The radiation therapy or ablation that the patient received as standard therapy treated only the tumors that were radiated or ablated. Radiation therapy or ablation plus pembrolizumab might lead to a stronger immune response that may control or destroy tumors that did not receive radiation therapy or ablation. The purpose of this study is to find out what effects, good and/or bad, pembrolizumab has on the patient, and the cancer that did not receive radiation therapy or ablation.

Inclusion Criteria:

• Be willing and able to provide written informed consent/assent for the trial.
• Histologically- or cytologically- confirmed CRC.
• Metastatic or recurrent CRC
• Subjects have received two or more standard available therapies known to prolong survival and for which they would be considered eligible. Such therapies should include regimens containing oxaliplatin and irinotecan in combination with a fluoropyrimidine if appropriate (e.g., FOLFOX and FOLFIRI or their variants).
• At least one tumor for which palliative RT is considered appropriate standard therapy (cohort 1); or, at least one tumor for which palliative ablation is considered appropriate standard therapy (cohort 2).
• At least one index lesion that will not undergo RT or ablation, and which is measurable based on RECIST 1.1.
• Be ≥ 18 years of age on day of signing informed consent. Consent for tumor biopsies and blood draws for research purposes.
• Consent for use of available archived tissue for research purposes.
• Have a performance status of 0 or 1 on the ECOG Performance Scale.
• Demonstrate adequate organ function as defined in Table 6.1, all screening labs should be performed within 6 weeks of treatment initiation.

Hematological

• Absolute neutrophil count (ANC) ≥1,500 /mcL

• Platelets ≥100,000 / mcL Renal

• Serum creatinine OR Measured or calculated* creatinine clearance (GFR can also be used in place of creatinine or CrCl)

• ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN Hepatic

• Serum total bilirubin ≤ 1.5 X ULN OR

• Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN

• AST (SGOT) and ALT (SGPT)

• ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases Coagulation

• International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

• Activated Partial Thromboplastin Time ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

  • Creatinine clearance should be calculated per institutional standard.

• Female subject of childbearing potential should have a negative serum pregnancy within 2 weeks prior to starting radiation therapy or undergoing ablation.

• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication (Reference Section 9.5.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.

• Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.

Exclusion Criteria:

• Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.

• Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.

• Has had prior chemotherapy, targeted small molecule therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.

  ° Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.

• If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.

• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.

• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment.

• Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study.

• Has evidence of interstitial lung disease or active, non-infectious pneumonitis.

• Has an active infection requiring systemic therapy.

• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.

• Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).

• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).

• Has received a live vaccine within 30 days prior to the first dose of trial treatment.

2 years