This is a prospective, single-center, randomized controlled phase II clinical trial.It plans to enroll a total of 24 eligible patients with locally advanced gastric/gastroesophageal junction adenocarcinoma who are HER2-positive and have potential benefit from immunotherapy (PD-L1 CPS≥1, EBV-positive, or dMMR/MSI-H). All patients were randomly assigned to the following two groups in a 1:1 ratio.
Group A:Trastuzumab Rezatecan Dosage: 4.8 mg/kg, intravenous infusion Frequency: Once every 3 weeks (Q3W) Retlirafusp alfa (SHR-1701) Dosage: 30 mg/kg, intravenous infusion Frequency: Once every 3 weeks (Q3W)
Group B:
Trastuzumab Rezatecan Dosage: 4.8 mg/kg, intravenous infusion Frequency: Once every 3 weeks (Q3W) Retlirafusp alfa (SHR-1701) Dosage: 30 mg/kg, intravenous infusion Frequency: Once every 3 weeks (Q3W) Pertuzumab biosimilar (Betta Pharma): 840mg at first usage; subsequent maintenance: 420mg per dose,Q3W The neoadjuvant treatment phase will consist of 4 cycles, with each cycle lasting 21 days, for a total treatment duration of approximately 12 weeks. Imaging examinations will be performed after 2 cycles.
Preoperative Assessment and Surgery Within 4 weeks after the completion of neoadjuvant therapy, patients will undergo imaging examinations for surgical feasibility assessment. Those eligible for surgery will undergo radical gastrectomy (D2 lymphadenectomy) 4-6 weeks after the last dose.
The endpoints are efficacy and safety, specifically including:
Primary Endpoint:
pCR rate (the percentage of subjects achieving pathological complete response, defined as the absence of residual viable tumor cells in the primary tumor bed);
Secondary Endpoints:
MPR rate (the percentage of subjects achieving major pathological response, defined as ≤10% residual viable tumor cells in the tumor bed); EFS (Event-Free Survival, defined as the time from the initiation of treatment to the first occurrence of any of the following events: disease progression precluding surgical resection, local or distant recurrence, or death from any cause); R0 resection rate (defined as macroscopically tumor-free surgical margins and microscopically negative tumor cells within 1 mm of the surgical margin); OS (Overall Survival, defined as the time from the start date of neoadjuvant therapy to death from any cause or the date of the last follow-up).
Safety: The incidence rates of adverse events (AE) and serious adverse events (SAE) and their correlation with the treatment.
Exploratory Endpoints:
Infiltration status of immune cell subsets in tumor tissue before and after treatment.
Voluntary Participation: The subject voluntarily agrees to participate in this study, is able to sign the informed consent form (ICF), and has good compliance.
Age and Gender: Aged 18 to 75 years (at the time of signing the ICF), regardless of gender.
Diagnosis and Staging: Histologically and/or cytologically confirmed gastric cancer or gastroesophageal junction adenocarcinoma. Diagnosed as locally advanced according to the AJCC 8th Edition criteria, with cTNM staged as T3-4N+M0 based on endoscopic ultrasound or contrast-enhanced CT/MRI scans (combined with diagnostic laparoscopy if necessary). The subject must agree to undergo radical surgery, and the investigator assesses the lesion as potentially resectable.
Treatment History: No prior systemic therapy for the current disease, including anti-tumor radiotherapy, chemotherapy, or immunotherapy.
Other Malignancies: Concomitant malignant diseases other than gastric cancer (excluding early-stage tumors that have been radically cured).
Bleeding Risk: Tumor lesions with a tendency to bleed (e.g., active ulcerative tumor lesions with positive fecal occult blood test, history of hematemesis or melena within 2 months prior to signing the ICF, or judged by the investigator to be at risk of massive gastrointestinal bleeding) or have received blood transfusion therapy within 4 weeks prior to the administration of the study drug.
Concurrent Studies: Currently participating in other interventional drug clinical studies, or have received other investigational drugs or investigational device therapy within 4 weeks prior to the first dose.
Prior Therapies: Previous exposure to the following therapies: anti-HER2, anti-PD-1, anti-PD-L1 agents, anti-PD-L2 agents, or drugs targeting another stimulatory or co-inhibitory T-cell receptor (including but not limited to CTLA-4, OX-40, CD137, etc.).