired gastrointestinal function or disease that maysignificantly alter the absorption of study drug (e.g., ulcerative diseases,uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreasedintestinal absorption)

• Participants must not have a history of inflammatory bowel disease, (includingulcerative colitis and Crohn's disease), symptomatic autoimmune disease (e.g.,rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupuserythematosus, autoimmune vasculitis [e.g., Wegener's Granulomatosis]); centralnervous system (CNS) or motor neuropathy considered of autoimmune origin (e.g.,Guillain-Barre Syndrome and myasthenia gravis, multiple sclerosis).

• Note: Participants with Graves' disease will be allowed

• Participants must not have a history of pneumonitis that has required oral orintravenous (IV) steroids within the last 12 months

• Participants must not have a history of a grade 3 or 4 allergic reaction attributedto humanized or human monoclonal antibody therapy

• Participants must not have a history of a prior allogeneic tissue or solid organtransplant

• Participants must not have a history of acute coronary syndromes (includingmyocardial infarction, unstable angina, coronary artery bypass grafting, coronaryangioplasty, or stenting) within 6 months prior to study registration

• Participants must not have uncontrolled blood pressure and hypertension within 28days prior to registration.

• Uncontrolled blood pressure and hypertension is defined as systolic bloodpressure (SBP) > 170 mmHg or diastolic blood pressure (DBP) > 100 mmHg within 28 days prior to registration. Participants are permitted to be receivingmultiple anti-hypertensive medications (unless otherwise indicated in thestudy). All blood pressure measurements within the 28 days prior toregistration must be SBP =< 170 and DBP =< 100. An exception can be made by ahealthcare provider for a participant with a single blood pressure elevationwho upon rechecking has a normal blood pressure

• Participants must not have a prior or concurrent malignancy whose natural history ortreatment (in the opinion of the treating physician) has the potential to interferewith the safety or efficacy assessment of the investigational regimen or requiresconcurrent therapy

• Participants must not be pregnant or nursing. Individuals who are of reproductivepotential must have agreed to use an effective contraceptive method with detailsprovided as a part of the consent process. A person who has had menses at any timein the preceding 12 consecutive months or who has semen likely to contain sperm isconsidered to be of "reproductive potential." In addition to routine contraceptivemethods, "effective contraception" also includes refraining from sexual activitythat might result in pregnancy and surgery intended to prevent pregnancy (or with aside-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy,bilateral tubal ligation/occlusion and vasectomy with testing showing no sperm inthe semen

• Participants must not be planning treatment with other systemic anti-cancer agents (e.g., chemotherapy, hormonal therapy, immunotherapy) or other treatments not partof protocol-specified anti-cancer therapy including concurrent investigationalagents of any type