Disitamab Vedotin Plus Radiotherapy for Adjuvant Treatment of HER2-Expressing Cisplatin-Ineligible Upper Tract Urothelial Carcinoma

A Randomized, Prospective, Multicenter, Phase II Study of Disitamab Vedotin Plus Radiotherapy as Adjuvant Treatment for HER2-Expressing Cisplatin-Ineligible Upper Tract Urothelial Carcinoma

This randomized, open-label, multicenter phase II study is designed to compare disitamab vedotin plus radiotherapy with gemcitabine plus carboplatin as adjuvant treatment in patients with HER2-expressing upper tract urothelial carcinoma after radical nephroureterectomy (RNU). Eligible patients must have postoperative pathologic stage pT3-pT4N0M0 or pTanyN+M0, HER2 expression defined as immunohistochemistry (IHC) 1+, 2+, or 3+, and be cisplatin-ineligible. Patients will be randomized in a 2:1 ratio to receive disitamab vedotin plus radiotherapy or gemcitabine plus carboplatin. The primary endpoint is 3-year disease-free survival. Secondary endpoints include overall survival, metastasis-free survival, local recurrence-free survival, bladder recurrence-free survival, incidence of adverse events, and patient-reported quality of life.

Inclusion Criteria:

• Aged 18 years or older.
• Histologically confirmed upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU).
• Postoperative pathologic stage pT3-pT4N0M0 or pTanyN+M0.
• HER2 expression confirmed by immunohistochemistry (IHC 1+, 2+, or 3+).
• Cisplatin-ineligible, defined as meeting at least one of the following criteria: ECOG performance status 2; creatinine clearance <60 mL/min; CTCAE grade 2 or higher hearing loss; CTCAE grade 2 or higher peripheral neuropathy; or New York Heart Association (NYHA) class III heart failure.
• Adequate organ function.
• Expected survival of at least 6 months.

Exclusion Criteria:

• History of other active malignancies, except for adequately treated malignancies with low risk of recurrence.
• Prior systemic antitumor therapy before study treatment, or unresolved toxicities from prior therapy.
• Known hypersensitivity to disitamab vedotin, related agents, or any component of the study treatment.
• Severe active infection.
• Not adequately recovered from surgery.
• Pregnant or breastfeeding women.
• Any other condition that, in the investigator's judgment, makes the patient unsuitable for participation in the study.