Astellas Submits New Drug Application in Japan for Padcev (Enfortumab Vedotin) to Treat PD-(L)1 Inhibitor–Refractory Patients with Locally Advanced or Metastatic Urothelial Cancer

Astellas recently announced that it has submitted a New Drug Application (NDA) to the Japanese Ministry of Health, Labour and Welfare (MHLW) for Padcev (enfortumab vedotin), a targeted anticancer drug for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC), the most common type of bladder cancer, whose disease has progressed after anticancer drug therapy. If approved, Padcev will become the first antibody-drug conjugate (ADC) indicated for this type of urothelial carcinoma (UC) in Japan.

Urothelial carcinoma (UC) is the most common type of bladder cancer, accounting for approximately 90% of bladder cancer cases. Padcev is a first-in-class antibody-drug conjugate (ADC) that targets a cell surface protein highly expressed in bladder cancer. The drug consists of enfortumab, a human IgG1 monoclonal antibody targeting Nectin-4, conjugated to the cytotoxic agent MMAE (monomethyl auristatin E), a microtubule-disrupting agent. Nectin-4 is a therapeutic target highly expressed in various solid tumors, including urothelial carcinoma (UC). In this drug, the ADC linker technology was provided by Seagen, while target identification was performed by Astellas.

In December 2019, Padcev received accelerated approval from the U.S. FDA for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC, the most common type of bladder cancer), specifically those who had previously received a PD-1/L1 inhibitor and had undergone a platinum-containing chemotherapy regimen either in the neoadjuvant (pre-surgical) or adjuvant (post-surgical) setting, or during treatment for locally advanced or metastatic disease.

Notably, Padcev is the first antibody-drug conjugate (ADC) approved globally for the treatment of urothelial carcinoma (UC), and the first drug approved for patients with locally advanced or metastatic UC who have previously received platinum-containing chemotherapy and a PD-1 or PD-L1 inhibitor. In the United States, the drug was approved through the FDA’s Priority Review program. Previously, the FDA had granted Padcev Breakthrough Therapy Designation for the treatment of the aforementioned UC patients.

In Japan, the New Drug Application (NDA) for Padcev was based on the results of two global clinical trials (EV-301 and EV-201), both of which included clinical trial sites in Japan. The Phase 3 confirmatory EV-301 trial compared Padcev with chemotherapy in adult patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-based chemotherapy and a PD-1/L1 inhibitor. The results showed that, with a median follow-up of 11.1 months, Padcev significantly prolonged overall survival (median OS: 12.88 months vs. 8.97 months; HR=0.70; p=0.001) and progression-free survival (median PFS: 5.55 months vs. 3.71 months; HR=0.62; p<0.001) compared to the chemotherapy group.

The Phase 2 EV-201 trial evaluated the efficacy and safety of Padcev in patients with locally advanced or metastatic urothelial carcinoma (UC) who had previously received PD-1/PD-L1 inhibitors, including those who had also received platinum-based chemotherapy (Cohort 1) and those who were platinum-naïve and ineligible for cisplatin therapy (Cohort 2). Results from Cohort 1 demonstrated that Padcev treatment rapidly reduced tumor size in most patients, with an objective response rate (ORR) of 44% (55/125; 95% CI: 35.1–53.2), a complete response rate (CR) of 12% (15/125), and a median duration of response (DOR) of 7.6 months (range: 0.95–11.3+). Results from Cohort 2 showed a confirmed ORR of 52%, including a CR rate of 20%; the median DOR was 10.9 months, and the median progression-free survival (mPFS) and median overall survival (mOS) were 5.8 months and 14.7 months, respectively.

In February this year, Astellas and Seagen submitted two supplemental Biologics License Applications (sBLAs) to the U.S. FDA. One application, based on the Phase 3 EV-301 trial, aims to convert Padcev’s accelerated approval into regular approval. The second application, based on Cohort 2 of the pivotal EV-201 trial, seeks to expand the current drug label to include patients with locally advanced or metastatic urothelial carcinoma (UC) who have previously received a PD-1/L1 inhibitor and are ineligible for cisplatin-based therapy.

The FDA will review these two applications under the Real-Time Oncology Review (RTOR) pilot program. The RTOR program aims to explore a more efficient review process to ensure that safe and effective therapies are made available to patients as early as possible.

Among them, the sBLA seeking regular approval for Padcev is based on data from the global Phase 3 EV-301 confirmatory trial. The second sBLA is based on results from Cohort 2 of the pivotal Phase 2 EV-201 trial. The EV-301 trial met its primary endpoint of improving overall survival (OS) and confirmed the objective response data from the EV-201 trial.

Original Source: Astellas Submits New Drug Application for Enfortumab Vedotin in Japan

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