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.