Unresectable Stage IIIA/IIIB Non-small Cell Lung Cancer (NSCLC)

Patients with unresectable stage IIIA or IIIB NSCLC (unresectable as defined by treating
physician) will be treated outside this study with concurrent chemoradiation with one of
three chemotherapy regimens (cisplatin/etoposide, cisplatin/pemetrexed, or weekly
carboplatin/paclitaxel) in addition to standard dose radiation (dosing can range from 59.4 Gy
to 66.6 Gy). If repeat imaging between 28-56 days following completion of chemoradiation
shows no progressive or metastatic disease, the patients will be eligible for enrollment on
the study.

Randomization and Stratification:

At the time of enrollment, patients will be randomized in a 1:1 fashion to receive either
nivolumab 480mg IV every 4 weeks or the combination of nivolumab 3mg/kg IV every 2 weeks with
ipilimumab 1mg/kg IV every 6 weeks. Consolidation immunotherapy will be continued until
progression or unacceptable toxicity for up to a total of 24 weeks.

Subjects will be stratified by stage (IIIA vs. IIIB) and histology (squamous vs.
non-squamous).

Dose Calculations:

Arm 1: The dose of nivolumab will be a fixed dose (not based on subject's weight) at 480mg.

Arm 2: The dose of nivolumab will be weight-based at 3mg/kg. The dose of ipilimumab will be
weight-based at 1mg/kg.

Nivolumab Alone (Arm 1):

Arm 1: Nivolumab Administration:

Nivolumab 480 mg will be administered as a 60 minute IV infusion on Day 1 of each 28 day
cycle. Sites should make every effort to target infusion timing to be as close to 60 minutes
as possible. However, given the variability of infusion pumps from site to site, a window of
-five minutes and +10 minutes is permitted (i.e., infusion time is 60 minutes: -5 min/+10
min). Treatment will continue for up to 6 cycles, in the absence of prohibitive toxicities or
disease progression.

Nivolumab Plus Ipilimumab (Arm 2):

Arm 2: Nivolumb Administration:

Nivolumab 3mg/kg will be administered as a 60 minute IV infusion on Day 1, 15, and 29 of each
42 day cycle. Nivolumab should not be given any earlier than 12 days from the previous dose.
Sites should make every effort to target infusion timing to be as close to 60 minutes as
possible. However, given the variability of infusion pumps from site to site, a window of
-five minutes and +10 minutes is permitted (i.e., infusion time is 60 minutes: -5 min/+10
min). Treatment will continue for up to 4 cycles, in the absence of prohibitive toxicities or
disease progression.

Arm 2: Ipilimumab Administration:

Ipilimumab 1mg/kg will be administered as a 90 minute IV infusion on Day 1 of each 42 day
cycle. Sites should make every effort to target infusion timing to be as close to 90 minutes
as possible. However, given the variability of infusion pumps from site to site, a window of
-five minutes and +10 minutes is permitted (i.e., infusion time is 60 minutes: -5 min/+10
min). Treatment will continue for up to 4 cycles, in the absence of prohibitive toxicities or
disease progression.

On day 1 of cycle 1, nivolumab will be given first, followed by 30 minutes of monitoring, and
then ipilimumab given second, followed by 30 minutes of monitoring. If the subject does not
have an infusion reaction during the first cycle, the post-ipilimumab monitoring may be
discontinued for subsequent cycles at the discretion of the treating physician. Day 1
monitoring between the nivolumab/ipilimumab infusions will continue throughout all 4 cycles.
Post nivolumab monitoring on days 15 and 29 is not mandatory and should follow the guidelines
of the local infusion center.

Inclusion Criteria:

Subject must meet all of the following applicable inclusion criteria to participate in this
study:

- Written informed consent and HIPAA authorization for release of personal health
information.

- Age ≥ 18 years at the time of consent.

- ECOG Performance Status of 0 or 1 within 14 days prior to registration.

- Histological or cytological confirmation of NSCLC. A pathology report confirming the
diagnosis of NSCLC must be obtained and reviewed by the treating physician prior to
registration to study.

- Must have unresectable or inoperable stage IIIA or IIIB disease. Subjects must be
considered unresectable or inoperable based on the judgment of the treating physician.

