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

A Multicenter, Randomized Phase II Study of Trastuzumab Rezetecan Combined With Retlirafusp Alfa With or Without CAPOX Regimen for Perioperative Treatment of Resectable Locally Advanced Gastric or 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 <1.5×ULN; ALT/AST ≤2.5×ULN
    • Serum Cr ≤1.5×ULN or CrCl >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 <50%, unstable angina, myocardial infarction within 1 year, prolonged QTc interval (male >450ms, female >470ms), family history of sudden cardiac death <40 years old
7. GI perforation/fistula within 6 months, intestinal obstruction within 3 months (not fully resolved)
8. Active severe bleeding disorder or active peptic ulcer disease
9. Arterial/venous thromboembolic event within past 6 months (stroke, DVT, pulmonary embolism etc.)
10. Severe uncontrolled infection (≥CTCAE grade 2) within 4 weeks prior to first dose
11. Active viral hepatitis (HBV DNA ≥2000 IU/mL; active HCV viremia) or HIV positive
12. History or active interstitial lung disease, pulmonary fibrosis, active tuberculosis
13. Active autoimmune disease requiring long-term systemic immunosuppressive therapy
14. Systemic corticosteroid dose >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