A Phase II Platform Study to Evaluate Treatment With Cemiplimab Monotherapy or Cemiplimab Plus Fianlimab or Other Novel Combinations in Patients With Colorectal Cancer With Minimal Residual Disease Following Definitive Surgery and Chemotherapy (EMPIRE)

The NSABP FC-13 study is being done to determine if using immunotherapies alone or in combination with other drugs will delay or prevent colorectal cancer from coming back in patients with colorectal cancer who are ctDNA-positive after their treatment. Immunotherapeutic drugs (immunotherapies) act on different proteins on the surface of cells of the immune system and trigger the immune system to destroy cancer cells. The drugs being studied in NSABP FC-13 are cemiplimab, fianlimab, and REGN7075.

Inclusion Criteria: * The patient must have consented to participate and, prior to beginning specific study procedures, must have signed and dated appropriate Institutional Review Board (IRB) -approved consent forms that conform to federal and institutional guidelines for study treatment. * Patients must be greater than or equal to18 years old. * The ECOG performance status must be 0-1. * Patients must have confirmed histologic and pathologic stage II/III colon, stage II/III rectal, or oligometastatic stage IV colorectal adenocarcinoma (per AJCC 8th edition). * There must be documentation by CT scan with contrast that the patient has no definitive evidence of (non-resected or non-ablated) metastatic disease including assessment of chest, abdomen, and pelvis at the time of study enrollment * All patients must have had a complete (R0) resection of their primary tumor and resected or ablated (radiofrequency ablation, stereotactic body radiation therapy \[SBRT\], microwave ablation, etc.\]) oligometastatic disease if present AND at least 3 months of a standard systemic chemotherapy regimen (e.g., FOLFOX or CAPOX or fluoropyrimidine monotherapy). This includes either adjuvant chemotherapy for colon cancer or perioperative (adjuvant or neoadjuvant) chemotherapy for rectal cancer or oligometastatic colon or rectal cancer. Chemoradiotherapy for rectal cancer (as a component of curative treatment) is acceptable. NOTE: Patients who achieve a clinical complete response and opt for a non-operative approach to their primary tumor management are not eligible. * Patients must be ctDNA-positive by an assay run in any CLIA-certified lab obtained within 2 weeks to 12 months following completion of definitive all curative therapy for colorectal cancer. * Tumor status of microsatellite stability (MSS) or Proficient mismatch repair (pMMR) is confirmed through a standard of care assay through a CLIA-certified lab. * At the time of study entry, blood counts performed within 28 days prior to study entry must meet the following criteria: * ANC must be greater than or equal to (≥) 1000/mm3, * Platelet count must be ≥ to 80,000/mm3; and * Hemoglobin must be ≥ 8 g/dL. (Note: transfusions may be used to correct hemoglobin for patients experiencing anemia from therapy who otherwise would be eligible for the study.) * Albumin greater than (\>) 3.0 g/dL. * The following criteria for evidence of adequate hepatic function performed within 28 days prior to study entry must be met: * Total bilirubin less than or equal to (≤) 1.5 x ULN * AST and ALT must be ≤ 3.0 x ULN for the lab. (Note: In patients with elevated ALT or AST, the values must be stable for at least 2 weeks and with no evidence of biliary obstruction on imaging.) * Creatinine must be ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 40mL/min. * All prior chemotherapy toxicities (excluding alopecia, amenorrhea, and peripheral neuropathy) must be less than (\ 1 to 2x ULN are permitted if repeat levels within 24 hours are ≤ 1x ULN. If TnT or TnI levels are \> 1 to 2x ULN within 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment by the investigator based on medical judgement in the patient's best interest. * Active, documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis). * Major surgical procedure within 28 days prior to study entry. * Other malignancies: unless the patient is considered disease-free and has completed therapy for the malignancy greater than or equal to 36 months prior to study entry. Patients with the following cancers are eligible if diagnosed and definitively treated within the past 12 months: carcinoma in situ of the cervix, and basal cell and squamous cell carcinoma of the skin. Other in situ neoplasms will be reviewed by the Protocol Officer and/or Protocol Chair. * Psychiatric or addictive disorders or other conditions that in the opinion of the investigator would preclude the patient from meeting the study requirements or interfering with interpretation of study results. * Pregnancy or lactation at the time of study entry. * Use of any investigational agent within 28 days prior to the first dose of study therapy.