Background: The phase 3 PRODIGY study showed that neoadjuvant docetaxel, oxaliplatin and S-1 (DOS) chemotherapy, as part of perioperative chemotherapy, was effective and tolerable in Asian patients with resectable locally advanced gastric cancer (LAGC). The current study aimed to evaluate the efficacy and safety of neoadjuvant durvalumab plus DOS, which was followed by surgery and adjuvant durvalumab plus S-1 chemotherapy in patients with resectable LAGC. Methods: In this single-center, open-label, phase II study, patients with locally advanced gastric or gastroesophageal junction cancer (i.e., cT2/3N+ or cT4Nany) were enrolled. In patients with proficient mismatch repair protein (pMMR) tumors (main arm), 3 cycles of neoadjuvant durvalumab plus DOS were administered every 3 weeks, which was followed by surgery and adjuvant S-1 plus durvalumab administered every 6 weeks for 12 months. The primary endpoints were the rate of pathologic complete regression (pCR) and the safety. For an exploratory purpose, patients with deficient mismatch repair protein tumors (exploratory arm) were treated with 3 cycles of neoadjuvant durvalumab and tremelimumab every 4 weeks followed by surgery and adjuvant durvalumab administered every 4 weeks for 12 months. At this interim analysis, we report the results of patients with pMMR. Results: As of SEP 2022, 40 subjects with pMMR were enrolled and received ≥ 1 dose of neoadjuvant treatment. Thirty-five subjects completed 3 cycles of neoadjuvant treatment, and 31 received surgery as of the data cut-off. Among 31 patients who received surgery, a pCR was confirmed in 9 (29.0%), meeting the primary efficacy endpoint (8 pCR out of 40) early. Among those who received 3 cycles of neoadjuvant treatment, 3 (8.6%) experienced the predefined unacceptable severe toxicities during the neoadjuvant treatment: febrile neutropenia (n=2) and G4 neutropenia persisted for ≥ 7 days (n=1). Conclusions: The current study met its primary efficacy endpoint and is expected to meet the primary safety endpoint (<20%). Neoadjuvant durvalumab plus DOS followed by surgery and adjuvant durvalumab plus S-1 chemotherapy deserves to be investigated in a phase 3 trial in Asian patients with LAGC. Clinical trial information: 04221555.