Neoadjuvant SHR-A1811 and SHR-A1701 for Potentially Immunotherapy-Sensitive GC or GEJ Adenocarcinoma

Plain-language summary

This is a prospective, single-center, single-arm, phase Ib clinical study. It plans to enroll 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). These patients will receive four cycles of neoadjuvant therapy with Trastuzumab Rezatecan plus Rilafup alfa, followed by radical surgery. All subjects will receive the same investigational treatment regimen, with no parallel control group. All enrolled subjects will receive the neoadjuvant treatment regimen of Trastuzumab Rezatecan combined with Retlirafusp alfa. The specific interventions are as follows: 5.1.1 Neoadjuvant Drug Information and Dosing Regimen Trastuzumab Rezatecan Supplier: Jiangsu Hengrui Medicine Co., Ltd. Dosage: 4.8 mg/kg, intravenous infusion Frequency: Once every 3 weeks (Q3W) Retlirafusp alfa (SHR-1701) Supplier: Jiangsu Hengrui Medicine Co., Ltd. Dosage: 30 mg/kg, intravenous infusion Frequency: Once every 3 weeks (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. 5.1.2 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 primary endpoint is safety and tolerability, specifically including: Primary Endpoint: Safety and Tolerability: including the incidence, type, and severity of dose-limiting toxicities (DLTs); the incidence and treatment-relatedness of adverse events (AEs) and serious adverse events (SAEs); and the determination of the recommended phase II dose (RP2D). Secondary Endpoints: pCR rate (the percentage of subjects achieving pathological complete response, defined as the absence of residual viable tumor cells in the primary tumor bed); 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). Exploratory Endpoints: Infiltration status of immune cell subsets in tumor tissue before and after treatment.

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