The Japanese Ministry of Health, Labour, and Welfare has approved enfortumab vedotin for the treatment of patients with radically unresectable urothelial carcinoma that has progressed after anticancer chemotherapy, according to Astellas Pharma and Seagen, the developers of the antibody-drug conjugate.
The approval is supported by data from the phase 3 EV-301 trial and the phase 2 EV-201 trial. Specifically in EV-301, enfortumab vedotin the reduced the risk of death by 30% versus chemotherapy in patients with heavily pretreated locally advanced or metastatic urothelial carcinoma.2,3
"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, Astellas, stated in a press release. "The MHLW's review of enfortumab vedotin in just six months, supported by overall survival 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."
The open-label, randomized EV-301 trial (NCT03474107) included 608 patients with histologically or cytologically confirmed urothelial cancer, including patients with squamous differentiation or mixed cell types, were enrolled in the study and randomized 1:1 with stratification to either the enfortumab vedotin (n = 301) arm or the chemotherapy arm (n = 307).
Eligible patients had radiographic progression or relapsed during or after immune checkpoint inhibition for the treatment of advanced urothelial cancer and had received prior platinum-containing chemotherapy; patients also had an ECOG performance status of 0 or 1. Stratification variables included ECOG performance status (0 or 1), region of the world, and the presence or absence of liver metastasis.
The median overall survival (OS) with enfortumab vedotin was 12.88 months versus 8.97 months with chemotherapy, which translated to a 30% reduction in the risk of death (HR, 0.70; P = .00142). Subgroup analyses for OS favored the enfortumab vedotin arm for all groups excepts female patients (HR, 1.17).
Median progression-free survival (PFS) with enfortumab vedotin was 5.55 months versus 3.71 months with chemotherapy (HR, 0.62; P <.00001).
Confirmed ORR in the enfortumab vedotin arm was 40.6%, which included CRs in 4.9%, and the disease control rate (DCR) was 71.9%. In the chemotherapy arm, the ORR was 17.9% with CRs in 2.7%, and a DCR of 53.4% (P < .001).
Treatment-related adverse event (TRAE) rates were similar between the 2 arms, with any-TRAE rates of 94% in the investigational arm and 92% in the control arm, and grade ≥3 TRAE rates of 51% and 50%, respectively. Serious TRAEs were reported in 23% of patients in each arm and TRAEs led to treatment discontinuation in 14% of patients in the enfortumab vedotin arm and 11% in the chemotherapy arm.
The single-arm, phase 2 EV-201 trial examined enfortumab vedotin in patients with locally advanced or metastatic urothelial cancer who had been previously treated with a PD-1/PD-L1 inhibitor, including those who have also been treated with a platinum-containing chemotherapy (cohort 1) and those who have not received a platinum-containing chemotherapy and who are ineligible for cisplatin (cohort 2).
Data for cohort 1 of the trial (n = 128) showed that the antibody-drug conjugate elicited an ORR of 44%, which included a 12% CR rate, and a 32% partial response rate.
The results for cohort 2 included 89 patients.4 The median time to response was 1.81 months with some patients who have durable responses that extend beyond a year or more. Median DOR was 10.9 months. At a median follow-up of 13.4 months, the median PFS was 5.8 months and median OS was 14.7 months.
1. Japan's MHLW Approves PADCEV® (enfortumab vedotin) for Advanced Urothelial Cancer. Published online September 27, 2021. Accessed September 27, 2021. https://prn.to/3icwkyv.
2. Powles T, Rosenberg JE, Sonpavde G, et al. Primary results of EV-301: A phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated locally advanced or metastatic urothelial carcinoma. J Clin Oncol. 2021;39(suppl 6):393. doi:10.1200/JCO.2021.39.6_suppl.393
3. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. Published online February 12, 2021. N Engl J Med. doi:10.1056/NEJMoa2035807
4. Balar AV, McGregor BA, Rosenberg JE, et al. EV-201 Cohort 2: Enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors. J Clin Oncol. 2021;39(suppl 6).394. doi: 10.1200/JCO.2021.39.6_suppl.394