Disitamab Vedotin Combined With Sintilimab and Multimodal Radiotherapy for HER2-Positive Advanced Gastric Cancer After Second-Line Treatment Failure: A Prospective, Single-Arm Phase II Clinical Trial

Patients with HER2-positive advanced gastric cancer who experience disease progression after standard first- and second-line therapies have limited subsequent treatment options. Disitamab vedotin, a novel anti-HER2 antibody-drug conjugate (ADC), has been approved in China for this patient population. Immune checkpoint inhibitors (ICIs) serve as a core therapeutic modality for advanced gastric cancer; however, treatment discontinuation often occurs due to disease progression or immune-related adverse events, which raises clinical demands for immunotherapy rechallenge. Preclinical and early clinical evidence suggests that disitamab vedotin may remodel the tumor immune microenvironment and generate synergistic anti-tumor activity with PD-1 blockade. Furthermore, multimodal radiotherapy combining low-dose radiotherapy (LDRT) and high-dose hypofractionated radiotherapy (HFRT) can enhance systemic anti-tumor immunity through tumor antigen release and remodeling of the tumor immune microenvironment.

This prospective, multicenter, interventional, single-arm phase II clinical study aims to evaluate the efficacy and safety of disitamab vedotin combined with sintilimab and multimodal radiotherapy in patients with HER2-positive advanced gastric cancer with progression following first- and second-line systemic therapy. Eligible participants will receive protocol-specified disitamab vedotin and sintilimab, followed by multimodal radiotherapy delivered to at least two independent lesions. The primary endpoint is progression-free survival (PFS) assessed according to 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 matched tumor tissue and peripheral blood specimens. A total of 30 participants will be enrolled. This trial is conducted in accordance with the Declaration of Helsinki and relevant Chinese biomedical research regulations. All enrolled patients will provide written informed consent, and the study has obtained ethical approval from the Ethics Committee of West China Hospital, Sichuan University.

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: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

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

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

1. Age: 18-75 years.
2. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2.
3. Liver function: Child-Pugh class A.
4. Histopathologically confirmed advanced gastric cancer with HER2-positive status, defined as HER2 IHC 2+ or 3+, as determined by central laboratory testing.
5. Failure of or intolerance to standard first-line and second-line treatments.
6. At least one measurable lesion based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). If a lesion has previously received local therapy, it may be considered measurable only when unequivocal disease progression has been confirmed. In addition, patients should have at least two measurable lesions suitable for radiotherapy, separate from the RECIST target lesions whenever feasible.
7. Patients with controlled hepatitis B virus (HBV) infection are eligible if they have received anti-HBV therapy for at least 1 month before the first dose of study medication, and have an HBV viral load < 2000 IU/mL (10 000 copies/mL) before the first dose. Patients receiving ongoing anti-HBV therapy must maintain the same regimen throughout the study treatment period.
8. Major organ function must meet the following criteria within 28 days before treatment initiation:

1)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.

2)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.

3)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.

4)Thyroid function: Normal T3 and T4 levels. (9)Women of childbearing potential must agree to use effective contraception during the study and for 120 days after the last dose of study treatment. A negative serum or urine pregnancy test is required within 7 days before study enrollment.

(10) Patients must provide written informed consent before enrollment. Exclusion Criteria

1. History of other malignant tumors within the past 5 years or concurrent other malignancies, except cured basal cell carcinoma of the skin, carcinoma in situ of the cervix, or papillary thyroid carcinoma.
2. History of anaphylaxis or severe hypersensitivity to disitamab vedotin, sintilimab, or any excipients of these drugs.
3. Prior treatment with disitamab vedotin or sintilimab.
4. Patients with symptomatic central nervous system metastases.
5. Patients receiving treatment with a strong CYP3A4 inhibitor within 1 week before enrollment, or treatment with a strong CYP3A4 inducer within 2 weeks before enrollment.
6. Congestive heart failure classified as New York Heart Association (NYHA) functional class III-IV.
7. History of an ischemic cardiovascular event within 1 year before enrollment.
8. Ongoing systemic immunosuppressive therapy.
9. Participation in another interventional clinical trial of investigational medicinal products within 4 weeks before the first dose of study medication.
10. Requirement for systemic corticosteroids, equivalent to > 10 mg prednisone per day, or other immunosuppressive agents within 2 weeks before the first dose of study medication.
11. Administration of an antitumor vaccine or a live attenuated vaccine within 4 weeks before the first dose of study medication.
12. Patients with severe infection within 4 weeks before the first dose of study medication.
13. Active autoimmune disease or history of autoimmune disease and history of immunodeficiency.
14. 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 anti-tuberculosis treatment.
15. 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.
16. Known history of psychotropic substance abuse, alcoholism, or illicit drug use.
17. Pregnancy or breastfeeding women.

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: Disitamab vedotin plus sintilimab combined with multimodal radiotherapy	Drug: Disitamab vedotin + Sintilimab + Multimodality radiotherapy; Patients receive disitamab vedotin (2.5 mg/kg intravenously every 2 weeks), sintilimab (200 mg intravenously every 2 weeks), combined with multimodal radiotherapy consisting of low-dose radiotherapy (2 Gy × 5 fractions) and hypofractionated radiotherapy (8 Gy × 3 fractions).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	Time from study enrollment to documented disease progression (per RECIST v1.1) or death from any cause, whichever occurs first. Patients without progression or death will be censored at the last valid tumor assessment.	Up to 24 months from enrollment of the last participant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	Percentage of participants achieving confirmed complete response (CR) or partial response (PR) according to RECIST v1.1.	Up to 24 months from enrollment of the last participant
Disease Control Rate (DCR)	Percentage of participants achieving confirmed CR, PR, or stable disease (SD) according to RECIST v1.1.	Up to 24 months from enrollment of the last participant
Overall Survival (OS)	Time from study enrollment to death from any cause. Participants alive at data cutoff will be censored at the last follow-up date	Up to 36 months from enrollment of the last participant

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): August 3, 2026
• Last Update Submitted That Met QC Criteria: July 30, 2026
• Last Verified: July 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