(UroToday.com) The 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium held in San Francisco, CA between January 25th and 27th was host to a urothelial carcinoma trials in progress poster session.
Dr. Matt Galsky presented DV-001, a 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 (LA/mUC) that expresses human epidermal growth factor receptor 2 (HER2).
Platinum-based chemotherapy had long been the standard 1st line therapy for LA/mUC, which is an aggressive disease with an estimated median overall survival of approximately 16 months. Recently, the combination of enfortumab vedotin, a nectin-4-directed antibody-drug conjugate (ADC) with a Monomethyl auristatin E (MMAE) payload, plus pembrolizumab has shown improved outcomes compared to chemotherapy, almost doubling the median overall survival of such patients compared to historic controls.
Novel biomarker-informed strategies may improve outcomes further. HER2 expression (defined as immunohistochemistry [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.1,2
Disitamab vedotin (RC48-ADC), or DV, is an investigational ADC consisting of a fully humanized HER2-directed monoclonal antibody, disitamab, conjugated to MMAE via a protease-cleavable mc-vc linker. DV elicits anti-tumor activity through multimodal mechanisms of action, including MMAE-mediated direct cytotoxicity, bystander effect, and immunogenic cell death.
DV has shown encouraging activity with a manageable safety profile in a population of patients with HER2-expressing LA/mUC:3
- As a single agent in the post-platinum setting (ORR: 50.5%; mPFS: 5.9 months; mOS, 14.2 months)
- In combination with a PD-1 inhibitor in the 1st line setting (ORR in HER2 IHC 2/3+, 83.3%; ORR in HER2 IHC 1+, 64.3%).
These data provide a robust rationale for a phase 3 trial of DV plus pembrolizumab in the 1st line setting for HER-2 expressing LA/mUC.
DV-001 is an open-label, randomized, multicenter, controlled phase 3 trial evaluating DV plus pembrolizumab versus chemotherapy in patients with previously untreated HER2-expressing LA/mUC.
The study eligibility criteria are summarized below. Key criteria include eligibility for platinum-containing chemotherapy, allowance for prior neoadjuvant/adjuvant systemic therapy, including PD-(L)-1 inhibitor if ≥12 months, and HER2 expression of 1+ or greater on IHC determined using the VENTANA 4B5 HER2 IHC assay at a central laboratory and using the most recent archival or fresh tumor sample.
The co-primary endpoints are blinded independent central review assessed PFS and OS.
The enrollment sites are illustrated below:
Presented by: Matt Galsky, MD, Professor of Medicine, Hematology and Medical Oncology, Director of Genitourinary Medical Oncology, Co-Director of the Center of Excellence for Bladder Cancer at The Tisch Cancer Institute, and Associate Director for Translational Research at The Tisch Cancer Institute, New York, NY
Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, San Francisco, CA, January 25th – January 27th, 2024
References:- Uzunparmak B, et al. HER2-low expression in patients with advanced or metastatic solid tumors. Ann Oncol. 2023;34(11):1035-46.
- Zhao J, et al. Prognostic role of HER2 expression in bladder cancer: a systematic review and meta-analysis. Int Urol Nephrol. 2015;47(1):87-94.
- Sheng X, et al. Efficacy and Safety of Disitamab Vedotin in Patients With Human Epidermal Growth Factor Receptor 2-Positive Locally Advanced or Metastatic Urothelial Carcinoma: A Combined Analysis of Two Phase II Clinical Trials. J Clin Oncol. 2023;JCO2202912.