Enfortumab Vedotin for Urothelial Carcinoma: Thomas Powles, MD, MBBS, MRCP

Thomas Powles, MD, MBBS, MRCP.

For patients with locally advanced or metastatic urothelial carcinoma, treatment options are limited after progression on chemotherapy and immune checkpoint inhibitors, and survival rates remain low. In the phase 3 EV-301 trial, results of which were recently presented at the American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, enfortumab vedotin demonstrated promising efficacy in this patient population. In this interview with Oncology Data Advisor, Dr. Thomas Powles, Director of Barts Cancer Centre in the United Kingdom, discusses the significance of the trial’s findings and the benefits of enfortumab vedotin for patients with locally advanced or metastatic urothelial carcinoma.

What are some of the most challenging aspects of managing patients with locally advanced or metastatic urothelial carcinoma?

Thomas Powles, MD, MBBS, MRCP: Patients with urothelial cancer are a challenging group of patients to manage because the disease is inevitably very difficult to treat. This population also tends to be more elderly, with a median disease presentation in the eighth decade of life. Many of these patients also have comorbidities, and smoking is a risk factor associated with the development of urothelial carcinoma. Overall, this is a challenging and complex patient population to manage.

Can you comment on the significance of your findings regarding enfortumab vedotin for patients with locally advanced or metastatic urothelial carcinoma?

Dr. Powles: Enfortumab vedotin is an antibody-drug conjugate that targets the protein Nectin-4 for the payload associated with the drug, the microtubule disrupting agent. Nectin-4 is overexpressed in the vast majority of patients with urothelial cancer, making it an attractive target in this setting. Phase 1 and phase 2 data were very supportive of moving the drug into phase 3, and we’re now seeing response rates of about 40% in the third-line setting. EV-301 is testing enfortumab vedotin versus chemotherapy in patients who progressed after receiving two standard-of-care therapies for urothelial cancer, both platinum-based chemotherapy and an immune checkpoint inhibitor. Patients were randomized in a 1:1 ratio to receive either enfortumab vedotin or chemotherapy.

The top-line results of the trial showed that enfortumab vedotin reduces the risk of death compared with chemotherapy by 51%, with a hazard ratio of 0.69. Median overall survival for patients who received enfortumab vedotin was approximately 13 months. These results are positive and very encouraging, and they are indeed practice-changing. The other efficacy components, including response rates, showed a better response and longer progression-free survival with enfortumab vedotin. The drug works across broad subgroups of patients, and the toxicity profile is largely manageable. Key adverse events associated with enfortumab vedotin in the trial included skin rash, hypoglycemia, and peripheral neuropathy. These three events were manageable and in line with previous results.

Overall, EV-301 showed a significant advantage for enfortumab vedotin over chemotherapy across a number of efficacy end points, and it also showed manageable toxicity. Enfortumab vedotin therefore has become the new standard of care for metastatic urothelial cancer, which is very exciting. It’s important to remember that in urothelial cancer, we’ve had very few treatment options up until now, with a median overall survival remaining very short for the vast majority of patients. This is a new chapter in the treatment of urothelial carcinoma, which I think will have a number of aspects to it as the drug moves earlier into the disease setting, helping more patients.

What are some of the questions you commonly encounter from patients with urothelial carcinoma, and how do you counsel them?

Dr. Powles: Many patients want to discuss whether or not they can tolerate treatment, which I think is very important. Ultimately, though, patients want to go into a long-term durable remission with treatment and receive drugs that are associated with a survival signal. The important aspect about the enfortumab vedotin data is that the drug is very actionable. What I mean by that is that when we give the drug, we see reduction in the size of the cancer and even in liver metastases, which previously were very difficult to treat. Essentially, enfortumab vedotin is important because patients with aggressive disease are a very high-need population, and it’s a population in which this drug is very active. It’s active in the other patient subgroups as well, but its efficacy is significant for the aggressive disease phenotype because we’ve struggled a bit more with this patient group. While enfortumab vedotin is going to be combined with other drugs in the future, it’s also going to move earlier in the disease setting so that we can control the disease in more patients earlier on.

About Dr. Powles

Thomas Powles, MD, MBBS, MRCP, is the Director of Barts Cancer Centre at Queen Mary University of London, where he is also a Professor of Genitourinary Oncology and the Lead for Solid Tumour Research. Dr. Powles specializes in the treatment of patients with genitourinary cancers, including urothelial carcinoma, renal cell carcinoma, and prostate cancer. He leads a spectrum of clinical trials focusing on the development of novel targeted and immune therapies for patients with genitourinary malignancies. Dr. Powles serves on the editorial board for several medical journals, and he has authored or coauthored more than 100 peer-reviewed publications.

For More Information

Powles T, Rosenberg JE, Sonpavde G, et al (2021). Primary results of EV-301: a phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated locally advanced or metastatic urothelial carcinoma. J Clin Oncol (Genitourinary Cancers Symposium Abstracts), 39(suppl_15). Abstract 393. DOI:10.1200/JCO.2021.39.6_suppl.393

Transcript edited for clarity. Any views expressed above are the speaker’s own and do not necessarily reflect those of Oncology Data Advisor. 

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