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

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.

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.