Phase 3 study of disitamab vedotin with pembrolizumab versus chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma that expresses HER2 (DV-001; trial in progress)

Abstract

Introduction & Objectives: Platinum-based chemotherapy (chemo) has been the standard first-line (1L) therapy for locally advanced or metastatic urothelial carcinoma (la/mUC). Recently, enfortumab vedotin + pembrolizumab (pembro) has shown improved outcomes over chemo. Novel biomarker-informed strategies may improve outcomes further. Human epidermal growth factor receptor 2 (HER2) expression (immunohistochemistry IHC] 1-3+) has been reported in approximately half of all patients in multiple tumor types, including UC, and may be associated with poor outcomes. Disitamab vedotin (DV; RC48-ADC) is an investigational antibody-drug conjugate comprising a fully humanized HER2-directed monoclonal antibody, disitamab, conjugated to monomethyl auristatin E (MMAE) via a protease-cleavable mc-vc linker. DV elicits antitumor activity through multimodal mechanisms of action, including MMAE-mediated direct cytotoxicity, bystander effect, and immunogenic cell death. DV has shown encouraging activity with a consistent safety profile in a Chinese population of patients with la/mUC, both as a single agent post-platinum and in combination with a PD-1 inhibitor in the 1L setting. In the ongoing RC48-C014 phase 1b/2 study, DV + toripalimab demonstrated an objective response rate (ORR) of 83.3% in patients with HER2 IHC 2/3+ la/mUC and an ORR of 64.3% in those with IHC 1+ tumors. These data provide a robust rationale for this phase 3 trial of DV plus pembro in the 1L setting for HER2-expressing la/mUC.