Radiation and Immune Checkpoints Blockade in Metastatic NSCLC (BMS # CA209-632)

Inclusion Criteria:

* Ability to understand and the willingness to sign a written informed consent document;
* Histologic diagnosis of NSCLC;
* Any Kras or epidermal growth factor receptor (EGFR) status is permitted; Patients with an EGFR sensitizing mutation must have received an EGFR tyrosine kinase inhibitor (either erlotinib, gefitinib or afatinib) and patients with anaplastic lymphoma kinase (ALK) translocation must have received anti-ALK therapy.
* Patients must have at least two distinct measurable metastatic sites, with one of at least 1 cm or larger in its largest diameter. Patients may have additional non-measurable metastatic lesions (e.g., bone metastases);
* Patients must have prior treatment with at least one line of therapy for metastatic NSCLC. Any prior therapy is permitted except prior therapy with ipilimumab, other anti cytotoxic T-lymphocyte-associated protein (CTLA) agents or Checkpoint inhibitors;
* An interval of 2 weeks from last previous therapy is required;
* Patients must have recovered from the toxic effect(s) of the most recent anti-cancer treatment to NCI CTCAE Grade 1 or less (except alopecia).
* Patients must have adequate organ and marrow function as defined by initial laboratory tests:

white blood cell (WBC) ≥ 2000/uL

* absolute neutrophil count (ANC) ≥ 1.5/uL
* Platelets ≥ 100 x 103/uL
* Hemoglobin ≥ 9 g/dL
* Creatinine ≤ 1.5 x upper limit of normal (ULN)
* Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 x ULN, or ≤ 5 x ULN if liver metastases are present.
* Bilirubin ≤ 1.5 x ULN, (except patients with Gilbert's Syndrome, who must have a total bilirubin ≤ 3.0 mg/dL;

  * Performance status Eastern Cooperative Oncology Group (ECOG) 0-1 or Karnofsky \> 70%;
  * Men and women, ages \> 18 years of age;
  * Life expectancy \> 3 months;
  * Patients may have brain metastases if these are stable for at least 4 weeks and patients are not steroid dependent;
  * Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the study.
* WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal \[defined as amenorrhea ≥ 12 consecutive months; or women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level \> 35 mIU/mL \]. Even women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g., vasectomy), should be considered to be of child bearing potential. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin (hCG)) within 72 hours prior to the start of study medication.Men should use avoid impregnating women during study and for 7 mos after the study.

Exclusion Criteria:

* Patients having no lesions outside the field of radiation thus nullifying the ability to measure an abscopal effect;
* Autoimmune disease: Patients with a history of inflammatory bowel disease are excluded from this study as are patients with a history of symptomatic auto immune disease (e.g., rheumatoid arthritis, progressive systemic sclerosis \[scleroderma\]), systemic lupus erythematosus, autoimmune vasculitis \[e.g., Wegener's granulomatosis\];
* Patients with a history of symptomatic interstitial lung disease OR a history of (non-infectious) pneumonitis that required oral or IV steroids or current pneumonitis.
* Patients with active HIV infection Patients with Hepatitis B and Hepatitis C infection.
* Any underlying medical or psychiatric condition, which in the opinion of the Investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events (AEs), such as a condition associated with frequent diarrhea;
* Concomitant therapy with any of the following: IL-2, interferon or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids; Tyrosine Kinase inhibitors such as erlotinib;
* Prior therapy with ipilimumab or another anti-CTLA-4 antagonist;
* Women and men who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 5mos (women) or 7mos(men) weeks after cessation of study drug, or have a positive pregnancy test at baseline, or are pregnant or breastfeeding;
* Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness.