Nab-Paclitaxel, S-1, and Tislelizumab as First-Line Therapy in Advanced Gastric/GEJ Adenocarcinoma: a Phase II Single-Arm Trial

Background Platinum-based chemoimmunotherapy is the standard first-line treatment for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma but is often limited by cumulative toxicity, particularly in older patients and those with stroma-rich metastases. Methods We conducted an investigator-initiated, single-arm, single-center, phase II trial at the First Affiliated Hospital of Zhejiang University. Adults (18–85 years) with previously untreated, histologically confirmed advanced gastric/gastroesophageal junction (G/GEJ) adenocarcinoma. Treatment comprised 21-day cycles of intravenous tislelizumab (200 mg, day 1), nab-paclitaxel (100 mg/m², days 1 and 8), and S-1 (an oral fluoropyrimidine) (80–120 mg orally twice daily, days 1–14). Surgical resectability was reassessed after 6–8 cycles by a multidisciplinary team; otherwise therapy continued until radiographic progression or unacceptable toxicity. Tumor response was assessed at baseline and every 2–4 cycles; adverse events were graded per NCI-CTCAE v5.0. Primary endpoints were objective response rate (ORR) and progression-free survival (PFS); secondary endpoints included conversion surgery rate, overall survival (OS), disease control rate (DCR), and safety. ORR/DCR were summarized with exact (Clopper-Pearson) 95% CIs; PFS/OS were estimated by Kaplan-Meier with Greenwood standard errors and Brookmeyer-Crowley medians; landmark survival at 6, 12, and 18 months was reported. Results Among 43 enrolled patients, the confirmed ORR was 81.4% (95% CI: 66.6–91.6%) and the DCR was 90.7% (95% CI: 77.9–97.4%). The median PFS was 7.5 months (95% CI: 6.3–11.3), and the median OS was 20.1 months (95% CI: 14.2–22.0). Nine patients (20.9%) underwent conversion surgery, with two achieving pathological complete response. There were significant differences in terms of OS (median 29.5 vs 16.5 months, P = 0.042) in patients with conversion surgery than without. Patients showed significantly prolonged PFS (median 11.8 vs 7.2 months, P = 0.040) and OS (median 29.2 vs 16.4 months, P = 0.020) with age ≥ 65 than age ˂ 65. Grade ≥ 3 treatment-related adverse events included neutropenia (9.3%), leukopenia (7.0%), and anemia (2.3%). Conclusions The platinum-free triplet regimen of nab-paclitaxel, S-1, and tislelizumab demonstrated promising efficacy, including high response rates, encouraging survival outcomes, and a substantial conversion surgery rate, with a manageable safety profile. These findings warrant further validation in randomized controlled trials, and suggest this regimen as a potential therapeutic strategy, especially for older patients who may be less tolerant of platinum-based therapies. Trial registration: This study is registered with chictr.org.cn, ChiCTR2200062653; registered on 14 August 2022.