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

N/ANot Yet RecruitingNCT07490990

West China Hospital30 enrolled

Overview

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 Type

OBSERVATIONAL

Enrollment

Conditions

HER2-positive Advanced Gastric Cancer or Gastroesophageal Junction Adenocarcinoma

Interventions

Disitamab vedotin + Sintilimab + Multimodality radiotherapyDRUG

Disitamab vedotin (generic name; code: RC48; Chinese name: 维迪西妥单抗): Administered per Chinese clinical practice guidelines for HER2-overexpressing advanced gastric cancer, via intravenous infusion at the recommended dosage and interval (e.g., 2.5 mg/kg every 2 weeks, adjusted for patient tolerance). Sintilimab (generic name; Chinese name: 信迪利单抗): A PD-1 monoclonal antibody administered according to routine clinical practice, via intravenous infusion at the standard dosage and cycle (e.g., 200 mg every 3 weeks, continued until disease progression or unacceptable adverse events). Multimodal radiotherapy (MMRT): Initiated after the first cycle of systemic therapy (disitamab vedotin + sintilimab), consisting of two distinct irradiation strategies for separate independent lesions. Specific regimens are determined by the radiation oncologist based on individual patient conditions (including lesion location/size, organs at risk, and other relevant factors): Low-dose Radiotherapy (LDRT): ≥ 1

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

progression-free survival (PFS)

the time from s enrollment to disease progression or death of any cause based on RECIST V1.

Time frame: 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

Time frame: 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 \[PR\]

Time frame: From study enrollment until disease progression, death, or study completion (whichever occurs first); estimated follow-up duration is 12-24 months.