Dr. Powles discusses the role of enfortumab vedotin in bladder cancer

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In July 2021, the FDA granted a standard approval to enfortumab vedotin-ejfv (Padcev) for the treatment of patients with bladder cancer, based on findings from the EV-3011 and EV-201 trials.

The antibody-drug conjugate is specifically approved for use in patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy; or patients who are ineligible for cisplatin-containing chemotherapy and have previously received 1 or more prior lines of therapy.

In an interview with Urology Times, lead EV-301 trial author Thomas Powles, MBBS, MRCP, MD, professor of Genitourinary Oncology, lead for Solid Tumour Research at Barts Cancer Institute, Director of Barts Cancer Institute, London, United Kingdom, discusses findings from the pivotal study and where enfortumab vedotin fits in the bladder cancer treatment paradigm.

Can you describe what outcomes look like currently for patients with locally advanced or metastatic urothelial carcinoma who progress after platinum-containing chemotherapy and on PD-1/PD-L1 regimens?

The standard treatment for metastatic urothelial cancer is to give platinum-based therapy predominantly given as a first-line treatment. And then in sequence with immune checkpoint inhibitors, maintenance avelumab [Bavencio] is a standard of care. Some individuals get second-line immunotherapy instead. So, we're sequencing chemotherapy and immunotherapy together. After progression occurs on those 2, there's a lot of uncertainty around treatment options, so we tend to rechallenge with chemotherapy then test some patients for FGF alterations. Overall, the data are limited for this patient group, and so it's an area where we need to develop new drugs.

What had been observed previously with enfortumab vedotin that led you to evaluate its use in this patient population?

Enfortumab vedotin is an antibody-drug conjugate targeting NECTIN-4, which is expressed on the vast majority of urothelial cancers. The payload is called MMAE, which is a microtubule disrupting agent. The drug is being tested in patients who have cancers that have progressed on chemotherapy and immune checkpoint inhibitors, and it has a response rate of about 40%, leading to accelerated FDA approval in 2019. The purpose of the randomized phase 3 EV-301 study was to test enfortumab vedotin against standard chemotherapy in a randomized phase 3 manner.

Can you discuss the results of this study?

This is a 650-patient study, which is robust, and it showed a significant survival advantage for enfortumab vedotin versus chemotherapy. The chemotherapy choice was docetaxel, which [is] standard. The hazard ratio was 0.70, which was statistically significant, suggesting or showing a 30% reduction in the risk of death. The overall survival in the enfortumab vedotin arm was approximately 13 months, which is long in this setting.

The response rate was 40% versus 18%, respectively. The percent and the hazard ratio for [progression-free survival] also favored enfortumab vedotin significantly, so that the efficacy signal was consistent, which is really important.

When I give this drug to my patients, this is reinforced, we see great responses and we see patients’ pain reducing with therapy. So, it’s a very active therapy in urothelial cancer.

Can you describe the toxicity profile of enfortumab vedotin as observed during the EV-301 study?

The toxicity profile is manageable. In fact, the adverse event profile showed that the percentage of grade 3 or 4 adverse events were about 50% in both groups. However, the antibody-drug conjugate had a different adverse event profile compared to standard chemotherapy. We looked out for neuropathy, skin toxicity, and hyperglycemia, particularly, which require attention. And we need to look at those while we're treating our patients. Some patients, indeed, require dose reductions or dose delays because of that. But overall, when you look at this, you say this is a new class of drug opening a new chapter in urothelial cancer…We're showing a drug with a very consistent [safety profile] with a high efficacy signal. I think this is going to be a big change for patients with bladder cancer over the next 10 years.

How do you envision this agent changing practice?

I think this is going to make a massive difference. I think it's going to be a standard of care. I think, for me, the standard of care currently is platinum-based chemotherapy and maintenance avelumab, and if [there is] progression, enfortumab vedotin is what we’ll use in the second line.

Reference

1. Powles T, Rosenberg JE, Sonpavde G, et al. 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. 2021;31(suppl 6:abstr 393). doi: 10.1200/JCO.2021.39.6_suppl.393

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