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/OTHER 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 4 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. 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.

      A081801: Patients are randomized to 1 of 3 arms.

      ARM A:

      INITIAL THERAPY: Patients receive 1 of 4 platinum doublet regimens* based on the treating
      physician's choice. Treatment repeats every 21 days for 4 cycles in the absence of disease
      progression or unacceptable toxicity.

      CONTINUANCE THERAPY: Patients then undergo observation.

      ARM B:

      INITIAL THERAPY: Patients receive 1 of 4 platinum doublet regimens* based on the treating
      physician's choice. Treatment repeats every 21 days for 4 cycles in the absence of disease
      progression or unacceptable toxicity.

      CONTINUANCE THERAPY: Patients then receive pembrolizumab intravenously (IV) over 25-40
      minutes on day 1. Treatment repeats every 21 days for 17 cycles in the absence of disease
      progression or unacceptable toxicity.

      ARM C:

      INITIAL THERAPY: Patients receive 1 of 4 platinum doublet regimens* based on the treating
      physician's choice and pembrolizumab IV over 25-40 minutes on day 1. Treatment repeats every
      21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

      CONTINUANCE THERAPY: Patients then receive pembrolizumab IV over 25-40 minutes on day 1.
      Treatment repeats every 21 days for 13 cycles in the absence of disease progression or
      unacceptable toxicity.

      *ACCEPTABLE REGIMENS: DOUBLET I: Patients receive cisplatin IV over 1-2 hours and pemetrexed
      IV over 10 minutes on day 1 of each cycle.

      DOUBLET II: Patients receive carboplatin IV over 30 minutes and pemetrexed IV over 10 minutes
      on day 1 of each cycle.

      DOUBLET III: Patients receive cisplatin IV over 1-2 hours on day 1 of each cycle and
      gemcitabine hydrochloride IV over 30 minutes on days 1 and 8 of each cycle.

      DOUBLET IV: Patients receive carboplatin IV over 30 minutes and paclitaxel IV over 3 hours on
      day 1 of each cycle.

      After completion of study, patients that are not enrolled on either A081105, E4512, EA5142,
      or A081801 are followed up every 6 months for 5 years.