The European Medicines Agency has accepted a marketing authorization application for enfortumab vedotin-ejfv for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy in the neoadjuvant or adjuvant, locally advanced or metastatic setting.
The European Medicines Agency has accepted a marketing authorization application for enfortumab vedotin-ejfv (Padcev) for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy in the neoadjuvant or adjuvant, locally advanced or metastatic setting.1
Enfortumab vedotin will be reviewed by the agency under accelerated assessment, and if approved, will be the first antibody-drug conjugate (ADC) available for use in patients with urothelial cancer who are living in the European Union.
The regulatory decision is based on data from the phase 3 EV-301 trial (NCT033474107), where the ADC demonstrated superior efficacy in terms of progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) over chemotherapy in patients with advanced urothelial carcinoma who had previously received platinum-based chemotherapy and PD-1/PD-L1 inhibition.2
“In the European Union, it is estimated that 118,000 people are diagnosed with urothelial cancer each year, and 52,000 die as a result of the disease,” Andrew Krivoshik, MD, PhD, senior vice president and head of the Oncology Therapeutic Area at Astellas, stated in a press release. “People with advanced urothelial cancer face an urgent need for new treatment options, which is reflected in the Committee for Medicinal Products for Human Use [CHMP]’s decision to grant accelerated assessment. We will continue to work with the CHMP toward our goal of securing marketing authorization as soon as possible.”
The open-label, phase 3 EV-301 trial was designed to confirm the benefit of enfortumab vedotin over chemotherapy following platinum-based chemotherapy and PD-1/PD-L1 inhibition in patients with advanced urothelial carcinoma.
To be eligible for enrollment, patients had to have histologically or cytologically confirmed urothelial carcinoma, radiographic progression or relapse during or following PD-1/PD-L1 inhibition for advanced disease, have previously received a platinum-containing regimen for advanced disease, and have an ECOG performance status of 0 or 1.
Participants were randomized 1:1 to receive either enfortumab vedotin at a dose of 1.25 mg/kg on days 1, 8, and 15 of each 28-day cycle (n = 301) or pre-selected chemotherapy in the form of docetaxel at 75 mg/m2 or paclitaxel at 175 mg/m2 or vinflunine at 320 mg/m2 on day 1 of each 21-day cycle (n = 307).
The primary end point of the trial was OS per investigator assessment and RECIST v1.1 criteria, and key secondary end points comprised PFS, disease control rate, ORR, and safety.
The median age of study participants was 68 years, and the majority were male. Additionally, 42% of patients resided in Western Europe, 60% had an ECOG performance status of 1, and most patients had a Bellmunt risk score that fell between 0 and 1. Thirty-one percent of patients had liver metastasis and most patients had received 1 to 2 prior lines of systemic treatment.
At the time of data cutoff, 98% of those in the investigative arm and 95% of those in the control arm received study treatment; they were exposed for 5.0 months (95% CI, 0.5-19.4) and 3.5 months (95% CI, 0.2-15.0), respectively.
Results presented during the 2021 Genitourinary Cancers Symposium showed that the median OS with the ADC was 12.88 months (95% CI, 10.58-15.21) vs 8.97 months (95% CI, 8.05-10.74) with chemotherapy (HR, 0.70; 95% CI, 0.56-0.89; P = .00142). The median PFS with enfortumab vedotin was 5.55 months (95% CI, 5.32-5.82) vs 3.71 months (95% CI, 3.52-3.94) with chemotherapy (HR, 0.62; 95% CI, 0.51-0.75; P <.00001).
Additionally, the investigator-assessed ORRs in the investigative and control arms were 40.6% (95% CI, 34.9%-46.5%) vs 17.9% (95% CI, 13.7%-22.8%), respectively (P <.001). Among those who responded to the ADC, 4.9% experienced a complete response (CR) and 35.8% achieved a partial response (PR); these rates were 2.7% and 15.2%, respectively, in those who received chemotherapy.
Regarding safety, all-grade adverse effects (AEs) were reported in 94% of those given enfortumab vedotin and 92% of those who received chemotherapy; 51% and 50%, respectively, were grade 3 or higher in severity. The most frequently reported toxicity of any grade in the investigative and control arms included alopecia (45% vs 36%, respectively), peripheral sensory neuropathy (34% vs 21%), pruritus (32% vs 4%), fatigue (31% vs 23%), and decreased appetite (31% vs 23%).
The most common grade 3 or higher AEs in the enfortumab arm included rash maculopapular (7%), decreased neutrophil count (6%), fatigue (6%), and neutropenia (5%). In the chemotherapy arm, the most commonly experienced grade 3 or higher effects included decreased neutrophil count (13%), anemia (8%), decreased white blood cell count (7%), and neutropenia (6%).
In both arms, 23% of patients experienced serious toxicities. Fourteen percent of those in the investigative arm experienced AEs that resulted in treatment withdrawal vs 11% of those on the control arm. Treatment-related AEs that resulted in death, excluding disease progression, were reported in 7 patients who received the ADC and 3 patients who were given chemotherapy.
In December 2019, the FDA granted an accelerated approval to enfortumab vedotin for the treatment of adult patients with locally advanced or urothelial carcinoma who had prior PD-1/PD-L1 inhibition and a platinum-containing chemotherapy. The decision was based on data from the phase 2 EV-201 trial (NCT033219333), where the ADC elicited an ORR of 44% in patients with locally advanced or metastatic urothelial cancer; this included a CR rate of 12% and a PR rate of 32%.3