Genetic Testing in Screening Patients With Stage IB-IIIA Non-Small Cell Lung Cancer That Has Been or Will Be Removed by Surgery (The ALCHEMIST Screening Trial)

PRIMARY OBJECTIVES:

I. To centrally test resected non-small cell lung cancer (NSCLC) for genetic mutations to
facilitate accrual to randomized adjuvant studies.

II. To obtain clinically annotated tumor tissue and patient-matched non-malignant
deoxyribonucleic acid (DNA) from peripheral blood, as well as detailed epidemiologic and
clinical follow-up data, to allow clinically annotated advanced genomic analyses in concert
with the National Cancer Institute (NCI) Center for Cancer Genomics (CCG).

SECONDARY OBJECTIVES:

I. To characterize the natural history of molecularly characterized NSCLC to allow subsequent
development of targeted therapies against genotype-defined subpopulations in the adjuvant and
recurrent settings.

II. To cross-validate local genotyping assays for epidermal growth factor receptor (EGFR) and
anaplastic lymphoma receptor tyrosine kinase (ALK) with a central reference standard.

EXPLORATORY OBJECTIVES:

I. To study the genomic evolution of lung cancers by comparing genomic characteristics at
resection and at recurrence.

II. To understand reasons behind lack of enrollment to adjuvant targeted therapy studies for
potentially eligible patients.

III. To study the clinical significance of circulating tumor DNA within the plasma cell-free
DNA (cfDNA) from early stage lung cancer patients.

OUTLINE:

STEP 1 (SCREENING): Patients undergo collection of blood and tissue samples for EGFR, ALK,
and programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1)/cytotoxic
t-lymphocyte-associated protein 4 (CTLA-4) testing via direct sequencing, fluorescence in
situ hybridization (FISH) and immunohistochemistry (IHC). Patients that have had surgery
prior to pre-registration will submit samples from the previous surgery for testing.

STEP 2 (TREATMENT): Patients with a mutation targeted by one or more of the investigational
drugs used in this study or those without mutations are assigned to 1 of 3 treatment
subprotocols.

A081105: Patients are randomized to 1 of 4 treatment arms.

ARM A (BLINDED ERLOTINIB- CLOSED 06/14/17): Blinded patients receive erlotinib hydrochloride
orally (PO) once daily (QD) on days 1-21. Treatment repeats every 21 days for up to 2 years
in the absence of disease progression or unacceptable toxicity.

ARM B (PLACEBO- CLOSED 06/14/17): Patients receive placebo PO QD on days 1-21. Treatment
repeats every 21 days for up to 2 years in the absence of disease progression or unacceptable
toxicity.

ARM C (UNBLINDED ERLOTINIB): Unblinded patients receive erlotinib hydrochloride PO QD on days
1-21. Treatment repeats every 21 days for up to 2 years in the absence of disease progression
or unacceptable toxicity.

ARM D (OBSERVATION): Patients (including patients previously randomized to placebo) undergo
observation at least every 6 months for 2 years.

E4512: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive crizotinib PO twice daily (BID) on days 1-21. Treatment repeats every
21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

ARM B: Patients undergo observation.

EA5142: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Courses 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, patients that are not enrolled on either A081105, E4512, or EA5142
are followed up every 6 months for 5 years.

Inclusion Criteria:

- PATIENT PRE-REGISTRATION ELIGIBILITY CRITERIA:

- For pre-surgical patients

- Suspected diagnosis of resectable non-small cell lung cancer; cancers with a
histology of "adenosquamous" are considered a type of adenocarcinoma and thus a
"nonsquamous" histology; patients with squamous cell carcinoma are eligible only
if the registering site has EA5142 Institutional Review Board (IRB) approved

- Suspected clinical stage of IIIA, II (IIA or IIB) or large IB (defined as size >=
4 cm); Note: IB tumors < 4 cm are NOT eligible; stage IB cancer based on pleural
invasion is not eligible unless the tumor size is >= 4 cm; the 7th edition of
American Joint Committee on Cancer (AJCC) staging will be utilized

- For post-surgical patients

- Completely resected non-small cell lung cancer with negative margins (R0);
patients with squamous cell carcinoma are eligible only if the registering site
has EA5142 IRB approved

- Pathologic stage IIIA, II (IIA or IIB) or large IB (defined as size >= 4 cm);
Note: IB tumors < 4 cm are NOT eligible; stage IB cancer based on pleural
invasion is not eligible unless the tumor size is >= 4 cm; the 7th edition of
AJCC staging will be utilized

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

- No patients who have received neoadjuvant therapy (chemo- or radio-therapy) for this
lung cancer

- No locally advanced or metastatic cancer requiring systemic therapy within 5 years
prior to registration; no secondary primary lung cancer diagnosed concurrently or
within 2 year prior to registration

- No prior treatment with agents targeting EGFR mutation, ALK rearrangement, and
PD-1/PD-L1/CTLA-4

- No patients known to be pregnant or lactating

- Patients who have had local genotyping are eligible, regardless of the local result

- No patients with recurrence of lung cancer after prior resection

- Note: Post-surgical patients should proceed to registration immediately following
preregistration

- PATIENT REGISTRATION ELIGIBILITY CRITERIA:

- Completely resected NSCLC with negative margins (R0); cancers with a histology of
"adenosquamous" are considered a type of adenocarcinoma and thus a "nonsquamous"
histology; patients with squamous cell carcinoma are eligible only if the registering
site has EA5142 IRB approved

- Pathologic stage IIIA, IIA or IIB, or large IB (defined as size >= 4 cm); Note: IB
tumors < 4 cm are NOT eligible; stage IB cancer based on pleural invasion is not
eligible unless the tumor size is >= 4 cm; the 7th edition of AJCC staging will be
utilized

- Tissue available for the required analyses (either clinical tissue block or slides and
scrolls)

- In order to allow for time for central genotyping and eligibility for the ALCHEMIST
treatment trial, patients must register within the following eligibility windows,
depending on the adjuvant treatment approach:

- If no adjuvant therapy, register patient within 75 days following surgery

- If adjuvant chemotherapy or radiotherapy only, register patient within 225 days
following surgery

- If adjuvant chemotherapy and radiation, register patient within 285 days
following surgery