Neoadjuvant Nivolumab, or Nivolumab in Combination With Ipilimumab, in Resectable NSCLC

The proposed study will evaluate the safety and feasibility of preoperative administration
nivolumab +/- ipilimumab in patients with high-risk resectable NSCLC, and will facilitate a
comprehensive exploratory characterization of the tumor immune milieu and circulating immune
cells and soluble factors in these patients. Data obtained in this study will provide
valuable information for planning further prospective clinical trials of anti-PD-1 and other
immunotherapies in NSCLC, both in the peri-operative and advanced disease setting.
Ultimately, it is highly desirable to discover prospective biomarkers of response and
toxicity to allow patients with NSCLC who are most likely to derive benefit to receive
anti-PD-1 treatment, and conversely to minimize the risk of toxicity and ineffective
treatment for patients who are unlikely to benefit.

In addition, an amendment to this study allows evaluation of the combination of nivolumab and
the anti-CTLA4 antibody, ipilimumab in the neoadjuvant setting for the treatment of
resectable NSCLC. In a large, multicohort, phase 1 trial, the ORR to combination ipilimumab
and nivolumab therapy in patients unselected by PD-L1 status ranged from 39-47%. Incidence of
grade 3-4 toxicity ranged from 33-37% across the combination ipilimumab and nivolumab cohorts
which compares favorably with the rates of toxicity due to platinum doublet chemotherapy in
this disease setting.

Inclusion Criteria:

- Histologically proven non-small-cell lung cancer (core biopsy required).

- Squamous or non-squamous histology

- Diagnostic core biopsy specimens must be reviewed by a faculty pathologist at
SKCCC or MSKCC

- Either a formalin fixed paraffin block or a minimum of fifteen 5-micron tissue
sections (slides) of tumor biopsy sample must be available for biomarker
evaluation (study pathologist must review for adequacy of sampling). This can be
obtained from archived tissues, or from a new biopsy if needed.

- Stage - High risk NSCLC with resection option for potential cure, as assessed by a
faculty surgeon at SKCCC or MSKCC. This may include clinical stage IB (≥4cm), II and
IIIA(see Appendix A). Subjects with N3 nodal involvement are not included.

ECOG performance status 0-1

-Adequate organ function as follows:

- Leukocytes ≥ 2,000/mm3

- Absolute neutrophil count (ANC) ≥ 1000/mm3

- Platelet count ≥ 100,000/mm3

- Hemoglobin ≥ 9 g/dL

- Creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥40 mL/min (if using the
Cockcroft-Gault formula below):

Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL

Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL

- Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total
bilirubin < 3.0 mg/dL)

- AST(SGOT), ALT(SGPT), and alkaline phosphatase ≤ 3 times the upper limit of normal

- Subjects must have adequate lung function to permit surgical resection determined by
pre-enrollment pulmonary function tests to include DLCO

- The effects of nivolumab on the developing human fetus are unknown. For this
reason, women of child-bearing potential (WOCBP) and men must agree to use
adequate contraception (hormonal or barrier method of birth control; abstinence)
prior to study entry and for the duration of study participation and for up to 23
weeks after the last dose of nivolumab. Should a woman become pregnant or suspect
she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately. Sexually active fertile men
must use effective barrier birth control if their partners are WOCBP for up to 31
weeks after the last dose of nivolumab. WOCBP must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within
two weeks of registration. Women must not be breastfeeding.

- Patient understands the study regimen, its requirements, risks and discomforts
and is able and willing to sign the informed consent form. Voluntary signed and
dated IRB/IEC approved written informed consent form in accordance with
regulatory and institutional guidelines must be obtained before the performance
of any protocol related procedures that are not part of normal patient care.
Subjects must be competent to report AEs, understand the drug dosing schedule and
use of medications to control AEs.

Exclusion Criteria:

- Subjects are excluded if they have an 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.

- Subjects are excluded if they have a condition requiring systemic treatment with
either corticosteroids (> 10 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. As there is potential for
hepatic toxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a
predisposition to hepatoxicity should be used with caution in patients treated with
nivolumab-containing regimen.

- Administration of chemotherapy or any other cancer therapy in the pre-operative
period.

- Subjects with active concurrent malignancies are excluded i.e. cancers other than
NSCLC (except non melanoma skin cancers, in situ bladder, gastric, breast, colon or
cervical cancers/dysplasia).

- Subjects with brain metastasis are excluded from this study, and all patients should
have brain imaging (either MRI brain or CT brain with contrast) prior to enrollment.

- Subjects with a history of symptomatic interstitial lung disease.

- Active systemic infection requiring therapy, positive tests for Hepatitis B surface
antigen or Hepatitis C ribonucleic acid (RNA).

- Known positive history or positive test for Human Immunodeficiency Virus or Acquired
ImmunoDeficiency Syndrome (AIDS).

- History of allergy to study drug components.

- Women who are pregnant or nursing.

- Men with female partners (WOCBP) that are not willing to use contraception.

- Prior therapy with an anti-PD-1, anti-PD-L1, anti-PDL-2, or anti-CTLA-4 antibody (or
any other antibody targeting T cell co-regulatory pathways).

- Underlying medical conditions that, in the Investigator's opinion, will make the
administration of study drug hazardous or obscure the interpretation of toxicity or
adverse events.

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