Intravesical Disitamab Vedotin (RC48) for HER2-Expressing High-Risk Non-Muscle-Invasive Bladder Cancer: A Single-Arm, Dose-Escalation Phase I Trial Study.

HER2 expression is correlated with diminished efficacy of Bacillus Calmette-Guérin (BCG) instillation in high-risk non-muscle-invasive bladder cancer (HR-NMIBC). The development of effective intravesical treatments for HER2-expressing HR-NMIBC is of great urgency. In this single-arm phase I trial (ChiCTR2300073975), HER2-expressing HR-NMIBC patients received an induction course of weekly intravesical Disitamab vedotin (RC48) following a 3+3 design (60, 120, or 180 mg) for 6 weeks, followed by optional maintenance dose monthly for 11 sessions. The primary objective was to assess the safety and tolerability of intravesical RC48. The secondary objective was to determine the oncological outcomes. Between August 2023 and March 2024, nine patients were enrolled, and all completed the induction course without dose-limiting toxicities (DLTs) or grade ≥3 drug-related adverse events (AEs). The reported drug-related AEs included urinary tract infection (55.6%, 5/9), urinary frequency (11.1%, 1/9), and hematuria (11.1%, 1/9). The 6-month and 12-month recurrence-free survival (RFS) rates were 100% (8/8) and 87.5% (7/8), respectively, whereas the progression-free survival (PFS) rates were 100% (8/8) and 100% (8/8). Taken together, these findings indicate that intravesical RC48 was well tolerated and showed preliminary efficacy in HER2-expressing HR-NMIBC. The maximum tolerated dose was not reached, and further dose exploration is ongoing (NCT06378242).