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

Trastuzumab Rezetecan Antibody-Drug Conjugate Combined With Retlirafusp α in Patients With HER2-Positive and Potentially Immunotherapy-Sensitive Gastric or Gastroesophageal Junction Adenocarcinoma,a Prospective Phase Ib Trial

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Gastric or Gastroesophageal Junction Adenocarcinoma
• Intervention / Treatment: Drug: Trastuzumab Rezatecan and Retlirafusp alfa

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: XU; Phone Number: 86-2568306505; Email: liuhongda@njmu.edu.cn

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210000
      • First Affiliated Hospital of Nanjing Medical Unviersity
      • Contact: Hao Xu; Phone Number: 86-2568306505; Email: liuhongda@njmu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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.
• HER2 Status: Confirmed HER2 IHC 3+ or HER2 IHC 2+ with positive FISH result based on endoscopic biopsy tissue IHC results.
• Biomarker Status: PD-L1 CPS ≥1, EBV-positive, or dMMR/MSI-H; at least one of the three criteria must be met.
• Performance Status: ECOG score of 0-1.
• Life Expectancy: Estimated life expectancy ≥6 months.
• Organ Function: Adequate major organ function
• Contraception and Pregnancy: Subjects of childbearing potential must use appropriate contraception methods during the study and for 120 days after the end of the study. Serum pregnancy test must be negative within 7 days prior to study enrollment, and the subject must not be breastfeeding.

Exclusion Criteria:

• 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.).
• Autoimmune Disease: Active autoimmune disease that required systemic treatment (e.g., use of disease-modifying agents, corticosteroids, or immunosuppressants) within 2 years prior to the first dose.

Note: The use of physiological doses of corticosteroids (≤10 mg/day prednisone or equivalent) is permitted. Replacement therapies (e.g., thyroxine, insulin, or physiological corticosteroids for adrenal or pituitary insufficiency) are not considered systemic treatment.

• Prior Medication: Received systemic treatment with Traditional Chinese Medicines with anti-tumor indications or drugs with immunomodulatory effects (including thymosin, interferon, interleukins, excluding local use for pleural effusion control) within 2 weeks prior to the first dose.
• Transplant History: Known history of allogeneic organ transplantation (excluding corneal transplantation) or allogeneic hematopoietic stem cell transplantation.
• Allergy: Known hypersensitivity to the drugs used in this study.
• Neuropathy: Peripheral neuropathy ≥ Grade 2.
• HIV Infection: Known history of Human Immunodeficiency Virus (HIV) infection (i.e., HIV 1/2 antibody positive).
• Hepatitis: Subjects with active Hepatitis B or Hepatitis C.
• Vaccination: Received live vaccines within 30 days prior to the first dose (Cycle 1, Day 1).

Note: Inactivated virus vaccines for seasonal influenza (injection) are permitted within 30 days prior to the first dose; however, live attenuated influenza vaccines administered intranasally are not permitted.

• Pregnancy/Lactation: Pregnant or breastfeeding women.
• Uncontrolled Systemic Disease: Presence of any severe or uncontrolled systemic disease.
• Patients with mental disorders who are unable to cooperate with treatment;
• Other: Any history or evidence of disease, treatment, or abnormal laboratory values that may interfere with trial results or hinder the subject's full participation in the study, or other conditions deemed by the investigator to pose potential risks or make the subject unsuitable for participation in this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Trastuzumab Rezatecan and Retlirafusp alfa treating group; All enrolled subjects will receive the neoadjuvant treatment regimen of Trastuzumab Rezatecan（Dosage: 4.8 mg/kg, intravenous infusion；Frequency: Once every 3 weeks (Q3W)） combined with Retlirafusp alfa（Dosage: 30 mg/kg, intravenous infusion ；Frequency: Once every 3 weeks (Q3W)	Drug: Trastuzumab Rezatecan and Retlirafusp alfa; neoadjuvant treatment regimen of Trastuzumab Rezatecan（Dosage: 4.8 mg/kg, intravenous infusion；Frequency: Once every 3 weeks (Q3W)） combined with Retlirafusp alfa（Dosage: 30 mg/kg, intravenous infusion；Frequency: Once every 3 weeks (Q3W)）

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of dose-limiting toxicities (DLTs) and adverse events (AEs)	Definition: Incidence of dose-limiting toxicities (DLTs) and adverse events (AEs)； Unit of Measure: Number and percentage of participants with DLTs/AEs Measurement Tool: NCI CTCAE v5.0	From enrollment to the end of treatment at 9 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease-free Survival (DFS)	Disease-free survival refers to the time from the start of randomization to disease recurrence or death due to disease progression. DFS will be defined as the last date the patient is last confirmed to be disease-free survival if the patient does not experience disease progression during the study.	2 years after surgery
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.	assessed within 4 weeks post-surgery
Major Pathological Response (MPR)	The percentage of subjects achieving major pathological response, defined as ≤10% residual viable tumor cells in the tumor bed.	from preoperative to 7 days postoperative
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.	2 years after surgery
R0 resection rate	Defined as macroscopically tumor-free surgical margins and microscopically negative tumor cells within 1 mm of the surgical margin.	from preoperative to 7 days postoperative
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.	2 years after surgery
Recommended phase II dose (RP2D)	Dose level (e.g., mg/m², mg/kg, or fixed dose in mg)	From enrollment to 9 weeks (end of treatment)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory Endpoints	Infiltration status of immune cell subsets in tumor tissue before and after treatment.	From the first administration of the drug to 2 years after the surgery

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital with Nanjing Medical University

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): May 31, 2029

Study Registration Dates

• First Submitted: April 28, 2026
• First Submitted That Met QC Criteria: May 11, 2026
• First Posted (Actual): May 12, 2026

Study Record Updates

• Last Update Posted (Actual): May 18, 2026
• Last Update Submitted That Met QC Criteria: May 14, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Other Study ID Numbers: ART-HER2

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No