EV-301 and EV-201 Trials: Enfortumab Vedotin-ejfv Improves Survival in Metastatic Urothelial Cancer

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Enfortumab vedotin-ejfv continues to move the needle forward as a validated treatment option for advanced urothelial carcinoma. At the 2021 Genitourinary Cancers Symposium, results from the phase III EV-301 study1 and EV-201 Cohort 22 provided support for the use of this agent in both patients previously treated with platinum-based chemotherapy and immune checkpoint inhibitors and cisplatin-ineligible patients, respectively.

“Enfortumab vedotin is the first drug beyond chemotherapy and immune therapy to show a significant survival advantage in previously treated advanced urothelial cancer. This is a big step in the right direction for patients with advanced urothelial cancer, for whom treatment options remain quite limited,” said lead author of EV-301, Thomas Powles, MD, PhD, of Barts Cancer Centre, Queen Mary University of London, United Kingdom.

Thomas Powles, MD, PhD

Thomas Powles, MD, PhD

Arlene O. Siefker-Radtke, MD

Arlene O. Siefker-Radtke, MD

The invited discussant for both studies, Arlene O. Siefker-Radtke, MD, of The University of Texas MD Anderson Cancer Center, Houston, commented: “We now know that enfortumab vedotin is here to stay in the armamentarium for the treatment of urothelial cancer.”

Enfortumab vedotin is an antibody-drug conjugate that combines a fully human monoclonal antibody and the microtubule-disrupting agent monomethyl auristatin E (MMAE). Enfortumab vedotin is targeted to nectin-4, which is ubiquitously expressed in urothelial cancer, and has shown benefit in previous early-phase clinical trials in advanced urothelial cancer.

EV-301 Details and Results

Sequenced platinum-based chemotherapy and immune checkpoint inhibitor therapy with PD-1/PD-L1 inhibition are the standard of care for patients with advanced urothelial cancer, but these treatments have drawbacks. Intrinsic and acquired resistance commonly occurs with chemotherapy, some patients are ineligible for platinum-based treatments, and durable responses to immune checkpoint inhibition are reported in only a minority of patients.

“Treatment after platinum-based chemotherapy and immune checkpoint inhibitors is challenging. Overall survival is short, [and] therapeutic options are also limited. In this setting, new therapeutic agents supported by randomized trials are needed,” Dr. Powles said.

The open-label, phase III EV-301 study randomly assigned 301 patients to receive enfortumab vedotin and 307 to receive investigator’s choice of chemotherapy (docetaxel, paclitaxel, or vinflunine). All patients had radiographic evidence of disease progression or relapse during or following PD-1/PD-L1 therapy and had received a prior platinum-containing regimen.


  • The phase III EV-301 trial demonstrated improved overall survival in pretreated advanced urothelial cancer with enfortumab vedotin.
  • The phase II EV-201 trial showed improved overall survival in cisplatin-ineligible patients previously treated with immunotherapy who received enfortumab vedotin.
  • Results of these studies support the use of enfortumab vedotin as a potential new standard of care in these patient subsets.

Demographic and disease characteristics of both treatment arms were comparable. The median age of both groups was 68, and more than three-quarters of each treatment arm were male. Enrolled patients were from Western Europe (42%), the United States (14%), and elsewhere in the world (44%).

The median overall survival with enfortumab vedotin was 12.88 months, compared with 8.97 months with chemotherapy—a 30% improvement in favor of the antibody-drug conjugate (P = .00142). At the time of data cutoff, 134 of the 301 patients in the enfortumab vedotin arm had died, compared with 167 of the 307 patients receiving chemotherapy.

The overall survival benefit of enfortumab vedotin was consistent across subgroups, although Dr. Powles noted that some subgroups were too small to draw conclusions. Enfortumab vedotin also improved progression-free survival: a median of 5.55 months compared with 3.71 months with chemotherapy—a 38% improvement favoring the antibody-drug conjugate (P < .00001). The confirmed response rate was 40.6% vs 17.9% with chemotherapy, respectively (P < .001). The disease control rate in the two groups was 71.9% and 53.4%, respectively (P < .001).

The rate of patients experiencing grade 3 or higher treatment-related adverse events was similar in both study arms: 51% with enfortumab vedotin and 50% with chemotherapy. Events leading to treatment withdrawal occurred in 14% of the patients given enfortumab vedotin and 11% of those given chemotherapy.

Results for Cisplatin-Ineligible Patients

Approximately half of patients with advanced urothelial cancer are not eligible to receive cisplatin-containing regimens, and only 20% to 30% of patients respond to immune checkpoint inhibition. The most common reasons for cisplatin ineligibility include a poor performance status, renal impairment, and other comorbidities.

