Phase 3 open-label, randomized, controlled study of disitamab vedotin with pembrolizumab versus chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma that expresses HER2 (DV-001).
Authors: Galsky Matt D. , Grande Enrique , Necchi Andrea , Koontz Michael Zach , Iyer Gopa , Campbell Matthew T , Drakaki Alexandra , Loriot Yohann , Sokolowski Kevin M. , Zhang Wei , Powles Thomas 
Published: January 2024

TPS717 Background: Locally advanced or metastatic urothelial carcinoma (la/mUC) is an aggressive disease. Platinum-based chemotherapy has been the standard first-line (1L) therapy, but novel biomarker-informed strategies are attractive to improve outcomes. 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 in a post-platinum setting and in combination with a programmed cell death protein 1 (PD-1) inhibitor in the 1L setting. In the ongoing RC48-CO14 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 pembrolizumab in the 1L setting for HER2-expressing la/mUC. Methods: DV-001 (NCT05911295) is an open-label, randomized, multicenter, controlled phase 3 trial evaluating DV with pembrolizumab vs chemotherapy in patients with previously untreated HER2-expressing la/mUC. Patients will be randomized 1:1 to Arm A or B. Those in Arm A will receive DV intravenously (IV) every 2 weeks and pembrolizumab IV every 6 weeks. Patients in Arm B will receive platinum-containing chemotherapy with gemcitabine IV on Days 1 and 8 of every 3-week cycle, and either cisplatin or carboplatin on Day 1 of every 3-week cycle. Maintenance therapy with avelumab may be used where approved and available after completion of 4-6 cycles of 1L platinum-based chemotherapy, if clinically appropriate. Patients must have previously untreated la/mUC, measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1, Eastern Cooperative Oncology Group performance status score of 0-2 and be eligible for platinum-containing chemotherapy. HER2 expression must be determined using the VENTANA 4B5 HER2 IHC Assay at a central laboratory and using the most recent archival or fresh tumor sample. Primary endpoints include progression-free survival per blinded independent central review and overall survival. Enrollment is currently ongoing in the United States and planned globally. Clinical trial information: NCT05911295 .