A research team led by Professor Lin Tianxin and Professor Chen Xu from the Sun Yat-sen Memorial Hospital of Sun Yat-sen University has published clinical trial results in the prestigious journal MedComm, titled “Intravesical Disitamab Vedotin (RC48) for HER2-Expressing High-Risk Non-Muscle-Invasive Bladder Cancer: A Single-Arm, Dose–Escalation Phase I Trial Study.” This marks the world’s first clinical study to evaluate the intravesical administration of the HER2-targeted antibody–drug conjugate (ADC) disitamab vedotin (RC48) in patients with HER2-positive high-risk non-muscle-invasive bladder cancer (HR-NMIBC). The study offers a novel bladder-sparing strategy for patients who are unresponsive or intolerant to Bacillus Calmette-Guérin (BCG) therapy.Background: Unmet Need in HR-NMIBC
Non-muscle-invasive bladder cancer (NMIBC) accounts for 75–80% of all bladder cancer cases, with high-risk NMIBC patients facing significantly increased risks of recurrence and progression. The current standard of care involves transurethral resection of bladder tumor (TURBT) followed by intravesical BCG instillation. However, due to global BCG shortages and its considerable toxicity, many patients are either unable to access or tolerate this treatment. Additionally, 70–85% of NMIBC cases overexpress HER2, and these patients often have poorer responses to BCG and a higher likelihood of early recurrence. Therefore, there is an urgent need to develop safer, more effective postoperative treatment strategies for this subset of patients.
RC48: A Novel Chinese-Developed HER2-Targeted ADC
RC48 is a domestically developed HER2-targeted ADC composed of an anti-HER2 monoclonal antibody linked to the cytotoxic microtubule inhibitor MMAE. It has demonstrated favorable efficacy and safety in metastatic urothelial carcinoma when administered intravenously, and is already approved in China for HER2-positive (IHC 2+/3+) locally advanced or metastatic urothelial cancer in patients previously treated with systemic chemotherapy.
Building on this, the research team proposed a novel approach using RC48 via intravesical instillation, aiming to deliver high concentrations of the drug directly to the tumor site while minimizing systemic toxicity. They initiated the first open-label, single-arm, dose-escalation Phase I clinical trial to evaluate the safety and preliminary efficacy of this strategy in HR-NMIBC patients.
Study Design and Key Findings
A total of 9 patients were enrolled using a traditional “3+3” dose-escalation design. Three dose levels were tested during the induction phase (60 mg, 120 mg, and 180 mg), with patients receiving weekly treatments for six weeks. This was followed by monthly maintenance therapy (dose adjustments permitted).
Safety: All nine patients successfully completed the 6-week induction phase. No dose-limiting toxicities (DLTs) or grade ≥3 treatment-related adverse events were observed. The most common adverse events were urinary tract infection (55.6%), urinary frequency (11.1%), and hematuria (11.1%), all of which resolved with temporary drug interruption or symptomatic treatment.
Efficacy: With a median follow-up of 16.97 months, the recurrence-free survival (RFS) rate was 100% at 6 months and 87.5% at 12 months. Progression-free survival (PFS) at both time points remained 100%. Notably, both cases of recurrence occurred in the 60 mg dose group, suggesting a potential dose-response relationship.
Clinical Implications
Compared to standard BCG therapy (1-year RFS 60–90%, PFS 80–90%) and combination therapies involving BCG with chemotherapy or immunotherapy (1-year RFS 80–90%), the RC48 intravesical instillation strategy demonstrates compelling advantages in safety and targeted treatment. These findings offer a promising new bladder-sparing approach for HER2-positive HR-NMIBC patients, especially those unable to undergo or tolerate BCG therapy.
Research Team
The study’s first and corresponding author is Professor Chen Xu from the Department of Urology, Sun Yat-sen Memorial Hospital. Joint first authors include Assistant Researcher Huang Ming and graduate student Chen Zehua. Professor Lin Tianxin also served as a corresponding author.
This pioneering research paves the way for future precision medicine strategies in the management of NMIBC.