“We know that the majority [of cisplatin-ineligible patients] still will not respond to immunotherapy, and after disease progression on immunotherapy, these patients have limited treatment options,” noted lead author Arjun V. Balar, MD, of the Perlmutter Cancer Center at NYU Langone Health, who presented the results of cohort 2 of the EV-201 trial.2

“The response rates to enfortumab vedotin in the EV-201 study are the highest numerically observed for any regimen in cisplatin-ineligible patients with advanced disease.”
— Arjun V. Balar, MD

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“In Cohort 2 of EV-201, the majority of patients with platinum-naive, cisplatin-ineligible, locally advanced, metastatic urothelial cancer who experienced disease progression on or after PD-1/PD-L1 achieved durable responses to enfortumab vedotin, with one in five achieving a complete response. Progression-free survival and overall survival were encouraging. Safety was consistent with the previously reported profile of enfortumab vedotin, within the context of a patient population with advanced malignancy and comorbidity. These data show the potential for this antibody-drug conjugate as a possible standard of care for patients with a high unmet need,” Dr. Balar stated.

EV-201 included two cohorts treated with enfortumab vedotin for advanced urothelial cancer. Dr. Balar presented results of Cohort 2, as mentioned above, comprising 89 patients treated with prior PD-1/PD-L1 therapy who were platinum-naive and cisplatin-ineligible. Cohort 1—the basis for drug approval—was previously reported3 and led to accelerated approval for enfortumab vedotin in the third-line setting after failure of platinum-based chemotherapy and immunotherapy.

The median age of patients was 75; 74% were male; and 79% had visceral metastases, including 24% with liver metastases. A total of 22 patients (25%) had previously responded to checkpoint inhibitor therapy and experienced disease progression. A total of 50% were obese, two-thirds had some decrease in kidney function, and upper tract lesions were overrepresented. The vast majority of patients stained positive for nectin-4, the target of the antibody-drug conjugate.

The confirmed overall response rate was 52%, according to a blinded independent central review. Confirmed complete responses were seen in 20% of patients, and partial responses, in 31%, with another 30% having stable disease as their best response. A total of 9% of patients had progressive disease, and 9% were not evaluable.

Of the 77 assessable patients, 88% had some tumor shrinkage from baseline, as seen on a waterfall plot. Responses were observed across all patient subgroups, including those with the primary tumor in the upper tract (61% response rate), those with liver metastases (48%), and those who did not previously respond to PD-1/PD-L1 inhibition (48%).

The median time to response was 1.8 months, and the median duration of response was 10.9 months. The median progression-free survival in the cohort was 5.8 months, and the median overall survival was 14.7 months. “These progression-free and overall survival results are promising, but they must be interpreted with caution in a single-arm study,” Dr. Balar.

Overall, 55% of patients had a grade 3 or higher treatment-related adverse event. Four treatment-related deaths were reported, including one each due to acute kidney injury, metabolic acidosis, multiple organ dysfunction syndrome, and pneumonitis. All four deaths occurred in people older than 75 who had other comorbidities. In general, treatment-related adverse events of special interest, such as skin reactions, peripheral neuropathy, and hyperglycemia, were manageable in both EV-201 and EV-301.

“The response rates to enfortumab vedotin in the EV-201 study are the highest numerically observed for any regimen in cisplatin-ineligible patients with advanced disease,” Dr. Balar said. “These data support potentially a new option for this patient population with an unmet need.” 

Publisher's Note: This article was originally published in the March 25, 2021 issue of The ASCO Post.


DISCLOSURE: Dr. Powles has received honoraria, served as a consultant or advisor to, and received research funding from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca, Ipsen, Merck, Pfizer, and Roche. Dr. Siefker-Radtke has served as a consultant or advisor to AstraZeneca, Basilea, Bavarian Nordic, Bristol Myers Squibb, EMD Serono, Genentech, Janssen, Merck, Mirati Therapeutics, the National Comprehensive Cancer Network, Nektar, and Seattle Genetics; has received research funding from Basilea, BioClin Therapeutics, Bristol Myers Squibb, Janssen, MSD, Michael and Sherry Sutton Fund for Urothelial Cancer, Nektar, the National Institutes of Health, and Takeda; and holds intellectual property in “methods of characterizing and treating molecular subsets of muscle-invasive bladder cancer.” Dr. Balar has received honoraria from AstraZeneca/MedImmune, Genentech/Roche, and Merck; has served as a consultant or advisor to AstraZeneca/MedImmne, Cerulean Pharma, Dragonfly Therapeutics, Genentech/Roche, GlaxoSmithKline, Incyte, Merck, Pfizer/EMD Serono, and Seattle Genetics/Astellas; has received research funding from Seattle Genetics; and has received institutional research funding from AstraZeneca/MedImmune, Genentech/Roche, and Merck.


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. 2021 Genitourinary Cancers Symposium. Abstract 393. Presented February 12, 2021.

2. Balar AV, McGregor BA, Rosenberg JE, et al: EV-201 Cohort 2: Enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors. 2021 Genitourinary Cancers Symposium. Abstract 394. Presented February 12, 2021.

3. Rosenberg JE, O’Donnell PH, Balar AV, et al: Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. J Clin Oncol 37:2592-2600, 2019.

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