The Japanese Ministry of Health, Labour, and Welfare has approved enfortumab vedotin for the treatment of patients with unresectable urothelial carcinoma that has progressed following chemotherapy.
The Japanese Ministry of Health, Labour, and Welfare (MHLW) has approved enfortumab vedotin (Padcev) for the treatment of patients with unresectable urothelial carcinoma that has progressed following chemotherapy.1
The regulatory decision is based on data from the phase 3 EV-301 trial (NCT03474107), where at a median follow-up of 11.1 months, enfortumab vedotin resulted in a longer overall survival (OS) vs investigator’s choice of chemotherapy in patients with locally advanced or metastatic urothelial carcinoma who had prior platinum-containing chemotherapy and experienced disease progression during or after treatment with a PD-1/-L1 inhibitor.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 (HR, 0.70; 95% CI, 0.56-0.89; P = .001).
“Unfortunately, advanced urothelial cancer has a relatively poor prognosis and can be challenging to treat with currently available therapies,” Andrew Krivoshik, MD, PhD, senior vice president and head of Development Therapeutic Areas at Astellas Pharma Inc., stated in a press release. “The MHLW’s review of enfortumab vedotin in just 6 months, supported by OS data from a pivotal phase 3 clinical trial, reflects the seriousness of this condition and the potential benefit of enfortumab vedotin for patients in Japan.”
EV-301 enrolled patients with histologically or cytologically confirmed urothelial carcinoma with radiologically documented metastatic or unresectable locally advanced disease at baseline who were 18 years of age or older and had an ECOG performance status of 0 or 1. Patients needed to have experienced radiographic progression or relapse during, or after, PD-1/PD-L1 treatment. Patients also needed to have received platinum-containing therapy.
If patients had pre-existing grade 2 or higher sensory or motor neuropathy or ongoing clinically significant toxic effects linked with prior treatment, active central nervous system metastases, uncontrolled diabetes, or active keratitis or corneal ulcerations, they were excluded. Other exclusion criteria included having received more than 1 prior chemotherapy regimen for locally advanced or metastatic disease, including neoadjuvant or adjuvant treatment.
A total of 608 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 a 28-day treatment cycle (n = 301) or investigator’s choice of chemotherapy, which could have included standard docetaxel, paclitaxel, or vinflunine, given on day 1 of a 21-day cycle (n = 307).
The primary end point of the trial was OS, and key secondary end points included investigator-assessed progression-free survival (PFS), clinical response, and safety.
Baseline characteristics of the patients were noted to be generally balanced between the 2 treatment arms. The median age of study participants was 68 years (range, 30-88) and 77.3% were male. In the investigative arm, 77.7% had visceral disease vs 81.7% in the control arm. A similar number of patients on both arms had liver metastasis.
At a data cutoff of July 15, 2020, the median duration of treatment with enfortumab vedotin was 5.0 months (range, 0.5-19.4) vs 3.5 months (range, 0.2-15.0) with chemotherapy.
Additional data published in the New England Journal of Medicine showed that enfortumab vedotin also resulted in a 38% reduction in the risk of progression or death vs chemotherapy. The median PFS in the investigative arm was 5.55 months (95% CI, 5.32-5.82) vs 3.71 months (95% CI, 3.52-3.94) in the control arm (HR, 0.62; 95% CI, 0.51-0.75; P < .001). The PFS benefit observed with enfortumab vedotin was consistent across several subsets analyzed.
Moreover, enfortumab vedotin elicited an ORR of 40.6% (95% CI, 34.9%-46.5%) vs 17.9% (95% CI, 13.7%-22.8%) with chemotherapy (P < .001). Among those who responded to enfortumab vedotin, the complete response (CR) rate was 4.9%; this rate was 2.7% in those who responded to chemotherapy. Among those who achieved a CR or a partial response to treatment, the median duration of response with enfortumab vedotin was 7.39 months vs 8.11 months with chemotherapy.
In the investigative and control arms, disease control rates were 71.9% (95% CI, 66.3%-77.0%) and 53.4% (95% CI, 47.5%-59.2%), respectively.
Regarding safety, treatment-related adverse effects (TRAEs) were experienced by 93.9% and 91.8% of those who received enfortumab vedotin or chemotherapy, respectively; grade 3 or higher TRAEs were reported in 51.4% and 49.8% of patients, respectively.
Grade 3 or higher TRAEs that were reported in at least 5% of patients who received enfortumab vedotin included maculopapular rash (7.4%), fatigue (6.4%), and decreased neutrophil count (6.1%); with chemotherapy, these effects were decreased neutrophil count (13.4%), anemia (7.6%), decreased white cell count (6.9%), neutropenia (6.2%), and febrile neutropenia (5.5%).
In the enfortumab arm, 32.4% of patients experienced a TRAE that led to a dose reduction, 51.0% experienced toxicity that resulted in treatment interruption, and 13.5% experienced a TRAE that resulted in treatment withdrawal. These rates were 27.5%, 18.9%, and 11.3%, respectively, in the chemotherapy arm.
The most frequently experienced TRAEs of special interest in the enfortumab vedotin arm were skin reactions and peripheral neuropathy. Specifically, 43.9% of patients reported treatment-related rash; this was grade 1 in 13.9% of patients, grade 2 in 15.5%, grade 3 in 14.2%, and grade 4 in 0.3%. In the chemotherapy arm, grade 1, 2, and 3 treatment-related rash was reported in 7.2%, 2.1%, and 0.3% of patients, respectively.
Treatment-related peripheral neuropathy was experienced by 46.3% of those in the investigative arm vs 30.6% of those on the control arm. In the investigative arm, peripheral sensory neuropathy was the most frequently experienced TRAE that resulted in dose reduction (7.1%), treatment interruption (15.5%), or treatment withdrawal (2.4%). Moreover, 6.4% and 0.3% of those in the investigative and control arms, respectively, experienced treatment-related hyperglycemia.
AEs that led to death were reported in 11 patients in each treatment arm. Eleven patients who received enfortumab vedotin experienced TRAEs that resulted in death per investigator assessment; these effects included multiorgan dysfunction syndrome (n = 2), abnormal hepatic function, hyperglycemia, pelvic abscess, pneumonia, and septic shock (n = 1 each). On the chemotherapy arm, 3 patients experienced TRAEs that resulted in death; these included neutropenic sepsis, sepsis, and pancytopenia (n = 1 each).
In July 2021, the FDA granted a regular approval to enfortumab vedotin-ejfv and expanded the agent’s indication to include adult patients with locally advanced or metastatic urothelial cancer who are ineligible for cisplatin-containing chemotherapy and who have previously received 1 or more lines of therapy.3,4 The decision was based on data from EV-301.