Enfortumab Vedotin Challenges Standard of Care in Urothelial Carcinoma

Oncology Live®Vol. 22/No. 18
Volume 22
Issue 18
Pages: 24

Two indications have been granted by the FDA to the Nectin-4directed antibody, enfortumab vedotin-ejfv, marking a shift in the treatment landscape for patients with advanced urothelial carcinoma.

Thomas Powles, MD, MBBS, MRCP

Thomas Powles, MD, MBBS, MRCP

Two indications have been granted by the FDA to the Nectin-4directed antibody, enfortumab vedotin-ejfv (Padcev), marking a shift in the treatment landscape for patients with advanced urothelial carcinoma. The first, a conversion of an accelerated approval granted in 2019, is for patients with locally advanced or metastatic urothelial cancer previously treated with a PD-1/PD-L1 inhibitor as well as with platinum-based chemotherapy. The second indication is for those who are ineligible for cisplatin-containing chemotherapy and have previously received 1 or more prior lines of therapy.1,2

“After progression occurs [following chemotherapy sequenced with immunotherapy], there’s a lot of uncertainty around treatment options, so we tend to rechallenge with chemotherapy then test some patients for FGF alterations,” said Thomas Powles, MD, MBBS, MRCP, in an interview with OncologyLive®. “The data are limited for this patient group, and so it’s an area where we need to develop new drugs,” added Powles, who is a professor of genitourinary oncology, director of the Bart Cancer Centre, and lead for Solid Tumour Research at Cancer Research UK in London, England.

“For me, the standard of care is platinum-based chemotherapy and maintenance avelumab [Bavencio], and [should patients] progress, enfortumab vedotin is what we’ll use in the second line,” Powles said.

EV-301 Results Usher in New Treatment Options

The converted approval was based on data from the EV-301 trial (NCT03474107), designed to confirm the benefit of enfortumab vedotin observed in phase 1 and 2 trials. Investigators administered enfortumab vedotin at a dose of 1.25 mg/kg vs investigator’s choice chemotherapy of docetaxel at a dose of 75 mg/m2; paclitaxel at a dose of 175 mg/m2; or vinflunine, where it is approved for treatment of patients with urothelial carcinoma, at a dose of 320 mg/m2.3

Among the 608 patients treated in the EV-301 study, patients who received enfortumab vedotin (n = 301) had a median overall survival of 12.9 months (95% CI, 10.6-15.2), compared with 9.0 months (95% CI, 8.1-10.7) for those randomized to investigator’s choice chemotherapy (n = 308; HR, 0.70; 95% CI, 0.56-0.89; P = .0014). The median progression-free survival was 5.6 months (95% CI, 5.3-5.8) for those who received enfortumab vedotin vs 3.7 months (95% CI, 3.5-3.9) for those who received chemotherapy (HR, 0.62; 95% CI, 0.51-0.75; P < .0001). Additionally, the ORRs were 40.6% (95% CI, 34.9%-46.5%) vs 17.9% (95% CI, 13.7%-22.8%), respectively.1,2

“The response rate was 40% vs 18%, [respectively]. The percent and the hazard ratio for [progression-free survival] also favored enfortumab vedotin significantly; the efficacy signal was consistent, which is really important,” Powles said. “When we give this drug to my patients, we see great responses and we see [a reduction in] patients’ pain with therapy. It’s a very active therapy in urothelial cancer.”

EV-201: Cisplatin-Ineligible

Limited treatment options exist for patients who are ineligible for treatment with cisplatin-based chemotherapy—approximately 50% of all patients with advanced urothelial carcinoma— and even more so for those who progress following treatment with first-line PD-1/PD-L1 inhibitors.

Investigators of EV-201 (NCT03219333) assessed efficacy of enfortumab vedotin in a cohort of 89 patients, which supported the approval for patients who were ineligible for cisplatin-containing chemotherapy. These patients had received prior treatment with a PD-1 or PD-L1 inhibitor and the median number of prior therapies was 1 (range, 1-4).

The agent elicited an overall response rate (ORR) of 51% (95% CI, 39.8%-61.3%); this included a complete response rate of 22% and a partial response rate of 28%. The median duration of response was 13.8 months (95% CI, 6.4-not estimable).

Cited reasons for cisplatin ineligibility included baseline creatinine clearance of 30 to 59 mL/min (66%), grade 2 or greater hearing loss (15%), ECOG performance status of 2 (7%), and 12% reported more than 1 cisplatin-ineligibility parameter.2

A Safe and Effective Option

“The toxicity profile is manageable [with enfortumab vedotin]. In fact, the adverse effect profile showed that the percentage of grade 3 or 4 adverse effects were approximately 50% in both groups [of EV-301],” Powles said, noting that “the antibody-drug conjugate had different adverse event profiles to standard chemotherapy.”

Specifically, the most common adverse effects observed with enfortumab vedotin in EV-301 were rash (all grade, 54%; grade 3/4, 14%), fatigue (50%; 9%), and peripheral neuropathy (50%; 5%). For those who received chemotherapy, the most common AEs were fatigue (40%; 7%), alopecia (38%; 0%), and peripheral neuropathy (34%; 3%).

“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 [required] dose reductions or dose delays because of that,” Powles added.

Of note, the label comes with a box warning for serious skin reactions, as enfortumab vedotin may cause severe and fatal cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Prescribers are advised to immediately withhold enfortumab vedotin and consider referral for specialized care for suspected Stevens-Johnson syndrome or toxic epidermal necrolysis. If grade 3 or 4 skin reactions occur, permanently discontinue treatment.

As the first therapy to receive approval following marked improvements in survival vs the standard of care for patients with urothelial carcinoma, Powles noted that the agent will leave an effect on the landscape. “Overall, when you look at [these data], this is a new class of drug opening a new chapter in urothelial cancer,” Powles said. “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 research is practice-changing,” Powles concluded. “I think this is going to make a massive difference [for these patients] and I think it’s going to be a standard of care.”


  1. FDA grants regular approval to enfortumab vedotin-ejfv for locally advanced or metastatic urothelial cancer. FDA. July 9, 2021. Accessed August 30, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-enfortumab-vedotin-ejfv-locally-advanced-or-metastatic-urothelial-cancer 
  2. Padcev. Prescribing information. Astellas Pharma US, Inc; 2021. Accessed August 31, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761137s006s008lbl.pdf 
  3. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384(12):1125-1135. doi:10.1056/NEJMoa2035807
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