ASCO GU 2024: Interim Analysis of a Phase I/Ib Study of Enfortumab Vedotin plus Cabozantinib in Patients with Metastatic Urothelial Carcinoma

( 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 poster session. Dr. Jacqueline Brown presented an interim analysis of a phase I/Ib study of enfortumab vedotin plus cabozantinib in patients with metastatic urothelial carcinoma.

Despite recent major breakthroughs, metastatic urothelial carcinoma remains a relatively deadly disease with a highest reported median overall survival of 31.5 months with enfortumab vedotin + pembrolizumab. Enfortumab vedotin is an antibody-drug conjugate consisting of a fully humanized monoclonal antibody directed against the extracellular domain of Nectin-4, conjugated to a microtubule-disrupting agent, monomethyl auristatin E (MMAE) via a protease-cleavable linker. Cabozantinib is a tyrosine kinase inhibitor (TKI) that inhibits VEGF, MET, and AXL with activity in heavily-pretreated urothelial carcinoma. Preclinical data suggest that anti-angiogenic agents may increase the tumoral cell penetration of antibody-drug conjugates, potentially synergizing their therapeutic efficacy. In this report, Dr. Brown and colleagues reported the safety and preliminary efficacy data from the dose escalation cohort of an ongoing phase I/lb trial investigating cabozantinib + enfortumab vedotin for metastatic urothelial carcinoma patients.

This trial included patients with metastatic urothelial carcinoma who received or were ineligible for platinum-based chemotherapy and immune checkpoint inhibitors. The phase 1 dose escalation cohort employed a 3+3 design exploring cabozantinib 20 mg or 40 mg daily plus standard dose enfortumab vedotin (1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle). The phase 1B dose expansion cohort is currently enrolling at cabozantinib 20 mg daily and will be reported in the future.

The primary endpoint of the phase I cohort was safety and tolerability to determine the recommended phase 2 dose. The key secondary endpoint was objective response rate (ORR) per RECIST v1.1. 

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To date, six patients (all male) have been enrolled. All patients had received prior chemotherapy (either gemcitabine/cisplatin or ddMVAC) and immune checkpoint inhibitors.

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With regard to safety outcomes, one serious adverse event occurred in the 20 mg cohort (dehydration). At the 40 mg dosing, three treatment-related serious adverse events occurred (neutropenia, acute kidney injury, superior vena cava syndrome). Neutropenia was the only grade 4 adverse event and drug-limiting toxicity observed. Cabozantinib 20 mg daily was selected as the recommended phase 2 dose, based on clinical judgment regarding longer-term tolerability. 

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With regards to efficacy outcomes, all six patients in the dose escalation cohort achieved a partial response as their best overall response. The median time to respond was 4.6 months.

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Presented by: Jacqueline T. Brown, MD, Assistant Professor, Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA

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