Enfortumab Vedotin Expands Treatment Paradigm for Urothelial Cancers

Thomas Powles, MD, MBBS, MRCP

The newly FDA-approved treatment, enfortumab vedotin (Padcev), for patients with locally advanced or metastatic urothelial cancer who are previously treated with a PD-1/PD-L1 inhibitor as well as with platinum-based chemotherapy; are ineligible for cisplatin-containing chemotherapy; and have previously received 1 or more prior lines of therapy is expected to replace the standard-of-care chemotherapy.

Approval was granted to enfortumab vedotin based on results from 2 clinical trials, EV-201 (NCT03219333) and EV-301 (NCT03474107), with EV-301 being the driver for the expanded indication to include patients with locally advanced or metastatic disease on the label.

In 608 patients randomized 1:1 to receive either enfortumab vedotin or combination chemotherapy, a robust clinical benefit was shown in the enfortumab vedotin arm along with a tolerable safety profile with adverse events occurring in 20% of patients. It was noted to be the first therapy to demonstrate a significant survival advantage over the standard of care.

In an interview with Targeted Oncology™, Thomas Powles, MD, MBBS, MRCP, a professor of genitourinary oncology, director of the Bart Cancer Centre, and lead for Solid Tumour Research at Cancer Research UK, discussed the latest research around enfortumab vedotin in locally advanced or metastatic urothelial cancer.

TARGTED ONCOLOGY™: 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?

POWLES: 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 micro tubal 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 EV301 study is to test that population 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 we 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 different adverse event profiles 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, recall, 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, when you look at the previous trials and other studies and looking at enfotrumab vedotin in different settings. 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.

This is the first therapy to show significant survival advantage over the standard of care in this patient population, that led to an FDA approval. How do you envision this agent changing practice?

Clearly, this research is practice-changing. We've not had many overall survival signals in urothelial cancer over the last 40 years. We know chemotherapy is active, but there weren't randomized trials to show that we had a survival signal for second-line pembrolizumab [Keytruda]. We had survival signal for maintenance of avelumab, and we haven't really had any other survival signals in bladder cancer. So, this is the third time we've achieved that with a new class of drugs in a very heavily treated population.

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 giving this progression, enfortumab vedotin is what we’ll use in the second line.

_Reference:

_{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}