Nivolumab After Surgery and Chemotherapy in Treating Patients With Stage IB-IIIA Non-small Cell Lung Cancer (An ALCHEMIST Treatment Trial)

PRIMARY OBJECTIVES:

I. To evaluate whether adjuvant therapy with nivolumab will result in improved overall
survival (OS) and/or disease-free survival (DFS) over standard observation in patients with
stage IB >= 4 cm, II and IIIA, non-small cell lung cancer (NSCLC) following surgical
resection and standard adjuvant therapy.

II. To evaluate whether adjuvant therapy with nivolumab will result in improved disease-free
survival (DFS) over standard observation in patients with stage IB >= 4cm, II and IIIA, NSCLC
with high PD-L1 expression (>= 50% staining) following surgical resection and standard
adjuvant therapy.

III. To evaluate whether adjuvant therapy with nivolumab will result in improved overall
survival (OS) over standard observation in patients with stage IB >= 4cm, II and IIIA, NSCLC
following surgical resection and standard adjuvant therapy.

SECONDARY OBJECTIVES:

I. To evaluate the safety profile of nivolumab when given as an adjuvant therapy.

II. To evaluate and compare disease free and overall survival in patients with tumors that
express programmed cell death ligand (PD-L)1 in various patterns associated with nivolumab
and standard observation.

III. To evaluate and compare disease free and overall survival in patients with tumors that
have high mutational load associated with nivolumab and standard observation.

IV. To evaluate OS and DFS by stage. V. To evaluate OS and DFS by each stratification factor.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Cycles repeat
every 4 weeks for up to 1 year in the absence of disease progression or unacceptable
toxicity.

ARM II: Patients are followed serially with imaging for 1 year.

After completion of study treatment, patients are followed up at 6 weeks, every 3 months for
2 years, every 6 months for 2 years, and then every 12 months for 6 years.

Inclusion Criteria:

- Patients must have undergone complete surgical resection of their stage IB (>= 4 cm),
II or IIIA NSCLC according to the American Joint Committee on Cancer (AJCC) 7th
edition and have had negative surgical margins

- Baseline chest computed tomography (CT) must be performed within 1 month (30 days) of
randomization to ensure no evidence of disease; if clinically indicated, additional
imaging studies must be performed to rule out metastatic disease

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1

- Patients must be registered to the ALCHEMIST-SCREEN (ALLIANCE A151216) trial prior to
randomization

- Non-squamous tumors must not be positive for epidermal growth factor receptor (EGFR)
exon 19 deletion or exon 21 L858R mutation (centrally as part of the ALCHEMIST-SCREEN
protocol) and anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangement
(centrally as part of ALCHEMIST-SCREEN and/or locally)

- NOTE: if the results of the central EGFR testing are negative, but the ALK
testing was not able to be completed by the ALCHEMIST central lab, the ALK status
will be considered negative (unless locally positive for ALK rearrangement) and
the patient may be considered for enrollment onto EA5142, once PD-L1 results are
received and all other eligibility requirements are met

- Tumors must have PD-L1 status tested centrally as part of the ALCHEMIST-SCREEN
protocol

- Women must not be pregnant or breast-feeding due to unknown and potentially harmful
effects of nivolumab on the developing fetus or child

- All females of childbearing potential must have a blood test or urine study within 2
weeks prior to registration to rule out pregnancy; a female of childbearing potential
is any woman, regardless of sexual orientation or whether they have undergone tubal
ligation, who meets the following criteria: 1) has not undergone a hysterectomy or
bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive
months)

- Women of childbearing potential and sexually active males must be strongly advised to
use an accepted and effective method of contraception or to abstain from sexual
intercourse during the treatment period and for 31 weeks after the last nivolumab
infusion

- Patients must NOT have uncontrolled intercurrent illness including, but not limited
to, serious ongoing or active infection, symptomatic congestive heart failure,
unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric
illness/social situation that would limit compliance with study requirements

- No prior treatment with an immune checkpoint inhibitor (anti-programmed cell death
[PD]-1, anti-PD-L1, anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA4]
monoclonal antibody)

- Patients must have adequately recovered from surgery and any administered
chemotherapy/radiotherapy at the time of randomization (NOTE: adjuvant chemotherapy
and/or radiation is not required)

- Minimum time between date of surgery and randomization is 4 weeks (28 days)

- Maximum time allowed between surgery and randomization:

- 3 months (90 days) if no chemotherapy is administered

- 8 months (240 days) if adjuvant chemotherapy was administered

- 10 months (300 days) if adjuvant chemotherapy and radiation therapy was
administered

- Patients must have completed and recovered from any adjuvant chemotherapy 2 or more
weeks prior to randomization (6 weeks for mitomycin and nitrosoureas; 4 weeks for
post-operative radiation therapy) (NOTE: adjuvant chemotherapy and/or radiation is not
required)

- Serum aspartate transaminase (aspartate aminotransferase [AST]) and serum alanine
transaminase (alanine aminotransferase [ALT]) =< 2.5 x upper limit normal (within 2
weeks prior to randomization)

- Total bilirubin =< 1.5 x upper limit of normal (ULN) (except in subjects with Gilbert
syndrome who must have a total bilirubin < 3.0 x ULN) (within 2 weeks prior to
randomization)

- White blood cell (WBC) >= 2000/uL (within 2 weeks prior to randomization)

- Neutrophils >= 1000/uL (within 2 weeks prior to randomization)

- Platelets >= 100 x 10^3/uL (within 2 weeks prior to randomization)

- Hemoglobin >= 8 g/dL (within 2 weeks prior to randomization)

- Serum creatinine =< 2 x ULN (within 2 weeks prior to randomization)

- Prior to randomization patients with any non-hematologic toxicity from surgery,
chemotherapy and radiation therapy must have recovered to grade =< 1 with the
exception of alopecia, ototoxicity and neuropathy

- Patients must not be receiving any other investigational anti-cancer agents while on
study

- Patients must not have known or suspected autoimmune disease; subjects with type I
diabetes mellitus, hypothyroidism requiring hormone replacement, or skin disorders not
requiring systemic treatment are permitted to enroll

- Patients must not have a condition requiring systemic corticosteroids equivalent to >
10 mg prednisone per day or other immunosuppressive medications within 2 weeks of
randomization; inhaled, intra-articular, and epidural steroids are permissible

- Patients must not have known interstitial lung disease that is symptomatic or may
interfere with the detection or management of suspected drug-related pulmonary
toxicity

- Patients must not have a known history of human immunodeficiency virus (HIV),
hepatitis B, or hepatitis C infection that is untreated and/or with a detectable viral
load

- Patients must not have a history of allergic reactions attributed to compounds of
similar chemical or biologic composition to nivolumab