- Subjects may have completed concurrent chemoradiation with a standard chemotherapy
regimen (Cisplatin/Etoposide, Carboplatin/Paclitaxel or Cisplatin/Pemetrexed
[non-squamous only]) and a dose of radiation ranging from 59.4-66.6 Gy. Subjects must
have stable disease or disease response as evidenced on CT or PET scan evaluation. For
those eligible, protocol therapy should begin a minimum of 28 days and a maximum 56
days following the completion of chemoradiation OR Subjects may have completed up to 2
cycles of consolidation therapy started within 4 weeks of completion of radiation.
After completion of consolidation chemotherapy, subjects must have stable disease or
disease response as evidenced by CT or PET scan evaluation. For those eligible,
protocol therapy should begin 3-4 weeks after the last cycle of chemotherapy.

- Prior cancer treatment must be completed at least 28 days prior to registration and
the subject must have recovered from all reversible acute toxic effects of the regimen
(other than alopecia) to ≤Grade 1 or baseline.

- Demonstrate adequate organ function, all screening labs to be obtained within 14 days
prior to registration:

Hematological:

- Absolute Neutrophil Count (ANC) ≥ 1.5 K/mm^3

- Hemoglobin (Hgb) ≥ 9 g/dL

- 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
subjects with creatinine levels >1.5 x institutional ULN

Hepatic:

- Bilirubin ≤ 1.5 × ULN OR Direct bilirubin of ≤ ULN for subjects with total bilirubin
levels of >1.5x ULN

- Aspartate aminotransferase (AST) ≤ 2.5 × ULN

- Alanine aminotransferase (ALT) ≤ 2.5 × ULN

Coagulation:

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

- Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7
days prior to registration. NOTE: Women are considered of childbearing potential
unless they are surgically sterile (have undergone a hysterectomy, bilateral
tubal ligation, or bilateral oophorectomy) or are post-menopausal. Menopause is
defined clinically as 12 months of amenorrhea in a woman over 45 in the absence
of other biological or physiological causes. In addition, women under the age of
62 must have a documented serum follicle stimulating hormone (FSH) level less
than 40 mIU/mL.

- Women of childbearing potential must be willing to abstain from heterosexual
activity or use an effective method of contraception from the time of informed
consent until 23 weeks after treatment discontinuation.

- Men who are sexually active with women of childbearing potential (WOCBP) must use
any contraceptive method with a failure rate of less than 1% per year. Men
receiving study drug 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
investigational product.

- As determined by the enrolling physician or protocol designee, ability of the
subject to understand and comply with study procedures for the entire length of
the study.

Exclusion Criteria:

Subjects meeting any of the criteria below may not participate in the study:

- 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 23 weeks (female) or 31 weeks (male) after the last dose of trial treatment.

- Active central nervous system (CNS) metastases. Subjects must undergo a head computed
tomography (CT) scan or brain MRI within 28 days prior to registration for protocol
therapy to exclude brain metastases if symptomatic or without prior brain imaging.

- Treatment with any investigational agent within 28 days prior to registration for
protocol therapy.

- Prior chemotherapy, adjuvant therapy, or radiotherapy for lung cancer other than
standard concurrent chemoradiation or up to 2 cycles of consolidation.

- Prior therapy with a PD-1, PD-L1, PD-L2 or CTLA-4 inhibitor or a lung cancer-specific
vaccine therapy.

- Presence of metastatic disease (stage IV NSCLC) is not allowed. Subjects must be
evaluated with a CT or PET scan prior to registration for protocol therapy to exclude
metastatic disease.

- Active second cancers.

- Evidence of active autoimmune disease requiring systemic treatment within the past 90
days 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
Sjogren's syndrome will not be excluded from the study.

- Interstitial lung disease or history of pneumonitis requiring treatment with
corticosteroids.

- Diagnosis of immunodeficiency or is receiving chronic systemic corticosteroid therapy
or other immunosuppressive therapy (excludes inhaled corticosteroids) within 7 days of
first dose of study drug.

- History of psychiatric illness or social situations that would limit compliance with
study requirements.

- Clinically active infection as judged by the site investigator (≥ Grade 2 by CTCAE
v4).

- History of human immunodeficiency virus (HIV) infection or chronic hepatitis B or C.

- 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 site investigator.

- Has a known history of active TB (Bacillus Tuberculosis).

- Hypersensitivity to nivolumab, ipilimumab, or any of their excipients.

- Has received a live vaccine within 30 days prior to planned start of study therapy.
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines
and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live
attenuated vaccines, and are not allowed.