First-in-Class ADC Padcev Submitted for Approval in Japan for PD-(L)1 Inhibitor–Refractory Bladder Cancer

March 20, 2021 News /BioValleyBIOON/ -- Astellas recently announced that it has submitted a New Drug Application (NDA) for the targeted anticancer drug Padcev (enfortumab vedotin) to the Japanese Ministry of Health, Labour and Welfare (MHLW). The drug is intended 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) in Japan for this type of urothelial carcinoma (UC).

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 protein expressed in various solid tumors, including urothelial carcinoma (UC).TumorTherapeutic targets with moderate-to-high expression. In this drug, the ADC linker technology is from Seattle.GeneticsSeagen, with target identification performed by Astellas.

In December 2019, Padcev received U.S.FDAAccelerated approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC, the most common type of bladder cancer), specifically those who have previously received a PD-1/L1 inhibitor and have been treated with 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.

Bladder Cancer - (Image source: medscape.com)

In Japan, the NDA for Padcev was based on the results of two global clinical trials (EV-301 and EV-201), both of which had sites in Japan.Clinical Trial3. The Phase 3 EV-301 confirmatory trial was conducted in adult patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-based chemotherapy and a PD-1/L1 inhibitor, comparing Padcev with chemotherapy. 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 ineligible for cisplatin therapy and had not received platinum-based chemotherapy (Cohort 2). Results from Cohort 1 showed that treatment with Padcev rapidly reduced tumor size in most patients.TumorThe objective response rate (ORR) was 44% (55/125, 95% CI: 35.1–53.2), the complete response rate (CR) was 12% (15/125), and the median duration of response (DOR) was 7.6 months (range: 0.95–11.3+). Results from Cohort 2 showed that among patients treated with Padcev, the confirmed ORR was 52%, including a CR rate of 20%; the median DOR (mDOR) 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 SeattleHeredityAstellas to the United StatesFDATwo supplemental Biologics License Applications (sBLAs) were submitted. One is based on the Phase 3 EV-301 trial, aiming to convert Padcev’s accelerated approval to regular approval. The second is based on Cohort 2 of the pivotal EV-201 trial, aiming 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.

FDAwill be in real-timeTumorReview of 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. (Bioon.com)

Original Source: Astellas Submits New Drugapplication for Enfortumab Vedotin in Japan