Background: Pembro monotherapy showed durable antitumor activity as third-line or later therapy for metastatic SCLC, leading to FDA approval in that setting. KEYNOTE-604 was a double-blind, phase 3 study of pembro + EP vs placebo + EP as first-line therapy for ES-SCLC (NCT03066778). Methods: Eligible patients (pts) with previously untreated ES-SCLC and no untreated CNS metastases were randomized 1:1 to pembro 200 mg Q3W or saline placebo for up to 35 cycles plus 4 cycles of standard-dose EP. Pts with CR or PR after cycle 4 could receive PCI at investigator discretion. Randomization was stratified by platinum choice (carboplatin vs cisplatin), ECOG PS (0 vs 1), and LDH (≤ULN vs > ULN). Primary endpoints were OS and PFS (RECIST v1.1, blinded central review) in the ITT population. ORR, DOR, and safety were secondary endpoints. OS and PFS treatment differences were assessed by the stratified log-rank test. The protocol specified 2 interim analyses (IAs) and a final analysis (FA). Prespecified efficacy boundaries were one-sided P = 0.0048 for PFS at IA2 (prespecified final PFS analysis) and 0.0128 for OS at FA. Results: 453 pts were randomized. 223/228 pts assigned to pembro + EP and 222/225 assigned to placebo + EP received ≥1 dose of assigned treatment; 1 pt assigned to pembro + EP received placebo + EP in error. Median age was 65 y, 74% had ECOG PS 1, and 57% had LDH > ULN; more pts in the pembro + EP arm had baseline brain metastases (14% vs 10%). At FA (median follow-up, 21.6 mo), 9% of pts in the pembro + EP arm and 1% in the placebo + EP arm remained on study treatment; 12% and 14% received PCI. At IA2 (median follow-up, 13.5 mo), pembro + EP significantly improved PFS in the ITT population (HR 0.75 [95% CI 0.61-0.91], P = 0.0023; median 4.5 vs 4.3 mo). At FA, pembro + EP prolonged OS in the ITT population, but the significance threshold was not met (HR 0.80 [95% CI 0.64-0.98], P = 0.0164; median 10.8 vs 9.7 mo). In a post hoc analysis of OS in the as-treated population, the nominal P value was smaller than the significance threshold (HR 0.78 [95% CI 0.63-0.97], P = 0.0124). ORR at FA was 71% for pembro + EP vs 62% for placebo + EP; median DOR was 4.2 vs 3.7 mo. Observed AEs were as expected; any-cause AEs were grade 3-4 in 77% vs 75%, grade 5 in 6% vs 5%, and led to discontinuation in 15% vs 6%. Conclusions: Pembro + EP significantly improved PFS and prolonged OS compared with placebo + EP as first-line therapy for pts with ES-SCLC. No unexpected toxicities were seen with pembro + EP. These data support the benefit of pembro-containing regimens for ES-SCLC. Clinical trial information: NCT03066778.