A first-in-human trial of intravesical enfortumab vedotin (EV), an antibody-drug conjugate (ADC), in patients with non-muscle invasive bladder cancer (NMIBC): Interim results of a phase 1 study (EV-104).
Authors: Kamat Ashish M. , Lotan Yair , Roupret Morgan , Steinberg Gary D. , Inman Brant A. , Powles Thomas , Redorta J. Palou , Porten Sima P. , Kulkarni Girish S. , Uchio Edward M. , Gorla Seema Rao , Haas Gabriel P. , Yu Yao , Chia Yen Lin , Birrenkott Matthew , Kates Max R. 
Published: June 2023

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Background: A majority of patients (pts) with bladder cancer present with non-muscle invasive disease; for pts with high-risk tumors, standard of care (SOC) is resection of tumor followed by intravesical Bacillus Calmette-Guerin (BCG). Once pts experience recurrence and develop BCG-unresponsive disease, SOC is radical cystectomy (RC), which many pts are unfit for or refuse. EV is an ADC directed to Nectin-4, which is highly expressed in bladder tumors. Intravenous EV has demonstrated survival benefit in pts with previously treated la/mUC. In preclinical models with intravesical administration, EV was well tolerated and showed antitumor activity. Here we present the first clinical data for intravesical administration of EV in pts with NMIBC. Methods: EV-104 (NCT05014139) is an ongoing phase 1, open-label, multicenter, dose-escalation and expansion study of intravesical EV evaluating the safety, tolerability, PK, and antitumor activity of intravesical EV in pts with high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary disease who are ineligible for or refuse RC. Dose escalation phase aims to identify the MTD or recommended dose of intravesical EV at the following dose levels: 125mg, 250mg, 500mg, and 750mg. Pts receive intravesical EV weekly for 6 weeks in the induction phase, followed by 9 monthly maintenance doses. Preliminary safety, PK, and efficacy data for 125mg and 250mg doses are presented in this abstract. Results: As of data cutoff (1 Dec 2022), 6 pts received intravesical EV across 2 dose levels: 4 pts at 125mg completed 6 induction cycles and proceeded to maintenance; 2 pts at 250mg had received at least 3 doses of intravesical EV. Of 6 pts across doses, there were no Grade ≥3 TRAEs, treatment-related SAEs, TRAEs leading to dose reduction or discontinuation. 4 of 6 pts (3 at 125mg and 1 at 250mg) experienced ≥1 treatment-related adverse event (TRAE) of Grade 1 or 2. Most common TRAEs were fatigue (3 of 6) and micturition urgency (2 of 6). As of data cutoff, no DLTs were observed for 125mg; the DLT evaluation period for 250mg was not complete. All blood PK analyses (ADC and unconjugated MMAE) for pts at 125mg were undetectable; no PK data was available for 250mg. Of 4 pts receiving 125mg of intravesical EV, 3 achieved CR and continue in response. The fourth pt discontinued tx due to persistent disease but remains on study. Pts at 250mg had not been evaluated for response at data cutoff. Detailed safety and additional efficacy data will be presented. Conclusions: Preliminary data from EV-104 show intravesical EV is well tolerated with no evidence of systemic exposure at 125mg. Preliminary antitumor activity was observed at 125mg with 3 of 4 pts achieving a CR. Dose escalation is ongoing to identify the MTD or recommended dose for dose expansion. Clinical trial information: NCT05014139 .