Interim analysis of a phase I/Ib study of enfortumab vedotin plus cabozantinib in patients with metastatic urothelial carcinoma.
Authors: Brown Jacqueline T , Nazha Bassel , Liu Yuan , Ranbhise Shreya , Lozada Kelsea , Hartman Caitlin , McClintock Greta Russler , Kucuk Omer , Carthon Bradley Curtis , Harvey R. Donald , Bilen Mehmet Asim 
Published: January 2024

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Background: Despite advances, effective treatments are needed for patients (pts) with metastatic urothelial carcinoma (mUC). Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) specific for Nectin-4 that is approved as monotherapy and in combination with pembrolizumab in patients who are cisplatin-ineligible. Cabozantinib (cabo) is a multi-tyrosine kinase that inhibits VEGF, MET and AXL with activity in heavily pretreated mUC. Preclinical data suggests antiangiogenic agents may increase ADC penetration of tumor cells, potentially leading to therapeutic synergy. We report safety and preliminary efficacy data from the dose escalation cohort of an ongoing phase I/Ib trial investigating cabo in combination with EV in mUC. Methods: This is a phase I/Ib, open label, single arm, trial at the Winship Cancer Institute of Emory University (NCT04878029). Pts with histologically confirmed mUC who received or were ineligible for platinum chemotherapy and a checkpoint inhibitor are eligible. The phase I dose escalation is a traditional 3+3 design exploring cabo 20 or 40 mg daily with standard dose EV (1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle). The dose expansion cohort is currently enrolling. The primary endpoint of the phase I cohort was safety and tolerability to determine the RP2D. Key secondary objective is preliminary evidence of efficacy via objective response rate (ORR) per RECIST v1.1. Results: As of the 22 September 2023 data cut, 6 pts with mUC have been treated. Three pts were enrolled at the cabo 20 mg and 40 mg dose levels, respectively. All are male with median age of 69 (61-85). 4 of 6 patients (66.7%) are white. One serious adverse event (SAE) occurred in the 20 mg cohort (dehydration) and 3 SAEs occurred at the 40 mg dose (neutropenia, acute kidney injury, superior vena cava syndrome); the neutropenia was the singular grade 4 AE. While this represented the sole dose-limiting toxicity of dose escalation, cabo 20 mg daily was selected as the RP2D based on clinical judgment regarding longer-term tolerability. Only one pt in the 40 mg cohort remains on the initial dose. The most common treatment-related AEs are ALT elevation, hypophosphatemia, rash (66%), fatigue, mucositis, AST elevation, hypomagnesemia, eye irritation, hand-foot syndrome, and anorexia (50%). Five pts had a grade 3 AE (83%); the most common were fatigue (33%) and AKI (33%). The ORR was 83% with each of the 5 of 6 responders experiencing a partial response. The median target lesion reduction was 49.7% (31.8-100). Conclusions: These preliminary data suggest that the combination of EV and cabo 20 mg daily is safe and tolerable with adverse events previously seen with each agent. Encouraging early evidence of activity has been observed based on response rates. Enrollment of mUC pts into dose expansion with cabo 20 mg daily continues and further results including long-term outcomes and correlatives are forthcoming. Clinical trial information: NCT04878029 .