Background: Pembrolizumab, anti–PD-1 antibody, provides response rates of around 15% in patients (pts) with PD-L1-positive advanced gastric cancer (AGC). Lenvatinib, a multikinase inhibitor of VEGF receptors and other receptor tyrosine kinases, substantially decreased the tumor-associated macrophages and increased infiltration of CD8-positive T cells and enhanced anti-tumor activity of PD-1 inhibitors in vivo model. This phase 2 study has been conducted to evaluate efficacy and safety of the combination of lenvatinib plus pembrolizumab in pts with AGC. Methods: Eligible pts were with AGC having measurable lesions according to RECIST ver. 1.1. Pts could be enrolled regardless of PD-L1 status. Pts received 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks. Primary endpoint was objective response rate (ORR). Planned sample size was 29 pts based on Simon’s optimal two-stage design with one-sided ɑ = 5% and power = 80%. The threshold and expected ORRs were 10% and 30%. PD-L1 combined positive score (CPS) was assessed using the anti–PD-L1 22C3 antibody. Results: From October 2018 to March 2019, 29 pts (27 MSS and 2 MSI-H) were enrolled and assessed for anti-tumor response. Fourteen pts received the study treatment as first-line and 15 pts as second-line. ORR was 69% (95% CI 49 to 85). The disease control rate was 100%. ORR in MSS pts was 70%. ORR was numerically higher in pts with CPS≥1 (n=19, ORR 84%) than that of pts with CPS<1 (n = 10, ORR 40%). Median progression-free survival was 6.9 months (95% CI, 4.4-9.4 months) with 14 pts with ongoing treatment at the data cut off in August 2019. Grade ≥ 3 treatment related adverse events occurred in 13 pts (45%) including hypertension (34%), proteinuria (17%), and platelet count decreased (7%). Conclusions: Lenvatinib with pembrolizumab showed a promising antitumor activity with acceptable safety profiles for pts with AGC, which warrants further investigations in a larger cohort. Clinical trial information: NCT03609359.