Efficacy and safety of disitamab vedotin combined with intravesical electromotive mitomycin-C in patients with HER2-expressing high-risk non–muscle-invasive bladder cancer: A phase II study.

772 Background: HER2 expression is an independent predictor of poor response to Bacillus Calmette–Guérin (BCG) therapy. Disitamab Vedotin (RC48-ADC), an anti-HER2 antibody–drug conjugate, inhibits HER2-mediated downstream signaling and delivers the cytotoxic payload monomethyl auristatin E (MMAE) to eradicate tumor cells, demonstrating efficacy in advanced bladder cancer. This study aimed to evaluate the safety and efficacy of RC48-ADC combined with intravesical electromotive mitomycin-C (MMC) in patients with HER2-expressing high-risk non–muscle-invasive bladder cancer (HR-NMIBC). Methods: In this single-arm, open-label, multicenter, phase II trial, 40 patients would be enrolled. All patients underwent complete transurethral resection of bladder tumor (TURBT) and were confirmed as HR-NMIBC according to European Association of Urology (EAU) guidelines. HER2 expression was defined as immunohistochemistry (IHC) 1+, 2+, or 3+. Eligible patients received RC48-ADC (2.0 mg/kg every 2 weeks for 4 cycles, followed by 2.0 mg/kg every 4 weeks for 4 cycles) plus intravesical MMC instillation for one year. The primary endpoint was 12-month disease-free survival (DFS). Secondary endpoints included DFS, overall survival (OS), and safety. Results: Between June 2024 and October 2025, 18 patients were enrolled. The cohort comprised 88.9% (16/18) males and 11.1% (2/18) females, with a median age of 63 years (range: 38–81). HER2 IHC expression levels were 1+ in 16.7%, 2+ in 61.1%, and 3+ in 16.7% of patients. High-risk features included pT1 stage (44.4%), grade 3 (G3) disease (38.9%), and multiple, recurrent, and large tumors ( > 3 cm; 11.1%). As of October 2025, no recurrence or progression events were observed. One death occurred due to causes unrelated to study treatment. All treatment-related adverse events (TRAEs) were grade 1-2, including peripheral sensory neuropathy (33.3%), alopecia (22.2%), fatigue (5.6%), and rash (5.6%). No grade ≥3 TRAEs were reported. Conclusions: The combination of RC48 and intravesical MMC demonstrated promising efficacy and favorable tolerability in patients with HER2-expressing HR-NMIBC, providing a viable alternative to BCG therapy and thereby preventing the need for subsequent cystectomy in this population.