Enfortumab Vedotin highly active in cisplatin-ineligible urothelial cancer

Based on these findings, an application has been filed with the FDA to expand enfortumab vedotin’s approval to include cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1/L1 inhibitor.

Findings from cohort 2 of the EV-201 trial showed that enfortumab vedotin (Padcev) achieved a 52% confirmed objective response rate (ORR) in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who had prior exposure to a PD-1/PD-L1 immune checkpoint inhibitor.1

The noncomparative phase 2 EV-201 trial included 2 cohorts. Previously reported data from cohort 1 of the study led to the December 2019 FDA accelerated approval of enfortumab vedotin for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have received prior treatment with a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy.2

“What I'll discuss today are data from cohort 2, which specifically focused on cisplatin-ineligible patients who received immunotherapy in the frontline setting, and who were ineligible for cisplatin-containing chemotherapy at the time of study enrollment,” Arjun V. Balar, MD, said when presenting the findings during the 2021 Genitourinary Cancer Symposium.

Cisplatin-based chemotherapy is considered the standard of care in advanced disease and is associated with some survival benefit, but approximately half of all of patients are ineligible for cisplatin-containing chemotherapy. Objective responses occur in about 20% to 30% of patients unselected for PD-L1 expression.. After progression on immunotherapy, these patients have limited treatment options.

Eighty-nine patients were enrolled in cohort 2. They received 1.25 mg/kg enfortumab vedotin IV on days 1, 8, and 15 of each 28-day cycle. The primary end point was centrally confirmed ORR and the secondary end points were duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and tolerability.

Eligible patients had locally advanced unresectable or metastatic urothelial carcinoma who were previously treated with a PD-1/PD-L1 inhibitor. These patients were ineligible for cisplatin-containing chemotherapy and had no prior exposure to platinum-containing chemotherapy in the locally advanced or metastatic setting. Exclusion criteria were ongoing or sensory motor neuropathy that was grade 2 or higher, active central nervous system metastases, and uncontrolled diabetes mellitus.

At the data cutoff of September 8, 2020, 91 patients had enrolled and 89 were treated, said Balar, who is director of the genitourinary medical oncology program at New York University Langone’s Perlmutter Cancer Center in New York. Eighty-two percent of patients discontinued treatment; the most common reason for discontinuing treatment was because of progressive disease in 51% of patients. The second most common reason was the development of an adverse event (AE) in 24% of patients.

Baseline characteristics showed that patients were a median age of 75, male (74%), and 15% were obese. Two-thirds (67%) of patients exhibited a moderate decrease in kidney function. Looking at the primary site of tumor, 43% had a tumor in the upper tract. “This is somewhat expected because these are patients who may have had prior surgery and also have kidney dysfunction,” Balar said.

Regarding metastatic sites, 79% had visceral disease and 24% had liver involvement, demonstrating the overall poor prognosis of patients enrolled in the trial, added Balar.

Levels of Nectin-4 overexpression were very high in the population, obviating the need for testing prior to treatment.

The confirmed ORR was 52%. “What’s notable is a 20% rate for complete responses and only 9% of patients had progressive disease as their best response to treatment,” Balar said.

Balar noted in the subgroup analysis that responses were observed across all subgroups including patients with primary tumor sites in the upper tract (ORR = 61%), with liver metastasis (ORR = 48%), and those who did not respond to prior PD-1/PD-L1 inhibitors (ORR = 48%).

“We identified a trend toward better responses in patients who had previously done well and responded to immunotherapy, which suggests 2 potential hypotheses underlying this observation. One is simply that patients who respond to treatment are the ones who will then respond to the next course of treatment, which highlights those patients who have a generally good prognosis.

“The other, more tantalizing explanation for this observation, is that there might be the presence of synergy between both enfortumab vedotin and immunotherapy,” Balar said. “This is being actively explored in randomized studies that are currently ongoing.”

Regarding secondary end points, the median time to response was 1.81 months with some patients who have durable responses that extend beyond a year or more. Median DOR was 10.9 months.

At a median follow-up of 13.4 months, the median PFS was 5.8 months and median OS was 14.7 months.

In terms of safety, any grade overall treatment-related adverse events (TRAEs) occurred in 97% of patients and grade 3 or higher TRAEs occurred in 55% of patients. TRAEs led to discontinuations in 16% of patients, and peripheral sensory neuropathy was the most common in 4%.

Balar noted that there were 4 deaths that were considered to be treatment related by the investigator and these were a result of acute kidney injury, metabolic acidosis, multiple organ dysfunction syndrome, and pneumonitis.

“The first 3 deaths occurred within 30 days of the first dose of enfortumab vedotin. The only common denominator that is jumping out right now is a body mass index of 30 or greater. All these patients were older than 75 years and had other comorbidities, which is very common in this population,” Balar said.

TRAEs specific to enfortumab vedotin include skin reactions, peripheral neuropathy, and hyperglycemia. Median onset for skin reactions and hyperglycemia was 15 days, with median onset of peripheral neuropathy at 2.4 months.

“We observed in this study and in clinical practice that dose reduction and interruptions can lead to resolution and improvement of symptoms. What we also find particularly helpful is physical therapy to help with these toxicities. In general, these AEs are quite management,” Balar said.

Based on the data from cohort 2 of EV-201, a supplemental Biologics License Application has been filed with the FDA to expand enfortumab vedotin’s approval to include patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1/L1 inhibitor and are ineligible for cisplatin.


1. 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. J Clin Oncol. 2021;39(suppl 6).394. doi: 10.1200/JCO.2021.39.6_suppl.394

2. FDA grants accelerated approval to enfortumab vedotin-ejfv for metastatic urothelial cancer. Press release. December 18, 2019. Accessed February 12, 2021. https://bit.ly/3aYylKk