Enfortumab Vedotin Approaches EU Approval for Locally Advanced or Metastatic Urothelial Cancer

The European Medicines Agency’s Committee for Medicinal Products for Human Use has adopted a positive opinion in favor of the approval of enfortumab vedotin as a monotherapy in the treatment of adult patients with locally advanced or metastatic urothelial cancer.

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion in favor of the approval of enfortumab vedotin (Padcev) as a monotherapy in the treatment of adult patients with locally advanced or metastatic urothelial cancer who previously received platinum-containing chemotherapy and a PD-1/PD-L1 inhibitor.1

The recommendation is based on findings from the phase 3 EV-301 trial (NCT03474107), which showed that at a median follow-up of 11.1 months, the antibody-drug conjugate (ADC) resulted in a longer overall survival (OS) compared with investigator’s choice of chemotherapy, at 12.88 months (95% CI, 10.58-15.21) vs 8.97 months (95% CI, 8.05-10.74), respectively (HR, 0.70; 95% CI, 0.56-0.89; P = .001).2

Enfortumab vedotin also prolonged progression-free survival (PFS) compared with chemotherapy, at 5.55 months (95% CI, 5.32-5.82) and 3.71 months (95% CI, 3.52-3.94), respectively, translating to a 38% lower risk of disease progression or death (HR, 0.62; 95% CI, 0.51-0.75; P < .001).

“People with advanced bladder cancer have few treatment options after platinum-based chemotherapy and immunotherapy,” Ahsan Arozullah, MD, MPH, vice president of Medical Sciences/Oncology at Astellas Pharma Inc., stated in a press release. “The CHMP’s positive opinion is an important step as we work to expand availability of enfortumab vedotin as quickly as possible.”

EV-301 enrolled patients who were at least 18 years of age and who had histologically or cytologically confirmed urothelial carcinoma and radiologically documented metastatic or unresectable locally advanced disease at baseline.

To be eligible for enrollment, patients needed to have an ECOG performance status of 0 or 1 and have experienced radiographic progression or relapse during or after treatment with a PD-1 or PD-L1 inhibitor. All patients also must have received a prior platinum-containing regimen.

Those who had pre-existing grade 2 or higher sensory or motor neuropathy or who experienced ongoing clinically significant toxic effects linked with prior treatment, active central nervous system metastases, uncontrolled diabetes, or active keratitis or corneal ulcerations, were excluded. Other exclusion criteria included those who previously received more than 1 chemotherapy regimen for locally advanced or metastatic disease.

Study participants were randomized 1:1 to receive enfortumab vedotin (n = 301) or chemotherapy (n = 307). Those in the investigative arm received the ADC intravenously (IV) at a dose of 1/25 mg/kg of body weight on days 1, 8, and 15 of a 28-day treatment cycle. Those in the control arm received investigator-selected chemotherapy, which could have included any of the following agents: IV docetaxel at 75 mg/m2 of body surface area (n = 117); IV paclitaxel at 175 mg/m2 (n = 112); or IV vinflunine at 320 mg/m2 (n = 78). Chemotherapy agents were delivered on day 1 of the 21-day cycle.

Stratification factors included ECOG performance status (0 vs 1), geographic region (Western Europe, United States, or rest of the world), and baseline liver metastases (present vs absent).

The primary end point of the trial was OS. Key secondary end points comprised investigator-assessed PFS and clinical response per RECIST v1.1 criteria. Safety also served as another secondary end point.

Baseline characteristics were noted to be well balanced between the 2 treatment arms. The median age was 68 years (range, 30-88), and 77.3% of patients were male. Moreover, 77.7% of patients in the investigative arm had visceral disease, along with 81.7% of those in the control arm. Across the 2 arms, the number of patients who had liver metastases were comparable.

At a data cutoff of July 15, 2020, the median duration of treatment was 5.0 months (range, 0.5-19.4) in the ADC arm and 3.5 months (range, 0.2-15.0) in the chemotherapy arm.

Additional findings from the trial showed that the estimated percentage of patients alive at 12 months was 51.5% (95% CI, 44.6%-58.0%) in the investigative arm and 39.2% (95% CI, 32.6%-45.6%) in the control arm. Moreover, the OS and PFS benefit with the ADC was also observed across most subsets examined on the trial.

Enfortumab vedotin elicited a confirmed overall response rate of 40.6% (95% CI, 34.9%-46.5%) vs 17.9% (95% CI, 13.7%-22.8%) with chemotherapy (P < .001). Data from subgroup analyses proved to be consistent with those observed in the primary analysis of the trial. A complete response (CR) was achieved by 4.9% of patients in the investigative arm vs 2.7% of those in the control arm. Among those who experienced a CR or partial response to treatment, the median duration of response was 7.39 months with the ADC and 8.11 months with the chemotherapy.

The disease control rates in the ADC and chemotherapy arms were 71.9% (95% CI, 66.3%-77.0%) and 53.4% (95% CI, 47.5%-59.2%), respectively (P < .001).

Regarding safety, 93.9% of patients who received enfortumab vedotin vs 91.8% of those who were given chemotherapy experienced treatment-related toxicities; 51.4% and 49.8% of patients, respectively, experienced effects that were grade 3 or higher.

The treatment-related adverse effects (TRAEs) that were most frequently experienced by patients included maculopapular rash (7.4%), fatigue (6.4%), and decreased neutrophil count (6.1%) with the ADC, and decreased neutrophil count (13.4%), anemia (7.6%), decreased white cell count (6.9%), neutropenia (6.2%), and febrile neutropenia (5.5%) with chemotherapy.

Additionally, 32.4% of patients experienced TRAEs that resulted in a dose reduction, 51.0% resulted in treatment interruption, and 13.5% resulted in withdrawal. These rates were 27.5%, 18.9%, and 11.3%, respectively, in the chemotherapy arm.

The most common treatment-related toxicities of special interest with the ADC were skin reactions and peripheral neuropathy. In the enfortumab vedotin arm, 43.9% experienced treatment-related rash; this rate was 9.6% in the chemotherapy arm.

Treatment-related peripheral neuropathy were reported in 46.3% of those in the ADC arm and 30.6% of those in the chemotherapy arm. Rates of treatment-related hyperglycemia were reported in 6.4% and 0.3% of patients in the investigative and control arms, respectively.

Eleven patients in each treatment arm died, irrespective of relationship to treatment. Treatment-related toxicities that resulted in death occurred in 2.4% of those who received the ADC; this included multiorgan dysfunction syndrome (n = 2), abnormal hepatic function (n = 1), hyperglycemia (n = 1), pelvic abscess (n = 1), pneumonia (n = 1), and septic shock (n = 1). TRAEs resulted in death for 3 patients and toxicities included neutropenia sepsis (n = 1), sepsis (n = 1), and pancytopenia (n = 1).


  1. Astellas and Seagen receive positive CHMP opinion for PADCEV (enfortumab vedotin) in locally advanced or metastatic urothelial cancer. News release. Astellas Pharma, Inc.; December 17, 2021. Accessed December 17, 2021. https://bit.ly/3q8NGzw
  2. 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