Background: Robust and durable antitumor activity was previously demonstrated with pembrolizumab in patients with advanced NSCLC, both as a monotherapy in the first- and second-line settings (in patients with PD-L1 tumor proportion score [TPS] ≥50% and ≥1%, respectively) and when combined with pemetrexed-carboplatin (in patients with nonsquamous histology). KEYNOTE-671 (NCT03425643) is a phase 3 study that evaluates standard neoadjuvant chemotherapy with perioperative pembrolizumab or placebo in early-stage NSCLC. Methods: This international double-blind phase 3 trial enrolls patients aged ≥18 years with previously untreated, resectable stage IIB/IIIA NSCLC, ECOG PS 0–1, and tumor samples for evaluation of PD-L1 expression. Patients are randomized 1:1 to neoadjuvant chemotherapy (cisplatin 75 mg/m² with gemcitabine 1000 mg/m² [days 1 and 8; squamous histology] or pemetrexed 500 mg/m² [nonsquamous histology]) combined with either pembrolizumab 200 mg or placebo Q3W for 4 cycles, followed by surgery, then adjuvant pembrolizumab 200 mg or placebo Q3W for 13 cycles. Randomization is stratified by disease stage, PD-L1 TPS < 50% vs ≥50%, squamous vs nonsquamous, and East Asia vs non-East Asia. Radiographic response is assessed 3 weeks after cycles 2 and 4, and every 12 weeks from adjuvant cycle 1 (RECIST v1.1, blinded independent central review). Disease recurrence/progression is confirmed by biopsy. Adverse events are graded per CTCAE v4.0 or later. Primary endpoints are event-free survival (time from randomization to first of disease/local progression, unresectable tumor, local/distant recurrence, or death) and overall survival (time from randomization to all-cause death). Secondary endpoints are major pathological response (≤10% viable tumor cells in resected primary tumor/lymph nodes), pathological complete response (no residual invasive cancer on H&E stained slides of resected lung specimen/lymph nodes post–neoadjuvant therapy), safety, and patient-reported outcomes. An estimated 786 patients will be enrolled, beginning March 9, 2018. Clinical trial information: NCT03425643