Cemiplimab with or without Fianlimab for the Treatment of Older Patients with Localized or Locally Advanced MSI-H Colorectal Cancer

Inclusion Criteria

• Age ≥ 70 years
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Have histologically proven localized or locally advanced (Stage I, II, or III) mismatch repair deficient (dMMR) or microsatellite unstable (MSI-H) colorectal cancer * NOTE: Patients with DNA mismatch repair deficiency (dMMR) who start therapy and subsequently have a polymerase chain reaction-capillary electrophoresis (PCR-CE) or next-generation sequencing (NGS) test that indicates microsatellite stability (MSS) will become ineligible for protocol and will be removed from the study (unless clinically responding as determined by the protocol chair)
• Patients have not received any prior systemic treatment or radiation for their colorectal cancer
• Patient agreeable to endoscopic, and CT surveillance for a total of 24 months
• Patient acceptance to tumor biopsy of primary lesion on-treatment if lesion can be biopsied with acceptable clinical risk (as judged by the investigator)
• Absolute neutrophil count ≥ 1,000/mcL
• Platelets ≥ 90 × 10^3/uL
• Hemoglobin ≥ 9.0 g/dL
• Total bilirubin ≤ 1.5 upper limit of normal (ULN) except subjects with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3.0 × ULN
• Creatinine clearance (CrCl) ≥ 40 mL/min (if using the Cockcroft-Gault formula)
• Left ventricular ejection fraction (LVEF) assessment with documented LVEF ≥ 45% by either transesophageal echocardiography (TTE) or multigated acquisition (MUGA) (TTE preferred) within 6 months from first study drug administration
• Men who are sexually active with women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 5 half-lives of study drug(s) plus 90 days (duration of sperm turnover) for a total of 7 months post-treatment completion
• Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria

• Patient has received an investigational agent or used an investigational device within 28 days of the first dose of study drug
• Patient is expected to require any other form of systemic or localized antineoplastic therapy while on study
• Patients who have had surgery within 28 days of dosing of investigational agent, excluding minor procedures (dental work, skin biopsy, etc.)
• Patients with a 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 (at doses exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy (steroid premedication for contrast is allowed)
• 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. Exceptions may be approved by protocol chair if the patient has subsequently tolerated an antibody
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, symptomatic cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Subjects with active autoimmune disease. Subjects with Graves or Hashimoto’s disease, vitiligo, type I diabetes mellitus, psoriasis or other conditions not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. Subjects with autoimmune conditions requiring systemic treatment in the past may be approved by the investigational new drug (IND) sponsor
• Presence of any tissue or organ allograft, regardless of need for immunosuppression, including corneal allograft. Exceptions can be approved by the IND sponsor if loss of the graft is not a clinical concern. Patients with a history of allogeneic hematopoietic stem cell transplant will be excluded
• Patient has a pulse oximetry of < 92% on room air
• Patient is on supplemental home oxygen
• Patient has clinically significant heart disease (such as uncontrolled angina, myocardial infarction within the last 3 months or congestive heart failure of New York Heart Association III or IV)
• Troponin T (TnT) or troponin I (TnI) > 2 x institutional ULN at baseline. Patients with TnT or TnI levels between > 1 to 2 x ULN are permitted to enroll if repeat levels within 24 hours are ≤ 1 x ULN. If TnT or TnI levels are > 1 to 2 x ULN within 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment by the investigator based on their medical judgment and the patient’s best interest
• Patient is, at the time of signing informed consent, a regular user (including “recreational use”) of any illicit drugs or other substance abuse (including alcohol) that could potentially interfere with adherence to study procedures or requirements
• Patient is unwilling or unable to follow the study schedule for any reason