Enfortumab vedotin (EV) will likely become the new standard of care for treating patients with previously treated locally advanced or metastatic urothelial carcinoma (la/mUC). A recent phase 3 trial  showed that treatment with EV resulted in prolonged overall survival (OS) rates in these patients, as compared with treatment with standard chemotherapy. Physician’s Weekly interviews lead study author Dr. Thomas Powles, professor of Genitourinary Oncology and Director, Barts Cancer Centre, London, UK, who presented these results during the 2021 ASCO Genitourinary Cancers Symposium [1], and which were simultaneously published in the New England Journal of Medicine [2].

OS is poor in patients who have previously received platinum-based chemotherapy and checkpoint (PD-1/PD-L1) inhibitor therapy. EV is an antibody-drug conjugate provisionally approved by the FDA in 2019 that is directed against nectin-4, a molecule that is highly expressed in la/mUC.

The EV-301 trial (NCT03474107) is an open-label, phase 3 trial comparing OS of participants with la/mUC in the 3rd or later-line setting, who were randomized to receive either EV or standard chemotherapy (docetaxel, vinflunine or paclitaxel).  The total number of patients enrolled was 608; 301 were randomized to the EV arm, and the remaining 307 were randomized to the chemotherapy arm. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and rate of adverse events (AEs).

EV-301 began in June 2018 and the primary completion date was July 2020. At the time of interim analysis, 301 deaths had occurred (49.5% of total number of participants). Of these deaths, 134 had occurred in the EV group (44.5% of participants) and 167 in the chemotherapy group (54.4%). With 11.1 months of follow-up, median OS was longer by 3.9 months in the EV group. PFS in the EV group was 5.6 months and 3.7 months in the chemotherapy group. Rates of adverse events were similar between the groups (93.9% in the EV group, and 91.8% in the chemotherapy group); the researchers concluded that EV has a tolerable safety profile.

Physician’s Weekly asked Dr. Powles for his insights.

Should EV be the new standard of care for this patient group?

“EV-301 is a randomized phase 3 study for patients with urothelial cancer, or bladder cancer. Essentially, in advanced urothelial cancer, the current standard of care is chemotherapy followed by immune therapy. While there are some permutations and combinations, those are essentially the two established treatments.”

“What we are investigating is, in patients whose cancers have progressed after those 2 existing treatments, whether enfortumab vedotin is better than standard chemotherapy. Enfortumab vedotin is an antibody drug conjugate, a new class of drug. Essentially, it has an antibody that targets nectin-4, which is expressed on the vast majority of urothelial cancers, and it is attached to chemotherapy payload via a linker molecule. The randomized phase 3 EV-301 trial tests this new drug, which was really active in quite large phase 2 trials. EV had a really robust initial signal. In fact, it has been tested in over a hundred patients and showed response rates 4 times higher than we expect from standard chemotherapy.”

“Based on terrific data on that phase 2 trial, provisional FDA approval was granted, awaiting this randomized phase 3 positive outcome. Ina heavily treated population like this, the median survival historical control is only about 8 months, which is what we benchmarked our statistics on. We wanted to show an increased overall survival by 25% with a hazard ratio of 0.75. What we observed in this trial was that enfortumab vedotin outperformed chemotherapy with a hazard ratio of 0.70 which is a 30% reduction in the risk of death. ”

“The median overall survival in the enfortumab vedotin arm was approximately 13 months, which is long. We also showed the other efficacy signals of progression-free survival and response rates were higher for enfortumab vedotin versus chemotherapy. Looking across different subgroups of patients, previous treatments used, aggressive nature of disease, enfortumab vedotin outperformed chemotherapy across broad subgroups of patients. Some subgroups were too small to draw conclusions from, which I think is an important issue.”

“The last piece was determining the toxicity profile of the drug. The safety profile of EV is distinct from chemotherapy. Nevertheless, we define the more serious adverse events as grade 3 or higher; and here the numbers were roughly the same in both groups, about 50%. It is a challenging population, because 3rd-line urothelial cancer patients often have many comorbidities. The drug is associated with a skin rash, peripheral neuropathy, and hyperglycemia, which are 3 side effects, we do not typically see with chemotherapy. There is definitely some education and training that needs to be done to recognize and manage side effects properly.”

“In summary, the drug is really impressive, and it will change, in my opinion, the way we treat bladder cancer. Individuals who have progressed on at least 2 agents will want to get enfortumab vedotin. My personal experience is the drug works extremely well. You can tell when trials are positive because my nurses come to me and said “That drug works, Tom.” That was very apparent very early on in this trial. We do not see that often and we have not seen that for a long time in urothelial cancer, so it is really exciting.”

What are the upcoming analyses?

“What we have at the moment is convincing efficacy and safety data. We have not seen the biomarker work yet, and we will see some of that soon. We need to look into how, and in whom, it works. We have also not yet seen the quality of life data, that is expected in the near future. Of course, we also have not seen frontline data which are upcoming;  there are also other trials including combinations with pembrolizumab, neoadjuvant trials, and more. This drug is a big deal in bladder cancer.“


  1. Powles T. 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. ASCO Genitourinary Cancers Symposium, 11-13 February 2021.
  2. Powles T, et al. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Feb 12.