Phase II Study of Trastuzumab Rezetecan Combined With Retlirafusp Alfa With or Without CAPOX as Perioperative Therapy for Resectable Locally Advanced Gastric/Gastroesophageal Junction Adenocarcinoma

This two-stage, multicenter, randomized open-label phase II trial enrolls untreated resectable stage II-III gastric/gastroesophageal junction adenocarcinoma patients with any HER2 expression. Stage 1 is a safety lead-in cohort of 6 patients receiving Trastuzumab Rezetecan(SHR-A1811)+Retlirafusp alfa(SHR-1701) plus CAPOX to assess dose-limiting toxicity (DLT) within 21 days after initial dosing. If safety risk is acceptable, stage 2 will randomize 74 eligible patients 1:1 into two parallel cohorts stratified by HER2 status. Cohort1 receives perioperative Trastuzumab Rezetecan(SHR-A1811)+Retlirafusp alfa(SHR-1701)+CAPOX; Cohort2 receives dual targeted-immunotherapy without chemotherapy (Trastuzumab Rezetecan+Retlirafusp alfa). All patients undergo D2 radical gastrectomy after neoadjuvant therapy, followed by adjuvant treatment and Retlirafusp alfa(SHR-1701) maintenance up to maximum 17 total cycles. The primary endpoint is pCR rate evaluated by CAP pathological criteria. Secondary endpoints include R0 resection rate, EFS, DFS, OS and perioperative/surgical/systemic safety profiles. Biomarker exploratory analysis will be performed to evaluate the correlation between PD-L1, MSI, TMB and clinical efficacy.

Inclusion Criteria: 1. Voluntarily sign written informed consent before any study-related procedures 2. Age ≥18 and ≤75 years old 3. Histopathologically confirmed gastric or gastroesophageal junction adenocarcinoma 4. AJCC 8th edition stage II-III resectable disease (cT1-2N+M0, T3-4aNanyM0); negative peritoneal cytology (CY0) confirmed by pre-study laparoscopy 5. HER2 expression status: High HER2 (IHC 3+ or IHC 2+ FISH-positive) OR Low/Intermediate HER2 (IHC 2+ FISH-negative / IHC 1+) 6. No prior systemic anti-tumor therapy (chemotherapy, targeted therapy, immunotherapy, radiotherapy, radical gastrectomy) 7. Planned radical D2 gastrectomy after neoadjuvant treatment completion 8. Able to swallow oral capecitabine tablets intact 9. ECOG Performance Status 0 or 1 10. Estimated overall survival ≥12 months 11. Adequate organ function (no blood products/G-CSF within prior 14 days): * ANC ≥1.5×10⁹/L; PLT ≥80×10⁹/L; Hb ≥90 g/L * Total bilirubin \50 mL/min * INR, PT, APTT ≤1.5×ULN 12. Fertile female subjects: Negative serum pregnancy test within 72 hours before first dose; all fertile participants agree to effective contraception during treatment and required post-treatment contraceptive window Exclusion Criteria: 1. Siewert type I GEJ tumor or Siewert II tumor requiring cervicothoracic surgical approach 2. Confirmed peritoneal metastasis, positive peritoneal cytology (CY1), or AJCC T4b disease 3. Tumor unresectable or absolute contraindication to radical gastrectomy 4. History of other malignant tumor within past 5 years (excluding cured basal cell skin carcinoma, cervical/breast carcinoma in situ) 5. Uncontrolled hypertension (SBP≥160 mmHg or DBP≥100 mmHg despite optimal medical management) 6. Cardiac dysfunction: NYHA grade ≥2 heart failure, LVEF \450ms, female \>470ms), family history of sudden cardiac death \10 mg prednisone equivalent within 7 days pre-treatment 15. Received live attenuated vaccine within 28 days before enrollment 16. Hypersensitivity to any study drug or excipients 17. Participation in other interventional clinical trials within 4 weeks prior to first dose 18. Lactating female subjects 19. Any medical, psychiatric or social condition judged by investigator to interfere with study compliance or subject safety