A Proof of Principle Study of Pembrolizumab With SBRT in TKI mRCC Patients

Inclusion Criteria: 1. Be willing and able to provide written informed consent for the trial. 2. Be ≥ 18 years of age on day of signing informed consent. 3. Patients with a histologic confirmation of renal cell carcinoma with a clear cell component where the best response to first line TKI therapy (sunitinib, pazopanib, axitinib etc) is progression, or untreated RCC patients with sarcomatoid differentiation. 4. Evidence of measurable metastatic kidney cancer according to RECIST 1.1 criteria. Patients should have an adequate number of non-irradiated metastatic sites in order to adequately assess the activity of the pembrolizumab therapy. 5. Karnofsky performance status of ≥80. 6. Favorable (0 risk factors), intermediate (1-2 risk factors) and poor risk (3-6 risk factors) patients by the Heng prognostic model are eligible based on the number of the following risk factors present. 7. Demonstrate adequate organ function, all screening labs should be performed within 10 working days of the first dose of trial treatment. 8. Male subjects should agree to use an adequate method of contraception starting with the first dose of trial treatment through 120 days after the last dose of trial treatment. 9. 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 trial treatment. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year. 10. One to three extra-cranial metastases eligible for SBRT. Exclusion Criteria: 1. 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. 2. Has had a prior monoclonal antibody within 4 weeks prior to the first dose of trial treatment or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. 3. Has more than one previous targeted small molecule therapy, or radiation therapy within 2 weeks prior to the first dose of trial treatment 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. * Note: If subject received major surgery, they must have recovered adequately in the opinion of the investigator from the toxicity and/or complications from the intervention prior to starting trial treatment. 4. 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. 5. Has known brain metastases and/or carcinomatous meningitis. Exceptions include patients who have completed treatment for brain metastases at least 3 months prior to starting treatment with pembrolizumab and remained stable and no longer require steroids to control brain edema. 6. Diagnosis of ataxia telangiectasia or active collagen vascular disease. 7. 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. 8. Has evidence of interstitial lung disease, a history of non-infectious pneumonitis that required steroids, or current pneumonitis. 9. Has a known active infection requiring systemic therapy. 10. 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. 11. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 12. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment. 13. 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). 14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 15. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected). 16. Has received a live vaccine within 30 days prior to the first dose of trial treatment.