Enfortumab Vedotin – Changing the Way We Think About Urothelial Cancer

The United States Food and Drug Administration (FDA) granted accelerated approval to enfortumab vedotin (Padcev®, manufactured and marketed by Astellas Pharma US, Inc., Northbrook, Illinois 60062; distributed and marketed by Seattle Genetics, Inc., Bothell, WA 98021) on December 18, 2019, for patients with locally advanced or metastatic urothelial cancer who have previously received platinum chemotherapy and a PD-L1 inhibitor.

Two years ago, I briefly mentioned enfortumab vedotin in a Clinical Trials Portal article focused on discussing the promising Antibody Drug Conjugate (ADC) class of drugs. 

Now, we have this new agent on the market to use to help our patients. The EV-301 randomized Phase III trial intended to demonstrate survival benefit with enfortumab vedotin over taxane chemotherapy is fully accrued and pending events driven analysis. However, the impressive single-agent activity of enfortumab vedotin in open-label Phase I and II trials for a patient population with great unmet need in the third-line setting justifies the accessibility of this agent for our patients.

To briefly review, enfortumab vedotin is an ADC specific for targeting Nectin-4, which is highly expressed in urothelial carcinoma.1 The monoclonal antibody targeting Nectin-4 is connected by a linker molecule to a cytotoxic drug payload. In the case of enfortumab vedotin, the payload is monomethyl auristatin E (MMAE), a potent antimitotic agent that blocks the polymerization of tubulin. MMAE is too toxic to utilize as a therapeutic agent itself, hence it is linked to the antibody resulting in the vedotin complex. The intent is for enfortumab vedotin to be intracellularly internalized by endocytosis and for the linker to be degraded in a lysosome to subsequently release the cytotoxic payload. 

The sum of the published data with enfortumab vedotin in metastatic urothelial carcinoma is from an open-label Phase I and another open-label Phase II trial. One hundred fifty-five heavily pretreated patients with metastatic urothelial carcinoma were enrolled in the Phase I trial, identifying the recommended Phase II dose of 1.25 mg/kg.1 Of the 112 patients treated at 1.25 mg/kg, the confirmed objective response rate (ORR) was 43% and the median overall survival was 12.3 months. Impressively, outcomes were similar in patients with and without prior anti-PD-L1 therapy, liver metastases or upper tract disease. The most common treatment-emergent adverse events were rash, peripheral neuropathy, fatigue, alopecia, and nausea. In the global Phase II trial, enfortumab vedotin was administered in a three week on, one week off schedule every 28 days.2 The trial was restricted to the post-platinum, post-PD-L1 inhibitor locally-advanced or metastatic urothelial carcinoma population, and 125 patients were treated with the primary endpoint of confirmed ORR. This rate was 44%, similar to the Phase I findings. Again, prespecified subgroup analyses identified similar efficacy across various prognostic populations such as those with and without liver metastases. Adverse events were similar to Phase I findings.

With the above data leading to accelerated FDA approval, more impressive results were presented at the 2019 European Society of Medical Oncology Congress with combination enfortumab vedotin and pembrolizumab in the EV-103 trial.3  

First-line metastatic urothelial carcinoma patients who were ineligible to receive cisplatin chemotherapy were treated with pembrolizumab 200 mg every three weeks and enfortumab vedotin 1.25 mg/kg on day one and eight of 21-day cycles. Of 45 treated patients, 32 (71%) had a confirmed ORR and six (13%) with a complete response. All but three patients had some level of tumor shrinkage translating into a 93% tumor reduction rate. Treatment-related serious adverse events were observed in seven (16%) patients. This level of impressive early efficacy has prompted consideration of this combination regimen for investigation in earlier disease states.

Given the recent FDA accelerated approval of enfortumab vedotin and the exciting early signs of efficacy, multiple clinical trials are ongoing. Please see below for more information and sites of accessibility for your patients. 

Ongoing trials with enfortumab vedotin:

  • Phase III enfortumab vedotin and pembrolizumab with or without chemotherapy vs. chemotherapy alone (EV-302) (NCT04223856)
  • Enfortumab vedotin plus atezolizumab (MORPHEUS mUC) (NCT03869190)
  • Enfortumab vedotin plus multiple combinations (with pembrolizumab, with cisplatin, with carboplatin, with gemcitabine, with pembrolizumab plus platinum) (EV-103) (NCT03288545)
  • Enfortumab vedotin in cisplatin-ineligible patients after prior PD-L1 inhibitor (EV-201) (NCT03219333)

Written by: Evan Yu, MD, Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine Member, Clinical Research Division, Fred Hutchinson Cancer Research Center Clinical Research Director, Genitourinary Oncology, Seattle Cancer Care Alliance Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium


1. Rosenberg, Jonathan, Srikala S. Sridhar, Jingsong Zhang, David Smith, Dean Ruether, Thomas W. Flaig, Joaquina Baranda et al. "EV-101: A Phase I Study of Single-Agent Enfortumab Vedotin in Patients With Nectin-4–Positive Solid Tumors, Including Metastatic Urothelial Carcinoma." Journal of Clinical Oncology (2020): JCO-19.

2. Rosenberg, Jonathan E., Peter H. O’Donnell, Arjun V. Balar, Bradley A. McGregor, Elisabeth I. Heath, Evan Y. Yu, Matthew D. Galsky et al. "Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy." Journal of Clinical Oncology 37, no. 29 (2019): 2592.

3. Hoimes, C. J., J. E. Rosenberg, S. Srinivas, D. P. Petrylak, M. Milowsky, J. R. Merchan, M. A. Bilen et al. "EV-103: Initial results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma." Annals of Oncology 30 (2019): v356.

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