Neoadjuvant treatment with disitamab vedotin monotherapy in patients with HER2-overexpressing muscle invasive bladder cancer (MIBC): An open-label, single-arm, phase II study.

e16584 Background: Radical cystectomy with pelvic lymph node dissection and urinary diversion (RC+PLND+/-UD) is considered the standard of care for patients (pts) with muscle-invasive bladder cancer (MIBC), and no neoadjuvant treatment modality has been shown to dramatically improve long-term survival. Disitamab vedotin (RC48-ADC), a novel humanized anti-HER2 antibody-drug conjugate (ADC), alone and in combination with immune checkpoint inhibitor (ICI), had shown significant improvement of overall survival (OS) in pts with previously treated and untreated HER2 expressing locally advanced or metastatic urothelial cancer, respectively (Guo JCO 2023; Sheng ASCO 2024). Here we present initial results from this open-label single-arm trial of neoadjuvant RC48-ADC monotherapy in pts with HER2-overexpressing MIBC. Methods: This study evaluates the efficacy and safety of RC48-ADC monotherapy as neoadjuvant therapy in pts with treatment-naïve HER2-overexpressing (immunohistochemistry, IHC 2+, 3+) MIBC (cT2-T4a, N0-1, M0; ECOG PS score 0-1). Eligible pts received neoadjuvant RC48-ADC (2.0 mg/kg D1 Q2W, 4 cycles) followed by RC+PLND. The primary endpoint was pathologic complete response (pCR, pT0N0M0). Secondary endpoints were investigator-assessed pathologic muscle-invasive response rate (PaIR, ≤ypT1N0), disease-free survival (DFS), overall survival (OS), OS rate at 12 months, and safety. Results: As of January 2025, 18 pts were enrolled and treated, 17 of whom had completed all 4 cycles of RC48-ADC and undergone surgery with no delays, and 1 was still receiving neoadjuvant therapy. Of the 17 pts, 70.59% (12/17) were male and 29.41% (5/17) were female, with a median age of 71 years (range, 35-79). HER2 2+ and 3+ expression status was 47.06% and 52.94%, respectively. Pts had cT2 (70.59%), or cT3 (29.41%) stage disease. The pCR rate was 41.18% (95% CI, 21.56-64.05), including 50.00% (4/8) in HER2 2+ pts, 33.33% (3/9) in HER2 3+ pts, and 50.00% (6/12) in cT2 pts, 20.00% (1/5) in cT3 pts. The PaIR rate was 64.71% (95% CI, 41.16-82.83). 88.27% pts (15/17) experienced treatment-related adverse events (TRAEs) of any grade, but all were grade 1-2, with no ≥ grade 3 TRAEs occurring during treatment. The most common TRAEs were alopecia (47.06%), aspartate aminotransferase increased (35.29%), alanine aminotransferase increased (23.53%), hyperglycemia (23.53%), peripheral sensory neuropathy (23.53%), and fatigue (23.53%). At a median follow-up of 10.1 months, one patient died due to progression at 13.2 months. Median DFS and OS were not reached and will be updated later. Conclusions: Neoadjuvant RC48-ADC monotherapy treatment demonstrated promising antitumor activity with a manageable safety profile in pts with HER2-overexpressing MIBC. These results support the essential value of RC48-ADC for the neoadjuvant treatment of MIBC. Clinical trial information: ChiCTR2300068270 .