The purpose of this study is to investigate the safety and efficacy of HFRT plus neoadjuvant ICT in locally advanced resectable GEJA.
Histologically and/or cytologically confirmed diagnosis of locally advanced adenocarcinoma of the gastroesophageal junction (GEJ) (Siewert types I-III), defined as cT3-4, any N, M0 or cT2 N+, M0 according to the 8th edition of the AJCC staging system.
Determined as resectable locally advanced disease after multidisciplinary team (MDT) evaluation.
Age ≥18 years, regardless of sex.
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
Confirmed dMMR or MSI-H by immunohistochemistry or genetic testing.
Evidence of peritoneal or visceral metastasis (based on thoracoabdominal CT, bone scan, or MRI if bone metastasis is suspected).
Other malignancies within the past 5 years, except cured basal cell or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix.
Known allergy or hypersensitivity to any study drugs or their excipients; contraindications to study drugs.
Parallel
hypofractionated radiotherapy
RadiationIn Phase Ib, hypofractionated radiotherapy (HFRT) will be administered at one of three dose levels: 3 Gy × 5 fractions, 4 Gy × 5 fractions, or 5 Gy × 5 fractions. The recommended dose determined in Phase Ib will be used in Phase II (delivered as 5 fractions).
PD-1 inhibitor
DrugSerplulimab will be administered concurrently with chemotherapy at a fixed dose of 300 mg via intravenous infusion on Day 1 of each 3-week cycle.
TS-1
DrugThe TS regimen includes paclitaxel at a dose of 175 mg/m² administered via intravenous infusion on Day 1, and oral administration of tegafur-gimeracil-oteracil (S-1) for 14 consecutive days followed by a 7-day rest period (21-day cycle). The S-1 dose is based on body surface area (BSA): 40 mg twice daily (bid) for BSA ≤ 1.5 m²; 50 mg bid for BSA 1.5-1.6 m²; and 60 mg bid for BSA ≥ 1.6 m².
Safety and tolerability in Phase Ib
Safety will be assessed based on clinical adverse events, vital signs, and abnormalities in laboratory tests during the study period. Adverse events (AEs) will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0. All deaths occurring within 90 days after the first dose of treatment or within 30 days after the last dose will be listed along with the causes of death. Laboratory abnormalities will be categorized according to NCI-CTCAE version 5.0. Maximum Tolerated Dose (MTD): If ≥1/3 of patients in a given dose cohort experience radiotherapy-related dose-limiting toxicities (DLTs) within 90 days, that dose level will be considered intolerable. The dose level immediately below will then be defined as the maximum tolerated dose (MTD). At least six evaluable patients are required in the MTD cohort.
pCR rate in Phase II
pCR rate: The proportion of patients who achieve pathological complete response (pCR), defined as the absence of viable tumor cells on microscopic examination after neoadjuvant therapy.
R0 resection rate
number of R0 surgery divide all participants
Objective response rate
Objective response rate (ORR) is defined as the proportion of subjects with a confirmed Complete Response (CR) or Partial Response (PR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A response (CR or PR) requires confirmation by a repeat assessment performed no less than 4 weeks after the criteria for response are first met.
DFS(disease free survival) rate
evaluate the DFS rate after the resection of primary lesion（only patients who acquire R0 resection）
OS(overall survival) rate
evaluate the OS rate after the neoadjuvant therapy
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