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.).
Parallel
Trastuzumab Rezatecan and Retlirafusp alfa
DrugTrastuzumab 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)
Trastuzumab Rezatecan and Retlirafusp alfa+Pertuzumab
DrugTrastuzumab 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, subsequent maintenance: 420mg per dose,Q3W
Complete pathological response (pCR) rate
The percentage of subjects achieving pathological complete response, defined as the absence of residual viable tumor cells in the primary tumor bed.
Major Pathological Response (MPR)
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.
Exploratory Endpoints
Infiltration status of immune cell subsets in tumor tissue before and after treatment.
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