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The European Medicines Agency’s Committee for Medicinal Products for Human Use has confirmed its recommendation to approve the use of enfortumab vedotin in adult patients with locally advanced or metastatic urothelial cancer who have received prior platinum-based chemotherapy and a PD-1/PD-L1 inhibitor.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has confirmed its recommendation to approve the use of enfortumab vedotin (Padcev) as a single agent in adult patients with locally advanced or metastatic urothelial cancer who have received prior platinum-based chemotherapy and a PD-1/PD-L1 inhibitor.1
In December 2021, the CHMP had adopted a positive opinion for the agent in this indication and provided its recommendation to the European Commission (EC) for review.2 The initial recommendation was based on data from the phase 3 EV-301 trial (NCT03474107), which demonstrated that enfortumab vedotin improved overall survival (OS) vs investigator’s choice of chemotherapy, at 12.88 months (95% CI, 10.58-15.21) and 8.97 months (95% CI, 8.05-10.74), respectively (HR, 0.70; 95% CI, 0.56-0.89; P = .001), at a median follow-up 11.1 months.3
The ADC also prolonged progression-free survival (PFS) vs chemotherapy, at 5.55 months (95% CI, 5.32-5.82) and 3.71 months (95% CI, 3.52-3.94), respectively, which translated to a 38% reduction in the risk of disease progression or death (HR, 0.62; 95% CI, 0.51-0.75; P < .001).
During the decision-making process, additional safety data was brought to the attention of the committee. After a request from the EC, and taking into consideration the latest data, the committee confirmed their positive opinion on the antibody-drug conjugate (ADC).
“If approved by the EC, enfortumab vedotin will be the first ADC authorized in the European Union for people living with advanced urothelial cancer,” according to the news release issued by Astellas Pharma Inc. and Seagen Inc.
EV-301 enrolled patients with histologically or cytologically confirmed urothelial carcinoma and radiologically documented metastatic or unresectable locally advanced disease at baseline who were at least 18 years of age, had an ECOG performance status of 0 or 1, and who had experienced radiographic disease progression or relapse during or following treatment with a PD-1 or PD-L1 inhibitor. All patients were required to have previously received a platinum-containing chemotherapy regimen.
If patients had pre-existing grade 2 or higher sensory or motor neuropathy or experienced ongoing clinically significant toxic effects associated with prior treatment, active central nervous system metastases, uncontrolled diabetes, active keratitis, or corneal ulcerations, they were excluded. If patients received more than 1 prior chemotherapy regimen for locally advanced or metastatic disease, they were also excluded.
Participants were randomized 1:1 to receive intravenous (IV) enfortumab vedotin at a dose of 1.25 mg/kg of body weight on days 1, 8, and 15 of a 28-day treatment cycle (n = 301) or chemotherapy (n = 307). Those in the control arm received investigator’s choice of 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 drugs were given on day 1 of each 21-day cycle.
Patients were stratified based on 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, and key secondary end points included investigator-assessed PFS and clinical response per RECIST v1.1 criteria, as well as safety.
Baseline characteristics were well balanced between the arms. The median age of participants was 68 years (range, 30-88), and 77.3% were male. Additionally, 77.7% and 81.7% of patients in the investigative and control arm, respectively, had visceral disease. Across the arms, the number of patients with liver metastases was 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 investigative arm and was 3.5 months (range, 0.2-15.0) in the control arm.
Additional data indicated that the estimated percentage of patients who were alive at 1 year in the investigative arm was 51.5% (95% CI, 44.6%-58.0%) vs 39.2% (95% CI, 32.6%-45.6%) in the control arm. The OS and PFS benefit achieved with the ADC was noted across most patient subgroups evaluated on EV-301.
The ADC elicited a confirmed objective response rate (ORR) of 40.6% (95% CI, 34.9%-46.5%) vs 17.9% (95% CI, 13.7%-22.8%) with chemotherapy (P < .001). Findings from subgroup analyses were consistent with those observed in the primary analysis of the trial. In the investigative and control arms, the complete response (CR) rates were 4.9% and 2.7%, respectively. In those who achieved a CR or partial response, the median duration of response was 7.39 months in the investigative arm and 8.11 months in the control arm.
Additionally, treatment with the ADC resulted in a disease control rate (DCR) of 71.9% (95% CI, 66.3%-77.0%) vs 53.4% (95% CI, 47.5%-59.2%) with chemotherapy (P < .001).
Treatment-related toxicities were reported in 93.9% of those who received the ADC vs 91.8% vs those who were given chemotherapy; these effects were grade 3 or higher in 51.4% and 49.8% of patients, respectively.
The most common treatment-related adverse effects (TRAEs) experienced with enfortumab vedotin included maculopapular rash (7.4%), fatigue (6.4%), and decreased neutrophil count (6.1%). In the chemotherapy am, the most common TRAEs included neutrophil count (13.4%), anemia (7.6%), decreased white cell count (6.9%), neutropenia (6.2%), and febrile neutropenia (5.5%).
TRAEs resulted in a dose reduction in 32.4% of patients in the investigative arm, 51.0% of patients had TRAEs that resulted in a treatment interruption, and 13.5% resulted in treatment withdrawal. In the chemotherapy arm, 27.5% of patients had TRAEs that resulted in dose reduction, 18.9% had effects that led to interruption, and 11.3% had effects that led to withdrawal.
Skin reactions and peripheral neuropathy were the most common TRAEs with enfortumab vedotin. Moreover, 43.9% of patients in the investigative arm experienced treatment-associated rash vs 9.6% of those in the control arm. In the investigative and control arms, treatment-related peripheral neuropathy was observed in 46.3% and 30.6% of patients, respectively; 6.4% and 0.3% of patients, respectively, had treatment-related hyperglycemia.
Eleven patients each in the investigative and control arms died. Treatment-related toxicities resulting in death were experienced by 2.4% of those on the enfortumab vedotin arm, and these effects 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 led to death in 3 patients who received chemotherapy, and these effects were neutropenia sepsis (n = 1), sepsis (n = 1), and pancytopenia (n = 1).
The positive opinion issued by CHMP will now be reviewed by the EC, and decisions made by the regulatory agency are valid in the European Union Member States, as well as in Inceland, Norway, and Liechtenstein.