Background: Platinum-based chemotherapy is the standard of care for treatment-naive NSCLC patients without an activating EGFR mutation or ALK gene rearrangement. Preliminary data from the phase 1/2 KEYNOTE-021 (NCT02039674) study suggest manageable toxicity and encouraging efficacy of platinum-doublet chemotherapy plus pembrolizumab, an anti–PD-1 monoclonal antibody, in treatment-naive NSCLC. KEYNOTE-189 (NCT02578680) is a randomized, double-blind, phase 3 study to compare the efficacy and safety of platinum-doublet chemotherapy with/without pembrolizumab as first-line treatment in nonsquamous NSCLC. Methods: Patients ≥ 18 years with advanced nonsquamous NSCLC in whom EGFR- or ALK-directed therapy is not indicated, ECOG PS 0-1, and no prior systemic chemotherapy are eligible. Approximately 570 patients will be randomly assigned (2:1) to pembrolizumab 200 mg plus pemetrexed 500 mg/m² and cisplatin 75 mg/m² or carboplatin AUC 5 Q3W for 4 cycles followed by pembrolizumab 200 mg plus pemetrexed 500 mg/m² Q3W or to placebo plus pemetrexed 500 mg/m² and cisplatin 75 mg/m² or carboplatin AUC 5 Q3W for 4 cycles followed by placebo plus pemetrexed 500 mg/m² Q3W. Patients are to be stratified by smoking status (never vs former/current), cisplatin vs carboplatin, and PD-L1 status (tumor proportion score [TPS] ≥ 1% vs < 1%). TPS < 1% group includes PD-L1–inevaluable patients. Pembrolizumab will continue for 35 cycles or until disease progression, intolerable toxicity, or investigator or patient decision to withdraw. Eligible patients may continue pembrolizumab monotherapy after initial disease progression. Treatment may be discontinued in patients with a complete response by immune-related RECIST. Adverse events (AEs) will be monitored throughout the study and for 30 days (90 days for serious AEs) after treatment end and graded per NCI CTCAE v4.0. Response will be assessed by RECIST v1.1 (central imaging vendor review) at weeks 6 and 12, then every 9 weeks until week 48 and every 12 weeks thereafter. The primary end point is PFS; secondary end points are ORR, DOR, OS, PFS in patients with PD-L1 TPS ≥ 1%, and safety. Clinical trial information: NCT02578680