(UroToday.com) The 2024 European Association of Urology (EAU) annual meeting featured a session on metastatic urothelial cancer, and a trial in progress presentation by Dr. Thomas Powles discussing DV-001, a phase 3 trial of disitamab vedotin with pembrolizumab versus chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma that expresses HER2. Platinum-based chemotherapy has been the standard first-line therapy for locally advanced/metastatic urothelial carcinoma, which is an aggressive disease. Recently, enfortumab vedotin, a nectin-4-directed antibody drug conjugate with a MMAE payload, + pembrolizumab has shown improved outcomes over chemotherapy.1 HER2 expression (defined as IHC >= 1+) has been reported in approximately half of all patients across multiple tumor types, including urothelial carcinoma, and may be associated with poor outcomes. Disitamab vedotin is an investigational antibody-drug conjugate comprising a fully humanized HER2-directed monoclonal antibody, disitamab, conjugated to MMAE via protease-cleavable mc-vc linker:
Nonclinical data suggest disitamab vedotin elicits antitumor activity through multimodal mechanisms of action, including MMAE-mediated direct cytotoxicity, bystander effect, and immunogenic cell death. Disitamab vedotin has shown encouraging activity with a manageable safety profile in a population of patients with locally advanced/metastatic urothelial carcinoma:
- As a single agent in a post-platinum setting (HER2 IHC 3+/2+ ORR 50.5%; median progression free survival 5.9 months; median overall survival 14.2 months)
- In combination with a PD-1 inhibitor in all comers (ORR 76.0% in treatment naïve patients; 83.3%, 64.3%, and 33.3% in HER2 IHC 3+/2+, IHC 1+, and IHC 0 subgroups, respectively)
Improved outcomes observed with an MMAE payload plus PD-1 inhibition across the antibody-drug conjugate landscape, along with disitamab vedotin data, provide a robust rationale for this phase 3 trial of disitamab vedotin with pembrolizumab in the first-line setting for HER2-expressing locally advanced/metastatic urothelial carcinoma. DV-001 (NCT05911295) is an open-label, randomized, multi-center, controlled phase 3 trial evaluating disitamab vedotin with pembrolizumab versus chemotherapy in patients with previously untreated HER2-expressing locally advanced/metastatic urothelial carcinoma:
The primary objective was to compare the efficacy of disitamab vedotin in combination with pembrolizumab to chemotherapy, with the primary endpoints of progression free survival and overall survival. Key secondary objectives include objective response rate, duration of response, disease control rate, and safety. This is a global trial with several countries with enrollment ongoing and planned:
Presented by: Thomas Powles, MBBS, MRCP, MD, Barts Health NHS Trust, Barts Cancer Centre, London, UK
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 European Association of Urology (EAU) annual congress, Paris, France, April 5th - April 8th, 2024
References:
- Powles T, Valderrama BP, Gupta S, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10)875-888.