Preliminary results of a phase II study to evaluate the efficacy and safety of disitamab vedotin (RC48-ADC) in combination with radiotherapy for adjuvant therapy in upper tract urothelial carcinoma.

Abstract

4605 Background: Although postoperative platinum-based adjuvant chemotherapy improves disease-free survival (DFS), many upper tract urothelial carcinoma (UTUC) patients (pts) were ineligible for cisplatin after radical nephroureterectomy (RNU). UTUCs did not seem to benefit from adjuvant immunotherapy. Previous evidence demonstrated adjuvant radiotherapy improvesd cancer-specific survival in HR UTUCs. Further exploration of alternative adjuvant treatment strategies is needed. This study aims to evaluate the therapeutic potential of RC48-ADC in combination with radiotherapy in HER2 overexpressing UTUCs. Methods: This is an open-label, phase II, non-randomised study to evaluate the efficacy and safety of disitamab vedotin (RC48-ADC), a humanized anti-HER2 antibody, in combination with radiotherapy as a novel adjuvant therapy strategy in UTUC. We recruited cisplatin-intolerant pts with HER2-overexpressing (Immunohistochemistry, IHC 2+, 3+) UTUC after nephroureterectomy staged as pT2N0M0 with high-grade/multifocal disease/positive surgical margin, pT3-4 N0 M0 or pTany N1-2 M0. Pts who declined any adjuvant therapy were assigned to the surveillance group. Pts in adjuvant therapy group received RC48-ADC (2.0 mg/kg D1 Q2W, 6 months) and radiotherapy (45-50Gy/25f/5w, lymphatic drainage regions; 62.5Gy/25f/5w, enlarged lymphnode). The therapy was initiated within 90 days of surgery. The primary end point was DFS. Secondary end points were overall survival (OS), metastasis-free survival (MFS), local-recurrence free survival (LRFS) and safety. The trial is registered with ClinicalTrials.gov, NCT06210490. Results: As of January 2026, 54 patients out of the planned 60 pts have been enrolled in the study. Thirty pts were assigned to adjuvant therapy group and 24 in surveillance. In therapy group, 17 pts completed adjuvant therapy, while 13 pts were undergoing treatment. At a median follow-up of 12.4 months, one recurrence was observed in the therapy group, while 9 patients in surveillance experienced recurrence. The 1-year disease-free survival rates were 95% (95% CI 85.9–100) in the adjuvant therapy group and 69.6% (95% CI 53.1–91.2) in the surveillance group. As of now, the most common (≥20%) treatment-related adverse events (TRAEs) were peripheral sensory neuropathy (40%), increased AST (28%), asthenia (28%) and alopecia (20%). Grade ≥ 3 TRAE was observed in 2 patients (8%), the patients experienced gastrointestinal hemorrhage and peripheral sensory neuropathy, respectively. Conclusions: This study is the first to evaluate the efficacy and safety in adjuvant treatment of ADC plus radiotherapy in UTUCs. The combination of RC48-ADC and radiotherapy as a new adjuvant therapy demonstrated a tolerable safety profile in pts with HER2-overexpressing UTUC. Clinical trial information: NCT06210490 .