Stereotactic radiosurgery (SRS) is increasingly administered as the sole treatment of brain metastases, in order to spare acute and long term side effects associated with whole brain radiotherapy. Local control of SRS treated lesions is good, but patients tend to develop additional brain metastases subsequently.

Nivolumab is a modulator of the immune system. Treatment with Nivolumab is associated with an increase in local control and survival in patients with non-small cell lung cancer and clear cell renal cell carcinoma. In the presence of Nivolumab, treatment of brain metastases with SRS may trigger an immune reaction against cancer. Therefore, the combination of SRS with Nivolumab may reduce the development of new brain metastases and improve patient survival.

The purpose of this study is to assess the effect of combining Nivolumab and SRS in controlling cancer progression. SRS will be administered to patients while they are receiving Nivolumab.

Inclusion Criteria:

1. Men and women, ≥ 18 years of age

2. Willing and able to give written informed consent

3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 within 28 days prior to registration

4. Radiation Therapy Oncology Group (RTOG) neurological function score of 0-1 within 28 days prior to registration

5. Histologic diagnosis of NSCLC, SCLC, Melanoma OR ccRCC

6. Stage IV cancer with brain metastases (Patients may have untreated primary disease)

7. Presenting with previously un-irradiated brain metastasis (10 cc maximum volume of brain disease based on the diagnostic screening MRI done within 28 days of registration))

8. Measurable/evaluable brain disease

9. Having received less than 4 lines of prior systemic treatments

10. Ability to be treated with either gamma knife or a linear accelerator based radiosurgery system

11. Ability to complete neurocognitive exams without assistance

12. Ability to complete QOL questionnaires with or without assistance

13. Screening laboratory values must meet the following criteria and should be obtained within 28 days prior to registration:

    • White Blood Cell (WBC) ≥ 2000/uL
    • Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L
    • Platelets≥ 100 x 109/L
    • Hemoglobin ≥ 90 g/L (may be transfused)
    • Serum creatinine ≤ 1.5 x Upper Limit of Normal (ULN) or Creatinine Clearance ≥ 50 ml/min (calculated -cockcroft-Gault)
    • Aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≤3 x ULN without liver metastasis,≤ 5 x ULN with liver metastases
    • Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)

14. Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (28 days plus the time required for Nivolumab to undergo five half-lives) after the last dose of investigational drug

15. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of Nivolumab

16. Women must not be breastfeeding

17. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving Nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of Nivolumab product. Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception).

Exclusion Criteria:

1. Brain metastasis in the brainstem
2. Patients who experienced prior seizures are eligible, however patients should not have had a seizure within 7 days of registration without the use of corticosteroids.
3. All other cancer histology other than NSCLC or ccRCC
4. Patients who cannot undergo MRI
5. Active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
6. Patients with a condition requiring systemic treatment with either corticosteroids including steroids used for treating peritumoral edema (> 50 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
7. Drugs with a predisposition to hepatoxicity should be used with caution in patients treated with Nivolumab-containing regimen
8. Any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of Nivolumab hazardous or obscure the interpretation of AEs, such as a condition associated with frequent diarrhea.
9. History of prior treatment with a CTLA-4, PD-1 or PD-L1 inhibitor, CD137 agonist, or anti-PD-L2.
10. Concomitant therapy with any of the following: IL-2, interferon, or other non-study immunotherapy regimens; immunosuppressive agents; other investigation therapies
11. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (eg, infectious) illness.
12. Known history of hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
13. History of allergy to study drug components.
14. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).