Abstract Background Locally advanced HER2-negative gastroesophageal junction (GEJ) adenocarcinoma has limited treatment options with suboptimal outcomes. While immunotherapy combined with chemotherapy shows promise in advanced gastric cancer, the role of short-course radiotherapy (SCRT) in perioperative regimens remains underexplored. This trial evaluates a novel approach integrating tislelizumab (PD-1 inhibitor), SCRT, and SOX chemotherapy (S-1+oxaliplatin) for resectable GEJ adenocarcinoma. Methods This prospective, single-arm, phase II trial (N=31) enrolls treatment-naive adults (18-75 years) with histologically confirmed, resectable Siewert type II/III GEJ adenocarcinoma (cT3-4aN+M0, AJCC 8th edition).Treatment Protocol: Neoadjuvant: 2 cycles of tislelizumab (200mg ivgtt, day 1)+SOX (S-1: BSA-based dose orally twice daily, days 1-14; oxaliplatin: 130mg/m2 ivgtt, day 1; 21-day cycles). Short-course Radiotherapy: Intensity-modulated radiation therapy (IMRT; 25Gy/5f) to primary tumor and involved nodes, initiated 1-2 weeks post-chemotherapy. Consolidation: 2 additional cycles of tislelizumab+SOX within 11-18 days post-radiotherapy. Surgery: Radical gastrectomy with D2 lymphadenectomy 6-8 weeks after last neoadjuvant dose. Adjuvant: 4 cycles of SOX. Endpoints: Primary: Pathological complete response (pCR). Secondary: R0 resection rate, major pathological response (MPR), disease-free survival (DFS), overall survival (OS), safety (NCI CTCAE v5.0). Discussion This is the first trial to combine tislelizumab, SCRT, and SOX in perioperative GEJ adenocarcinoma. SCRT may enhance immunogenicity while reducing toxicity. If successful, it may expand treatment options for locally advanced HER2-negative GEJ adenocarcinoma. Limitations include single-arm design and small sample size. Trial Registration Chinese Clinical Trial Registry (ChiCTR2500105244)
Meng et al. (Mon,) studied this question.