The antibody-drug conjugates sacituzumab govitecan (SG) and enfortumab vedotin (EV) are standard monotherapies for metastatic urothelial carcinoma (mUC). Given different targets and payloads, we evaluated the safety and efficacy of SG+EV in a phase I trial in mUC (NCT04724018).

Patients with mUC and ECOG PS ≤1 who had progressed on platinum and/or immunotherapy were enrolled. SG+EV were administered on Days 1+8 of a 21-day cycle until progression or unacceptable toxicity. Primary endpoint was the incidence of dose-limiting toxicities (DLTs) during cycle one. The number of patients treated at each of four pre-specified dose levels (DL) and the maximum tolerated doses in combination (MTD) were determined using a Bayesian Optimal Interval design. Objective response, progression-free survival and overall survival were secondary endpoints.

Between May 2021 and April 2023, 24 patients were enrolled; one patient never started therapy and was excluded from the analysis. Median age was 70 years (range 41‒88); 11 patients received ≥ 3 lines of therapy. 78% (18/23) of patients experienced grade ≥3 adverse event (AE) regardless of attribution at any DL, with one grade 5 AE (pneumonitis possibly related to EV). The recommended phase 2 doses are SG 8 mg/kg with EV 1.25 mg/kg with GCSF support; MTDs are SG 10 mg/kg with EV 1.25 mg/kg. The objective response rate was 70% (16/23, 95% Confidence interval: 47‒87%) with 3 complete responses; 3 patients had progressive disease as best response. With median follow-up of 14 months, 9/23 patients have ongoing response including 6 responses lasting over 12 months.

The combination of SG+EV was assessed at different DLs and a safe dose for phase 2 was identified. The combination had encouraging activity in patients with mUC with high response rates, including clinically significant complete responses. Additional study of this combination is warranted.