Adjuvant or rescue disitamab vedotin for high-risk non–muscle invasive bladder cancer with HER2 overexpression: A phase II multi-center study.

4616 Background: Disitamab vedotin (DV), a HER2-targeted antibody–drug conjugate (ADC), has shown efficacy in metastatic urothelial carcinoma. However, its role in high-risk non-muscle-invasive bladder cancer (HR-NMIBC) patients with HER2 overexpression remains unexplored. We report preliminary findings from an ongoing phase II trial evaluating DV as adjuvant or rescue therapy in this population. Methods: Two cohorts were enrolled: patients receiving adjuvant therapy following transurethral resection (cohort A) and those undergoing rescue therapy after BCG failure (cohort B). Eligible patients had HR-NMIBC with HER2 overexpression. DV was administered at 120 mg intravenously every 2 weeks for up to 10 cycles. The primary endpoints were safety, 12-month recurrence-free survival (RFS) in cohort A, and 3-month clinical complete response (cCR) rate in cohort B. Secondary endpoints included 6-month RFS (cohort A) and duration of response (DOR, cohort B). Exploratory analyses evaluated the prognostic value of urinary tumor DNA (utDNA) using samples collected at baseline, end of treatment, and at the time of disease recurrence. This study is registered with ClinicalTrials.gov (NCT05996952). Results: Between September 2023 and October 2025, 28 patients were enrolled—22 in cohort A (median age 62 years [range, 33–75]; 3 women [13.6%]) and 6 in cohort B (median age 66 years [range, 60–72]; all men). Median follow-up was 13.4 months (range, 2.1–24.2) for cohort A and 17.0 months (range, 1.8–22.9) for cohort B. In cohort A, 6- and 12-month RFS rates were 95.2% and 73.4%, respectively. In cohort B, the 3-month cCR rate was 100%, and the median DOR was not reached (range, 1.7–19.7 months). All patients experienced treatment-related adverse events (TRAEs); 4 patients (14.3%) had grade ≥ 3 TRAEs. The most common TRAEs were elevated alanine aminotransferase (42.9%), alopecia (42.9%), and fatigue (35.7%). Exploratory analysis of baseline utDNA status demonstrated significant prognostic stratification, with positive patients exhibiting inferior 1-year RFS compared to those with negative status (50% vs. 91%, P=0.043). Conclusions: DV demonstrated a manageable safety profile and encouraging efficacy in patients with HR-NMIBC and HER2 overexpression in both adjuvant and rescue settings. The trial is ongoing, following a Simon two-stage optimal design, with a target enrollment of 52 patients in cohort A and 25 in cohort B. Study initiation was in May 2023. Clinical trial information: NCT05996952 .