Intravesical disitamab vedotin (RC48) for patients with HER2-expressing high-risk non-muscle-invasive bladder cancer: A dose-escalation phase I trial.

Abstract

4605 Background: HER2 expression is associated with poor efficacy of Bacillus Calmette-Guérin (BCG) instillation in patients (pts) with high-risk non-muscle-invasive bladder cancer (HR-NMIBC). Developing effective treatment for HER2-expressing HR-NMIBC is of great urgency. Our previous study demonstrated that intravesical disitamab vedotin (DV, RC48, an anti-HER2 antibody-drug conjugate) had promising anti-tumor effects in the orthotopic BCa mouse model (Hong, X. et al., Advanced Science , 2023). We aimed to evaluate the safety and efficacy of intravesical DV in pts with HER2-expressing HR-NMIBC. Methods: Key eligibility criteria included HR-NMIBC (stage: cTa/T1±CIS, N0, M0) pts who were unsuitable for cystectomy, 18-75 years of age, HER2-expressing (IHC 1/2/3+) , BCG naive or BCG-unresponsive, and conducted transurethral resection of bladder tumor (TURBT) within 3 weeks prior to study treatment. Pts received intravesical DV (60, 120, or 180 mg) following a 3+3 design once weekly for six weeks (induction), followed by optional DV maintenance treatment once monthly until disease recurrence/progression, intolerable toxicity, or completion of nine treatments. The primary objective of this study was to assess the safety and tolerability of DV. The scheduled efficacy assessment included ultrasound and cystoscopic examination every three months. This study was registered with ClinicalTrials.gov , NCT06378242. Results: Between August 15, 2023 and December 1, 2024, nine pts were enrolled and completed the induction treatments at designated doses; no dose-limiting toxicities (DLTs) or any≧grade 3 treatment-related adverse events (TRAEs) occurred. The most common TRAEs included urinary tract infection (55.6%, 5/9), pollakiuria (11.1%, 1/9) and hematuria (11.1%, 1/9). All the patients underwent regular efficacy assessments, except for one patient who withdrew from the study in advance. As of December 1, 2024, after a median follow-up of 12.0 months (interquartile range [IQR]: 9.0–12.3), two pts developed recurrent disease, and no disease progression occurred. At 6 months, 8 pts were assessed for efficacy; both recurrence-free survival (RFS) and progression-free survival (PFS) were 100%. At 12 months, 6 pts were efficacy-evaluable; RFS rate was 83.3% (95% CI: 27.3, 97.5) and PFS rate was 100%. Conclusions: Intravesical DV was well-tolerated and showed preliminary efficacy in pts with HER2-expressing BCG-naive/unresponsive HR-NMIBC. The maximum tolerated dose was not reached, further dose exploration is ongoing in RC48-C029 study (NCT06378242). Clinical trial information: NCT06378242 .