Randomized Phase II Trial of Encorafenib and Cetuximab with or Without Nivolumab (NSC #748726) for Patients with Previously Treated, Microsatellite Stable, BRAFV600E Metastatic and/or Unresectable Colorectal Cancer

5.1 Disease Related Criteria

a. Participants must have a histologically or cytologically confirmed diagnosis of adenocarcinoma of the colon or rectum. The date of diagnosis will be determined according to the pathologic date of diagnosis.

b. Participants must have measurable disease according to RECIST1.1 criteria. CT scans or MRIs used to assess measurable disease (as defined in Section 10.1) must have been completed within 28 days prior to registration. CT scans or MRIs used to assess non-measurable disease must have been completed within 42 days prior to registration. All disease must be assessed and documented on the Baseline Tumor Assessment Form.

c. Participants must have documented unresectable and/or metastatic disease on CT or MRI imaging. All disease must be assessed and documented on the Baseline Tumor Assessment Form.

d. Participants must have BRAFV600E mutated colorectal cancer as tested in a CLIA-certified laboratory.

e. Participants must have proficient mismatch repair (pMMR) or Microsatellite Stable (MSS) status as tested in a CLIA-certified laboratory and documented by the treating clinician. Proficient mismatch repair status can be determined by intact expression by immunohistochemistry of all 4 mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2). Microsatellite instability can be determined by polymerase chain reaction (PCR).

f. 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 the brain showing no new or enlarging lesions within 42 days prior to registration. These participants must also be neurologically asymptomatic and without corticosteroid treatment for at least 7 days prior to registration. Metastatic brain parenchymal disease must have been treated and participant must be off steroids for 7 days prior to registration. The presence of leptomeningeal disease (LMD) is not considered stable disease, and participants with LMD are not eligible for this study.

g. Participants must not have a known positive serology for human immunodeficiency virus (HIV). Encorafenib is contraindicated with concomitant use of non-nucleoside analog reverse transcriptase inhibitors like efavirenz and etravirine. In addition, it is recommended in the Investigator Brochure of encorafenib to avoid using encorafenib with protease inhibitors. Therefore, because all participants on this study would receive encorafenib for either randomized arm of treatment, participants with HIV who receive these components of highly active antiretroviral therapy (HAART) would be at high risk for complications of drug-drug interaction.

h. Participants with known evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load on suppressive therapy within 28 days prior to registration.

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

 
5.2 Prior/Concurrent Therapy Criteria

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

b. Participants must not have had prior treatment with a BRAF inhibitor (including, but not limited to, encorafenib, dabrafenib, or vemurafenib), MEK inhibitor (including, but not limited to, trametinib, selumetinib, or binimetinib), or ERK inhibitor (of note, regorafenib is not considered a BRAF inhibitor for the context of eligibility criteria).

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

d. 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 specifically targeting T-cell co-stimulation or immune checkpoint pathways.

e. Participants must not have a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of registration. Inhaled or topical steroids and adrenal replacement doses <10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if <10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted, as long as there has been a washout period for corticosteroids of ≥7 days prior to registration.

f. Participants must not have received a live vaccine within 30 days prior to study registration. Seasonal flu and COVID vaccines that do not contain a live virus are permitted.

g. Participants must not be receiving any other investigational agents