Neoadjuvant/adjuvant serplulimab vs. placebo combined with chemotherapy for PD-L1–positive gastric cancer: A randomized, double-blind, multicenter phase 3 study.

4009 Background: The addition of immune checkpoint inhibitors (ICIs) to chemotherapy (chemo) in the neoadjuvant/adjuvant setting for gastric cancer (GC) has yielded mixed efficacy. Target population and treatment regimen remain to be optimized. This study compared the efficacy of serplulimab (anti-PD-1 antibody) plus chemo versus placebo plus chemo as neoadjuvant therapy and serplulimab versus chemo as adjuvant therapy for resectable GC. Methods: Patients with PD-L1 positive (PD-L1 CPS ≥ 5), histologically confirmed, untreated, resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma were randomized 1:1 to receive 3 cycles of neoadjuvant intravenous (iv) serplulimab (4.5 mg/kg) or placebo, plus chemo (iv oxaliplatin, 130 mg/m 2 and oral S-1, 40-60 mg based on body surface area), followed by post-surgery adjuvant serplulimab monotherapy (up to 17 cycles) or adjuvant chemo (5 cycles), Q3W. The primary endpoint was investigator (INV)-assessed event-free survival (EFS). Efficacy superiority was first evaluated and established in patients with PD-L1 CPS ≥ 10 followed by that in the PD-L1 CPS ≥ 5 population. Results: Between November 26, 2019 and April 19, 2024, 588 patients were enrolled across 57 sites, with 292 randomized to the serplulimab group and 296 to the placebo group. As of the data cutoff date of August 19, 2025 with a median follow-up duration of 35.9 months, INV-assessed median EFS was significantly longer in the serplulimab group (n = 193) than in the placebo group (n = 217) in the PD-L1 CPS ≥ 10 population (not reached [NR], 95% CI 43.0–not estimable [NE] vs. 42.0 months, 95% CI 20.5–NE; HR 0.65, 95% CI 0.47–0.90; p = 0.0082), and in the PD-L1 CPS ≥ 5 population (NR, 95% CI 37.9–NE vs. 35.9 months, 95% CI 21.3–52.0; HR 0.73, 95% CI 0.56–0.94; p = 0.0152), meeting the protocol-specified superior criteria. Blinded independent central review-assessed median EFS was consistent with that of the investigator. Pathological complete response rate was higher in the serplulimab group than in the placebo group (21.6% vs 6.4%; odds ratio 3.95). Median OS was immature in both groups. Grade ≥ 3 treatment-related adverse events (TRAEs) were reported in 136 (46.6%) and 172 (58.5%) patients in the serplulimab and placebo groups, respectively. Discontinuation of any component of the study regimen due to TRAEs occurred in 19 (6.5%) and 31 (10.5%) patients in the respective groups. Conclusions: Neoadjuvant serplulimab plus chemo, followed by adjuvant serplulimab monotherapy, significantly prolonged EFS in patients with PD-L1-positive, resectable GC or GEJ adenocarcinoma. Improvements in other efficacy endpoints were also observed along with a favorable safety profile compared to neoadjuvant/adjuvant chemo. This world-first chemotherapy-free regimen (adjuvant) represents a promising treatment option for this indication. Clinical trial information: NCT04139135 .