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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
80
1. Drug: Trastuzumab Rezetecan Description: IV infusion Q3W; Cycle 1 loading dose 6.4 mg/kg, subsequent cycles 4.8 mg/kg; administered for 3 neoadjuvant cycles and 3 adjuvant cycles 2. Drug: Retlirafusp alfa Description: IV infusion 1800 mg Q3W; 3 neoadjuvant, 3 adjuvant cycles, then single-agent maintenance up to total 17 cycles 3. Drug: Oxaliplatin Description: 60 mg/m² IV Q3W, only 3 neoadjuvant cycles 4. Drug: Capecitabine Description: 750 mg/m² oral twice daily, 2 weeks on / 1 week off; 3 neoadjuvant + 3 adjuvant cycles 5. Procedure: Radical D2 Gastrectomy Description: R0 curative resection performed 3-6 weeks post final neoadjuvant dose
1. Drug: Trastuzumab Rezetecan Description: IV infusion Q3W; Cycle 1 loading dose 6.4 mg/kg, subsequent cycles 4.8 mg/kg; administered for 3 neoadjuvant cycles and 3 adjuvant cycles 2. Drug: Retlirafusp alfa Description: IV infusion 1800 mg Q3W; 3 neoadjuvant, 3 adjuvant cycles, then single-agent maintenance up to total 17 cycles 3. Procedure: Radical D2 Gastrectomy Description: R0 curative resection performed 3-6 weeks post final neoadjuvant dose
Tianjin Medical University Cancer Institute & Hospital
Tianjin, Tianjin Municipality, China
Pathological Complete Response (pCR)
Proportion of subjects achieving CAP Tumor Regression Grade 0 (TRG0), defined as no viable malignant cells detected in primary gastric tumor and all regional lymph nodes after radical D2 gastrectomy
Time frame: after surgery,within approximately 4-6 weeks
R0 Resection Rate
The proportion of subjects who achieve R0 resection confirmed by postoperative surgical pathology.
Time frame: within approximately 2 weeks after surgery
Event-Free Survival (EFS)
EFS is the time from date of randomization until the date of disease progression or death.(assessed by the investigator per RECIST v1.1 criteria)
Time frame: Up to 5 years
Overall Survival (OS)
Overall survival is length of time from randomization until the date of death due to any cause.
Time frame: Up to 5 years
Incidence, severity and causality of TEAEs, SAEs graded by NCI-CTCAE 6.0.
Assessment of safety
Time frame: From first study drug to 90 days after last drug administration
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