Background: The phase 3 KEYNOTE-181 study compared pembrolizumab (pembro) vs chemo as second-line therapy for patients (pts) with advanced/metastatic squamous cell carcinoma (SCC) and adenocarcinoma (ACC) of the esophagus (NCT02564263). Methods: Eligible pts were randomized 1:1 to pembro 200 mg Q3W for up to 2 years or choice of paclitaxel, docetaxel, or irinotecan. Randomization was stratified by histology (SCC vs adenocarcinoma) and region (Asia vs rest of world). Primary end points were OS in the SCC, PD-L1 combined positive score (CPS) ≥10, and the ITT. Secondary endpoints included PFS, ORR, safety; exploratory endpoints included health-related quality of life (HRQoL) in CPS ≥10. Results: 628 pts were randomized (401 with SCC; 222 with CPS ≥10). As of Oct. 15, 2018, median follow-up was 7.1 mo (pembro) vs 6.9 mo (chemo). In CPS ≥10, OS was superior with pembro vs chemo (median 9.3 vs 6.7 mo; HR 0.69; 95% CI 0.52-0.93; P= 0.0074). In CPS ≥10 SCC, median OS was 10.3 mo vs 6.7 mo and in CPS ≥10 ACC, median OS was 6.3 mo vs 6.9 mo; 12-mo OS rates were higher with pembro vs chemo (Table). In SCC, median OS was 8.2 mo vs 7.1 mo; HR 0.78; 95% CI 0.63-0.96; P= 0.0095. In the ITT, median OS was 7.1 mo vs 7.1 mo; HR 0.89; 95% CI 0.75-1.05; P= 0.0560. Updated OS will be presented. Grade 3-5 drug-related AEs (≥10% incidence in either arm) included decreased white blood cells (0% vs 10%), decreased neutrophils (0.3% vs 10%). In CPS ≥10, HRQoL improved with pembro vs chemo only for EQ-5D VAS (difference in LS mean change from baseline 5.57; 95% CI 0.58-10.56). Conclusions: Pembro significantly improved OS vs chemo as second-line therapy for advanced esophageal cancer with PD-L1 CPS ≥10, with a more favorable safety profile and stable and similar QOL. These data support pembro as a new second-line standard of care for esophageal cancer with PD-L1 CPS ≥10. Clinical trial information: NCT02564263