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The European Commission has approved enfortumab vedotin for use as a single agent in adult patients with locally advanced or metastatic urothelial cancer who have received prior platinum-containing therapy and a PD-1/L1 inhibitor.
The European Commission has approved enfortumab vedotin (Padcev) for use as a single agent in adult patients with locally advanced or metastatic urothelial cancer who have received prior platinum-containing therapy and a PD-1/L1 inhibitor.1
The regulatory decision was supported by findings from the phase 3 EV-301 trial (NCT03474107), in which the antibody-drug conjugate (ADC) was found to improve overall survival (OS) over investigator’s choice of chemotherapy in this patient population (n = 608).2 The median OS in the investigative arm was 12.88 months (95% CI, 10.58-15.21) vs 8.97 months (95% CI, 8.05-10.74) in the control arm, which translated to a 30% reduction in the risk of death with the ADC (HR, 0.70; 95% CI, 0.56-0.89; P = .001).
“The approval of enfortumab vedotin in the European Union is a significant milestone for people living with advanced urothelial cancer who have had limited treatment options and poor survival rates,” Ahsan Arozullah, MD, MPH, vice president of Medical Sciences-Oncology, at Astellas Pharma, Inc., stated in a press release. “We look forward to working with health authorities to ensure people living with advanced urothelial cancer can access this new treatment option as soon as possible.”
Patients with histologically or cytologically confirmed urothelial carcinoma and radiologically documented metastatic or unresectable locally advanced disease at baseline were enrolled to EV-301. To be eligible, patients needed to be at least 18 years of age, have an ECOG performance status ranging from 0 to 1, and have experienced radiographic disease progression or relapse during or after a PD-1/L1 inhibitor. All patients needed to have received prior platinum-containing chemotherapy.
Patients were randomized in a 1:1 fashion to receive enfortumab vedotin intravenously (IV) at 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 chemotherapy arm received 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). These chemotherapy agents were given on the first day of each treatment cycle.
Key stratification factors included 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 was OS, and secondary end points included investigator-assessed progression-free survival (PFS), clinical response in accordance with RECIST v1.1 criteria, and safety.
Baseline characteristics were noted to be well balanced between the treatment arms. Patients had a median age of 68 years (range, 30-88), and the majority (77.3%) were male. Moreover, most patients in the investigative (77.7%) and control (81.7%) arms had visceral disease. The number of participants who had liver metastases was comparable between the arms.
The median duration of treatment received was 5.0 months (range, 0.5-19.4) in the ADC arm and 3.5 months (95% CI, 0.2-15.0) in the chemotherapy arm, at a data cutoff date of July 15, 2020.
Enfortumab vedotin was also found to prolong PFS compared with chemotherapy. The median PFS with the ADC was 5.55 months (95% CI, 5.32-5.82) vs 3.71 months (95% CI, 3.52-3.94) with chemotherapy; this translated to a 38% reduction in the risk of disease progression or death (HR, 0.62; 95% CI, 0.51-0.75; P < .001).
The ADC also induced a confirmed objective response rate of 40.6 % (95% CI, 34.9%-46.5%) compared with 17.9% (95% CI, 13.7%-22.8%) with chemotherapy (P < .001). In the investigative arm, the complete response (CR) rate achieved was 4.9% vs 2.7% in the control arm.
Among those who experienced a CR or partial response, the median duration of response was 7.39 months in the enfortumab vedotin arm and 8.11 months in the chemotherapy arm. The disease control rates in the investigative and control arms were 71.9% (95% CI, 66.3%-77.0%) and 53.4% (95% CI, 47.5%-59.2%), respectively (P < .001).
Regarding safety examined across all trials evaluating enfortumab vedotin, the most common adverse effects include alopecia, fatigue, decreased appetite, peripheral sensory neuropathy, diarrhea, nausea, dysgeusia, anemia, weight decrease, maculopapular rash, dry skin, vomiting, aspartate aminotransferase increase, hyperglycemia, dry eye, alanine aminotransferase increase, and rash.
“The EV-301 study is the first randomized trial to show improved OS in patients with advanced urothelial cancer who received a platinum-containing chemotherapy and an immunotherapy,” Ignacio Durán, MD, PhD, of Hospital Universitario Marqués de Valdecilla, added in the press release. “This approval of enfortumab vedotin from the European Commission is an important moment for these patients and their physicians.”
In December 2019, the FDA granted an accelerated approval to enfortumab vedotin for use in adult patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy.3 The regulatory decision was supported by findings from the phase 2 EV-201 trial (NCT03219333), which showed that the ADC induced an ORR of 44% in this population.4
In July 2021, the regulatory agency granted a regular approval to the ADC and expanded the agent’s indication to include adult patients with locally advanced or metastatic urothelial cancer who are not eligible for cisplatin-containing chemotherapy and who have previously received 1 or more lines of therapy.5,6 The decisions were supported by data from EV-301.