Updated interim analysis of a phase I/Ib study of enfortumab vedotin plus cabozantinib in patients with metastatic urothelial carcinoma.

4586 Background: Despite recent advances, metastatic urothelial carcinoma (mUC) remains a deadly disease. Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) specific for Nectin-4 approved in combination with pembrolizumab in 1L treatment and as monotherapy in later-line therapy. Cabozantinib (cabo) is a multi-tyrosine kinase inhibitor (TKI) that inhibits VEGF 1-3, 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 and currently accruing dose expansion cohort of an ongoing phase I/Ib trial investigating cabo in combination with EV in patients (pts) with 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 explored 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) in 6 patients. Cabo 20 mg was chosen as the recommended dose for dose expansion and 4 patients have been treated to date. The primary endpoint is safety and tolerability of the combination. Key secondary objective is preliminary evidence of efficacy via objective response rate (ORR) per RECIST v1.1. Results: As of the 6 January 2024 data cut, 10 pts have been treated. All are male, 80% are white, and median age is 67.3 (49-85). Four pts were enrolled at the cabo 40 mg daily dose level in dose escalation and six pts have received cabo 20 mg daily in dose escalation and then expansion cohorts. The most common treatment-related AEs are fatigue (55.6%), skin rash, hand-foot syndrome, anorexia (all 44.4%), hyponatremia, hypophosphatemia, mucositis, ALT elevation, and peripheral sensory neuropathy (all 33.3%). Eight pts (88.9%) had a grade ≥ 3 treatment-related AE; the most common were neutropenia, hyponatremia, AKI and fatigue (all 22.2%). Of the 9 response-evaluable pts, the ORR was 88.9% with 7 responders achieving PR and 1 CR; the remaining 1 pt achieved SD with 18.94% target lesion reduction to date and remains on trial. The median target lesion reduction is 52.51% (18.94-100). Pts on cabo 40 mg and cabo 20 mg have a 100% and 60% dose reduction rate, respectively. Conclusions: This is the first clinical trial combining an ADC and TKI in mUC. These preliminary data suggest that the combination of EV and cabo is safe and tolerable with an AE profile consistent with that previously seen with each agent. Encouraging early evidence of activity has been observed. Enrollment of mUC pts into dose expansion with cabo 20 mg daily continues and further results including long-term outcomes and correlatives will be reported at a later date. Clinical trial information: NCT04878029 .