Pembrolizumab and Radiation Therapy in Treating Patients with Microsatellite Instability-High and Mismatch Repair Deficient Metastatic or Unresectable Solid Tumors or Colorectal Cancer

Inclusion Criteria

• Provision to sign and date the consent form.
• Stated willingness to comply with all study procedures and be available for the duration of the study.
• Eastern Cooperative Oncology Group (ECOG) 0 or 1.
• Unresectable or metastatic MSI-H/dMMR tumors eligible to receive pembrolizumab according to Food and Drug Administration (FDA)-approved indications: * Solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options OR * Colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
• Confirmation from medical or gynecologic oncology that the patient is eligible to receive pembrolizumab per FDA-approved indication for patients not currently receiving pembrolizumab.
• At least one site of disease amenable to radiation therapy per the acceptable dosing regimens and at least one additional site of measurable disease suitable for out-of-field response assessment.
• Absolute neutrophil count (ANC) >= 1,000/uL.
• Platelets >= 75,000/uL.
• Hemoglobin >= 8 g/dL.
• Serum creatinine < 1.5 x upper limit of normal (ULN).
• Serum total bilirubin < 1.5 x ULN.
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x ULN, or < 5 x ULN if liver metastasis are present.

Exclusion Criteria

• Pregnant women. Pregnancy testing is required for all female subjects of childbearing potential.
• Patients with active collagen vascular disease (CVD), specifically systemic lupus erythematosus or scleroderma. Patients with a history of CVD without evidence of active disease are eligible for enrollment at the discretion of the study principal investigator (PI).
• History of immunodeficiency, hypersensitivity to pembrolizumab, or other medical contraindication to receipt of pembrolizumab.
• Active infection.
• Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with the use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Active central nervous system (CNS) metastases. Patients with treated CNS metastases are eligible.
• Receipt of corticosteroid therapy at greater than physiologic dosing within 14 days of the start of radiation therapy.
• Patients with a separate non-cutaneous cancer diagnosis for which the patient has not been without evidence of disease for at least 5 years.