Cemiplimab With or Without Fianlimab to Treat Older Patients With Localized or Locally Advanced MSI-H Colorectal Cancer

Inclusion Criteria for Cohort A and B:

* Age ≥70 years.
* Eastern Cooperative Oncology Group (ECOG) performance status 0 -2
* Have histologically proven localized or locally advanced mismatch repair deficient (dMMR) or microsatellite unstable (MSI-H) colorectal cancer.
* Must not have received any prior systemic treatment or radiation.
* Must be agreeable to endoscopic, and CT surveillance for a total of 24 months.
* Patient's acceptance to have a tumor biopsy.
* Patients must have adequate organ and marrow function defined by study-specified laboratory tests and procedures.
* LVEF assessment with documented LVEF ≥ 45% by either TTE or MUGA (TTE preferred) within 6 months from first study drug administration.
* For both Women and Men, must use acceptable form of birth control while on study.
* Ability to understand and willingness to sign a written informed consent document.

Inclusion Criteria for Cohort C and D:

* Age ≥18 years.
* Eastern Cooperative Oncology Group (ECOG) performance status 0 -3.
* Have histologically proven localized or locally advanced mismatch repair deficient (dMMR) or microsatellite unstable (MSI-H) colorectal cancer.
* Patient deemed a poor surgical candidate after evaluation by a surgeon or unwilling to undergo surgery.
* Must not have received any prior systemic treatment or radiation.
* Must be agreeable to endoscopic, and CT surveillance for a total of 24 months.
* Patient's acceptance to have a tumor biopsy.
* Patients must have adequate organ and marrow function defined by study-specified laboratory tests and procedures.
* For both Women and Men, must use acceptable form of birth control while on study.
* Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria for Cohorts A and B:

* Have received an investigational agent or used an investigational device within 28 days of the first dose of study drug.
* Have expected to require any other form of systemic or localized antineoplastic therapy while on study.
* Have had surgery within 28 days of dosing of investigational agent, excluding minor procedures (dental work, skin biopsy, etc.).
* History of prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4, or anti-Lag-3 antibodies for any reason in the 5 years proceeding their colorectal cancer diagnosis.
* Currently using any chronic systemic steroids.
* Patient has received a live vaccine within 30 days of the first dose of study drug.
* History of severe hypersensitivity reaction to any monoclonal antibody.
* Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, symptomatic congestive heart failure, unstable angina, cardiac arrhythmia, metastatic cancer, or psychiatric illness/social situations that would limit compliance with study requirements.
* Active autoimmune disease.
* Any tissue or organ allograft, regardless of need for immunosuppression, including corneal allograft.
* Patient has a pulse oximetry of \<92% on room air.
* Patient is on supplemental home oxygen.
* Has clinically significant heart disease.
* Cohort B Only: Troponin T (TnT) or troponin I (TnI) \> 2x institutional ULN at baseline.
* Conditions, including alcohol or drug dependence, intercurrent illness, or lack of sufficient peripheral venous access, that would affect the patient's ability to comply with study visits and procedures.
* Unwilling or unable to follow the study schedule for any reason

Exclusion for Cohort C and D:

* Have received an investigational agent or used an investigational device within 28 days of the first dose of study drug.
* Have expected to require any other form of systemic or localized antineoplastic therapy while on study.
* Currently using any chronic systemic steroids.
* Patient has received a live vaccine within 30 days of the first dose of study drug.
* History of severe hypersensitivity reaction to any monoclonal antibody.
* Any tissue or organ allograft, regardless of need for immunosuppression, including corneal allograft.
* Patient is pregnant or breastfeeding.
* Cohort D Only: Troponin T (TnT) or troponin I (TnI) \> 2x institutional ULN at baseline.
* Conditions, including alcohol or drug dependence, intercurrent illness, or lack of sufficient peripheral venous access, that would affect the patient's ability to comply with study visits and procedures.
* Participation deemed not in the best interest of the patient.
* Unwilling or unable to follow the study schedule for any reason.