A Real-World, Single-Arm Study Protocol of Disitamab Vedotin in Combination With Immunotherapy and Multimodal Radiation Therapy for HER2-Positive Advanced Gastric Cancer: After Second-Line Treatment Failure

Patients with HER2-positive advanced gastric cancer who have failed standard first-line and second-line therapies have limited treatment options. Disitamab vedotin, a novel anti-HER2 antibody-drug conjugate, has been approved in China for this patient population. Additionally, immune checkpoint inhibitors (ICIs) have become a cornerstone of treatment for advanced gastric cancer, but disease progression or immune-related adverse events often lead to treatment discontinuation, raising the clinical question of immunotherapy rechallenge. Preclinical and early clinical evidence suggests that disitamab vedotin may modulate the tumor immune microenvironment and synergize with PD-1 blockade. Furthermore, multimodality radiotherapy (MMRT), combining low-dose radiotherapy (LDRT) and stereotactic body radiotherapy (SBRT), may enhance systemic anti-tumor responses by releasing tumor antigens and remodeling the immune microenvironment.

This prospective, single-center, multicenter, non-interventional study aims to evaluate the efficacy and safety of disitamab vedotin in combination with PD-1 inhibitor immunotherapy and multimodality radiotherapy in patients with HER2-positive advanced gastric cancer after failure of first- and second-line treatment. Eligible patients will receive disitamab vedotin and PD-1 inhibitor per standard clinical guidelines, followed by MMRT targeting at least two independent lesions. The primary endpoint is progression-free survival (PFS) assessed by RECIST v1.1. Secondary endpoints include overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety profile. Exploratory biomarker analyses will be conducted using tumor tissue and peripheral blood samples. A total of 30 patients will be enrolled. This study is conducted in compliance with the Declaration of Helsinki and relevant Chinese regulations, with approval from the West China Hospital Ethics Committee and written informed consent from all participants.

Study Overview

• Status: Not yet recruiting
• Conditions: HER2-positive Advanced Gastric Cancer or Gastroesophageal Junction Adenocarcinoma
• Intervention / Treatment: Drug: Disitamab vedotin + Sintilimab + Multimodality radiotherapy

• Study Type: Observational
• Enrollment (Estimated): 30

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

This study will enroll adult patients with histologically or cytologically confirmed HER2-positive advanced gastric cancer (including gastroesophageal junction cancer) who have failed standard first-line and second-line systemic therapies. Eligible patients must have measurable or evaluable disease per RECIST Version 1.1, and plan to receive or have initiated the combination therapy of disitamab vedotin (RC48), sintilimab, and multimodal radiotherapy (low-dose radiotherapy + stereotactic body radiotherapy) as part of routine clinical practice. Key demographic and clinical characteristics include: age ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, adequate organ function, and no contraindications to the study interventions. Patients will be recruited from multiple clinical centers in China, with a planned sample size of 30 participants.

Description

Inclusion Criteria:

Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2; Liver function: Child-Pugh class A; Histopathologically confirmed advanced gastric cancer with HER2-positive status (HER2 2+ or 3+), which was determined by the central laboratory; Failure of or intolerance to standard first-line and second-line treatment; At least one measurable target lesion based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), or at least one measurable target lesion with confirmed disease progression after local therapy; in addition, ≥ 2 measurable lesions eligible for radiotherapy, which were separate from the aforementioned target lesions; Patients with controlled hepatitis B virus (HBV) infection are eligible once they meet the following criteria: receiving anti-HBV therapy for at least 1 month before the first dose of study medication, and HBV viral load below 2000 IU/mL (10,000 copies/mL) prior to the first dose. Patients with HBV viral load < 2000 IU/mL (10,000 copies/mL), receiving ongoing anti-HBV therapy must maintain the same regimen throughout the study treatment period; Major organ function meets the following criteria within 28 days before treatment initiation: a) Hematological parameters (without blood transfusion within the preceding 14 days): Hemoglobin (HB) ≥ 80 g/L; Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; Platelet count (PLT) ≥ 80 × 10⁹/L; b) Biochemical parameters: Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN, or ≤ 5 × ULN in subjects with liver metastasis; Serum creatinine (Cr) ≤ 1.5 × ULN or creatinine clearance ≥ 60 mL/min; c) Coagulation parameters: International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN; Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN. For subjects on anticoagulant therapy, PT and APTT within the therapeutic range are acceptable; d) Thyroid function: Normal T3 and T4 levels; Women of childbearing potential must agree to use effective contraception during the study and for 120 days after study completion. A negative serum or urine pregnancy test is required within 7 days before study enrollment; Patients are required to offer a signed informed consent for the study.

Exclusion Criteria:

History of other malignant tumors within the past 5 years or concurrent, except cured basal cell carcinoma of the skin, carcinoma in situ of cervix, and papillary thyroid carcinoma; Anaphylactic reaction to RC48 (disitamab vedotin), the active ingredients of PD-1 monoclonal antibodies (sintilimab), or any excipients of the aforementioned drugs; Prior treatment with RC48, as well as prior radiotherapy to the planned targeted radiation lesion; Patients with symptoms of central nervous system metastases; Patients receiving treatment with a powerful CYP3A4 inhibitor within 1 week before enrollment, or treatment with a powerful CYP3A4 inducer within 2 weeks before enrollment; Congestive heart failure classified as New York Heart Association (NYHA) functional class III-IV; History of an ischemic cardiovascular event within 1 year before enrollment; Ongoing systemic immunosuppressive therapy; Participation in another interventional clinical trial of investigational medicinal products within 4 weeks before the first dose of study medication; Requirement for systemic corticosteroids (equivalent to > 10 mg prednisone once a day) or other immunosuppressive agents within 2 weeks before the first dose of study medication; Administration of an antitumor vaccine, or administration of a live attenuated vaccine within 4 weeks before the first dose of study medication; Patients with severe infection within 4 weeks before the first dose of study medication; Active autoimmune disease, history of autoimmune disease, or history of immunodeficiency; Active pulmonary tuberculosis, history of active pulmonary tuberculosis within 1 year before enrollment, or history of active pulmonary tuberculosis more than 1 year before enrollment without standard antituberculosis treatment; Active viral hepatitis: HBV DNA ≥ 2000 IU/mL (10,000 copies/mL); or hepatitis C virus (HCV) infection, defined as positive anti-HCV antibody and HCV-RNA above the lower limit of detection of the assay; Known history of psychotropic substance abuse, alcoholism, or illicit drug use; Pregnancy or breastfeeding women.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
progression-free survival (PFS)	the time from s enrollment to disease progression or death of any cause based on RECIST V1.	From study enrollment until disease progression, death, or study completion (whichever occurs first); estimated follow-up duration is 12-24 months.
overall survival (OS)	the interval from study entry to mortality of any cause	From study enrollment until disease progression, death, or study completion (whichever occurs first); estimated follow-up duration is 12-24 months.
objective response rate (ORR)	the proportion of complete response [CR] plus partial response [PR]	From study enrollment until disease progression, death, or study completion (whichever occurs first); estimated follow-up duration is 12-24 months.

Collaborators and Investigators

• Sponsor: West China Hospital
• Collaborators: Chengdu First People's Hospital; Jiangsu Taizhou People's Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: March 18, 2026
• First Submitted That Met QC Criteria: March 18, 2026
• First Posted (Actual): March 24, 2026

Study Record Updates

• Last Update Posted (Actual): March 24, 2026
• Last Update Submitted That Met QC Criteria: March 18, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: disitamab vedotin; sintilimab
• Other Study ID Numbers: 20252707

Drug and device information, study documents

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