Abstract
BACKGROUND: Platinum-based chemoimmunotherapy is used as a first-line treatment for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma under specific regulatory circumstances, but effectiveness is often limited by cumulative toxicity, particularly in older patients and those with stroma-rich metastases. METHODS: This single-arm, phase II trial evaluated the efficacy and safety of a platinum-free triplet regimen as first-line therapy in patients with metastatic or unresectable G/GEJ adenocarcinoma. Participants received intravenous tislelizumab (200 mg, day 1), nab-paclitaxel (100 mg/m², days 1 and 8), and oral S-1 (80–120 mg twice daily, days 1–14) every 21 days. Primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Secondary endpoints included overall survival (OS), surgical conversion rate, disease control rate (DCR), and safety. RESULTS: Among 43 enrolled patients, the confirmed ORR was 81.4% (95% confidence interval [CI]: 66.60-91.61%) and the DCR was 90.7% (95% CI: 77.86–97.41%). The overall median PFS was 8.6 months (95% CI: 6.10-11.04), and the overall median OS for the ITT population was 20.1 months (95% CI: 17.69–22.45). In subgroup analyses, patients who underwent conversion surgery had significantly longer OS compared with those who did not (median 29.5 months vs. 18.3 months; hazard ratio [HR]: 0.42, 95% CI: 0.20–0.90; P = 0.050). Patients aged ≥ 65 years showed longer PFS (13.7 vs. 7.2 months; HR: 0.39, 95% CI 0.19–0.80; P = 0.006) and OS (29.2 vs. 16.4 months; HR: 0.42, 95% CI 0.20–0.88; P = 0.021) than those aged < 65 years. Eight patients (18.6%) underwent conversion surgery, with 2 achieving pathological complete response. Grade ≥ 3 treatment-related adverse events included neutropenia (9.3%), leukopenia (7.0%), and anemia (2.3%). CONCLUSIONS: This triplet regimen of nab-paclitaxel, S-1, and tislelizumab showed encouraging antitumor activity with a manageable safety profile. These findings warrant further validation in phase III randomized controlled trials, and support this regimen as a potential strategy, especially for older patients who may be less tolerant of platinum-based therapies. TRIAL REGISTRATION: ChiCTR2200062653 registered August 14, 2022 (retrospectively registered). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-026-15849-y.