SYLT-030: Efficacy and safety of tislelizumab plus mFOLFOX6 versus tislelizumab plus POF (paclitaxel + mFOLFOX6) as first-line therapy for advanced gastric/gastroesophageal junction adenocarcinoma (AGC): A multicenter, open-label, randomized phase III trial.

TPS463 Background: Tislelizumab is an anti-PD-1 antibody. The addition of tislelizumab to a doublet chemotherapy regimen with platinum and fluoropyrimidine is a standard first-line treatment for AGC. The combination of paclitaxel, oxaliplatin, and 5-FU/leucovorin (POF) is a standard triplet regimen for AGC in China, as recommended by the Chinese Society of Clinical Oncology (CSCO). However, no phase III trial has evaluated the efficacy and safety of an anti-PD-1/PD-L1 antibody combined with a triplet chemotherapy regimen. The SYLT-030 study aims to evaluate the efficacy and safety of tislelizumab plus POF versus tislelizumab plus mFOLFOX6 as first-line therapy for AGC. Methods: This is an open-label, randomized, multicenter, phase III trial. Key inclusion criteria are: 1) age 18-75 years; 2) ECOG performance status 0-1; 3) unresectable, locally advanced, or metastatic gastric/gastroesophageal junction adenocarcinoma; 4) no prior chemotherapy (patients who received perioperative chemotherapy may be included if ≥6 months have elapsed since fluorouracil alone or ≥1 year since oxaliplatin- or taxane-based therapy combined with fluoropyrimidine), radiotherapy, or immunotherapy; and 5) known PD-L1 CPS, MMR (or MSI), HER2, and CLDN18.2 status, or sufficient samples for testing. Main exclusion criteria are: 1) HER2-positive or dMMR/MSI-high status; 2) palliative radiation within 28 days prior to randomization; and 3) clinically significant bowel obstruction (CTCAE ≥ grade 2). Approximately 224 patients with PD-L1 CPS ≥1 will be randomized 1:1 to receive tislelizumab plus mFOLFOX6 (oxaliplatin + 5-FU/leucovorin) or tislelizumab plus POF (paclitaxel + mFOLFOX6). Stratification factors include PD-L1 expression (1 ≤ CPS < 5 vs CPS ≥ 5), presence of liver metastasis (yes vs no), and CLDN18.2 expression (positive vs negative). The primary endpoint is progression-free survival (PFS) per RECIST v1.1. Secondary endpoints include overall survival (OS), objective response rate (ORR), disease control rate (DCR) per RECIST v1.1, quality of life (QoL), and safety. An exploratory cohort (approximately 45 patients) will evaluate the efficacy and safety of tislelizumab plus POF in patients with PD-L1 CPS <1. Clinical trial information: NCT06793917 .