Neoadjuvant treatment with disitamab vedotin plus perioperative toripalimab in patients with HER2-expressing muscle-invasive bladder cancer (MIBC) in the phase II RC48-C017 trial: Updated results.

Abstract

766 Background: Disitamab vedotin (DV, a HER2-targeted antibody-drug conjugate with monomethyl auristatin E as the payload) in combination with toripalimab (a PD-1 inhibitor) has demonstrated significant and clinically meaningful improvement in both progression-free survival and overall survival (OS) in patients (pts) with untreated, HER2-expressing, advanced urothelial cancer (UC) in the phase III RC48-C016 study (Sheng, et al. NEJM 2025). However, its efficacy in the early-stage disease setting is not fully explored. The single-arm phase II RC48-C017 trial evaluated the efficacy and safety of the combination of DV and toripalimab in pts with HER2-expressing MIBC in the perioperative setting. The previous analysis showed a pathological complete response (pCR) rate of 63.6% in the surgical pts, and manageable safety (Sheng, et al. ASCO GU 2025). Methods: This study enrolled pts with previously untreated MIBC (cT2-4aN0-1M0) with locally confirmed HER2 expression (defined as immunohistochemistry [IHC] ≥1+). All pts must be eligible for and plan to undergo curative-intent radical cystectomy and pelvic lymph node dissection (RC+PLND). Eligible pts received 6 cycles of DV (2 mg/kg, once every 2 weeks [Q2W]) plus toripalimab (3 mg/kg Q2W) at the neoadjuvant phase. After RC+PLND, pts received 20 cycles of adjuvant toripalimab (3 mg/kg Q2W). The primary objective was to assess efficacy. We present the updated results, including event-free survival (EFS), OS, and safety, with a longer follow-up. The data cutoff (DCO) date for this analysis was August 14, 2025. Results: A total of 47 pts were enrolled and treated, with the majority (83.0%) at T2-4N0M0 stage. RC+PLND was performed in 33 pts. As of DCO, the median OS follow-up was 26.4 (95% CI: 24.4-28.2) months. The median EFS was not reached. At 12 and 18 months, the EFS rate was 93.2% (95% CI: 75.4-98.3) and 80.9% (54.4-92.9), respectively, in pts who underwent surgery, and was 91.0% (77.8-96.5) and 81.5% (64.3-90.9), respectively, in the total pts. The median OS was not reached; the 12- and 24-month OS rates were 95.7% (95% CI: 83.9-98.9) and 91.3% (95% CI: 78.6-96.7), respectively. No new safety signals were observed. Conclusions: These updated data demonstrated that the initial treatment response has translated into a durable long-term disease control and survival, as evidenced by the EFS and OS outcomes. This sustained treatment effect of neoadjuvant DV plus perioperative toripalimab in pts with HER2-expressing MIBC in the perioperative setting deserves further evaluation in pivotal clinical studies. Clinical trial information: NCT05297552 .