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

NSCLC patients with metastatic disease who have failed at least one prior treatment and have
a minimum of two metastatic lesions (at least one measurable), are eligible if they have an
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. Patients must be willing
to undergo a required pre-treatment biopsy prior to enrolling onto the study.

Non-ablative radiotherapy (6GyX5) is directed to one lesion during a first immunotherapy
treatment with Ipilimumab 3 mg/kg (± 24hrs from first RT dose). On day 22 the combined
treatment of ipilimumab plus nivolumab will start (nivolumab 240mg q 2 weeks, ipilimumab
1mg/kg q 6 weeks), and administered until evidence of progression.

Patients are re-imaged at Week 9 (day 70 ± 7) to evaluate for response (defined as an
objective response by RECIST of the measurable metastatic sites outside the radiation field).
This response will be evaluated assessing clinical and positron emission computed tomography
(PET/CT) responses in the non-irradiated measurable metastatic sites using RECIST 1.1.

Inclusion Criteria:

1. Ability to understand and the willingness to sign a written informed consent document;

2. Histologic diagnosis of NSCLC;

3. 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.

4. 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);

5. 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;

6. An interval of 2 weeks from last previous therapy is required;

7. 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).

8. 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;

9. Performance status Eastern Cooperative Oncology Group (ECOG) 0-1 or Karnofsky > 70%;

10. Men and women, ages > 18 years of age;

11. Life expectancy > 3 months;

12. Patients may have brain metastases if these are stable for at least 4 weeks and
patients are not steroid dependent;

13. 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:

1. Patients having no lesions outside the field of radiation thus nullifying the ability
to measure an abscopal effect;

2. 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];

3. 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.

4. Patients with active HIV infection Patients with Hepatitis B and Hepatitis C
infection.

5. 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;

6. 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;

7. Prior therapy with ipilimumab or another anti-CTLA-4 antagonist;

8. 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;

9. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for
treatment of either a psychiatric or physical (e.g., infectious) illness.