PRIMARY OBJECTIVES:

I. To compare the disease free survival (DFS) and overall survival (OS) (dual primary endpoints) between combination MK-3475 (pembrolizumab) plus standard of care (Arm C) versus (vs.) standard of care (Arm A) in patients with stage IB-IIIA non-small cell lung cancer.

II. To compare the DFS and OS (dual primary endpoints) between sequential MK-3475 (pembrolizumab) following standard of care (Arm B) vs. standard of care (Arm A) followed by observation in patients with stage IB-IIIA non-small cell lung cancer.

SECONDARY OBJECTIVES:

I. To compare the DFS and OS between combination MK-3475 (pembrolizumab) with standard of care (Arm C) vs. sequential standard of care followed by MK-3475 (pembrolizumab) (Arm B) in patients with stage IB-IIIA non-small cell lung cancer.

II. To compare the adverse event rates and drug discontinuation rates due to adverse events with the addition of MK-3475 (pembrolizumab) plus standard of care (combination and/or sequential; Arms B and C) vs. standard of care alone (Arm A) as well as Arm B versus Arm C in patients with stage IB-IIIA non-small cell lung cancer.

III. To compare the DFS and OS between MK-3475 (pembrolizumab) plus standard of care (combination and/or sequential; Arms B and C) vs. standard of care alone (Arm A) by PD-L1 expression status (>= 50% vs < 50%) in patients with stage IB-IIIA non-small cell lung cancer.

IV. To compare the DFS and OS between MK-3475 (pembrolizumab) plus standard of care (combination and/or sequential; Arms B and C) vs. standard of care alone (Arm A) in patients with stage IB-IIIA non-small cell lung cancer that receive at least 2 cycles of initial adjuvant chemotherapy.

QUALITY OF LIFE OBJECTIVES:

I. To compare patient-reported quality of life (QOL) one year after randomization as assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-Core (C)30 between patients randomized to receive adjuvant chemotherapy followed by MK-3475 (pembrolizumab) (Arm B), and those randomized to receive adjuvant chemotherapy + observation (Arm A).

II. To compare patient reported QOL one year after randomization as assessed by EORTC QLQ-C30 between patients randomized to receive adjuvant chemotherapy + MK-3475 (pembrolizumab) concomitantly (Arm C) and those randomized to receive adjuvant chemotherapy + observation (Arm A).

III. To compare patient-reported QOL at completion of chemotherapy as assessed by the EORTC QLQ-C30 between patients randomized to receive adjuvant chemotherapy + MK-3475 (pembrolizumab) concomitantly (Arm C) and those randomized to receive adjuvant chemotherapy + observation or adjuvant chemotherapy followed by MK-3475 (pembrolizumab) (Arms A and B combined).

IV. To present longitudinal trajectories by arm of patient-reported dyspnea and coughing as assessed by the EORTC QLQ-Lung Cancer (LC13).

CORRELATIVE SCIENCE OBJECTIVES:

I. To compare the DFS and OS with the addition of MK-3475 (pembrolizumab) (combination and/or sequential) to standard of care platinum-based adjuvant therapy (Arms B and C) vs standard of care (Arm A) in the PD-L1 subgroup of patients with PD-L1 expression status (>= 1% vs < 1%).

II. To compare the DFS and OS with the addition of MK-3475 (pembrolizumab) (combination and/or sequential) to standard of care platinum-based adjuvant therapy (Arms B and C) vs. standard of care (Arm A) by tumor mutational burden status (high vs. low) in patients with stage IB-IIIA non-small cell lung cancer.

III. To identify a cell-free deoxyribonucleic acid (cfDNA) marker associated with high-risk of recurrence and improved DFS and OS with the addition of MK-3475 (pembrolizumab) to standard adjuvant chemotherapy (Arms B and C).

OUTLINE: 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 treatment, patients are followed up at 6 weeks, then every 3 months for 2 years from randomization, every 6 months for years 2-4, and then annually for up to 10 years from randomization.