Astellas Pharma Inc. (TSE: 4503, President and CEO: Naoki Okamura, "Astellas") and Seagen Inc. (Nasdaq: SGEN) announced the U.S. Food and Drug Administration (FDA) has granted PADCEV^® (enfortumab vedotin-ejfv) with KEYTRUDA^® (pembrolizumab) accelerated approval in the U.S. as a combination therapy for the treatment of adult patients with locally advanced or metastatic urothelial cancer (la/mUC) who are not eligible to receive cisplatin-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication is contingent upon verification and description of clinical benefit in the EV-302 confirmatory trial.

"The accelerated approval for the combination of PADCEV and pembrolizumab marks an important milestone for the approximately 8,000 to 9,000 patients in the United States with locally advanced or metastatic urothelial cancer who are not eligible for cisplatin-containing chemotherapy," said Ahsan Arozullah, M.D., M.P.H., Senior Vice President, Head of Oncology Development, Astellas. "This patient population now has an additional treatment option to treat advanced bladder cancer at first diagnosis of metastatic disease."

"Advanced-stage urothelial cancer is aggressive and associated with devastating outcomes," said David R. Epstein, Chief Executive Officer, Seagen. "In the EV-103 clinical trial, the use of PADCEV in combination with pembrolizumab resulted in confirmed and durable tumor responses in over two-thirds of patients with advanced bladder cancer. Global enrollment in the confirmatory trial, EV-302, is complete. With this approval, we look forward to providing a new treatment option that helps address a high unmet need for these patients."

The U.S. Prescribing Information for PADCEV includes a BOXED WARNING for Serious Skin Reactions as well as the following Warnings and Precautions: hyperglycemia, pneumonitis/interstitial lung disease, peripheral neuropathy, ocular disorders, infusion site extravasation, and embryo-fetal toxicity. Please see below for additional Important Safety Information.

The approval is based on objective response rates (ORR) and median duration of response (DOR) in combined Dose Escalation/Cohort A and Cohort K of the phase 1b/2 EV-103 trial (NCT03288545, also known as KEYNOTE-869). In these EV-103 cohorts, patients treated with PADCEV in combination with pembrolizumab (n=121) obtained a 68% confirmed ORR (95% CI: 58.7 to 76.0) per RECIST v1.1 by blinded independent central review (BICR), with 12% of patients experiencing a complete response and 55% of patients experiencing a partial response. The median DOR per BICR for Dose Escalation/Cohort A was 22.1 months (range: 1.0+ to 46.3+) and was not reached (range: 1.2 to 24.1+) for Cohort K.¹The median number of treatment cycles (per 21-day treatment cycle) was nine in Dose Escalation/Cohort A and 11 in Cohort K.^2,3

The most common adverse reactions (≥20%), including laboratory abnormalities, in patients treated with PADCEV in combination with pembrolizumab were glucose increased (74%), aspartate aminotransferase increased (73%), rash (71%), hemoglobin decreased (69%), creatinine increased (69%), peripheral neuropathy (65%), lymphocytes decreased (64%), fatigue (60%), alanine aminotransferase increased (60%), sodium decreased (60%), lipase increased (59%), albumin decreased (59%), alopecia (52%), phosphate decreased (51%), decreased weight (48%), diarrhea (45%), pruritus (40%), decreased appetite (38%), nausea (36%), dysgeusia (35%), potassium decreased (35%), neutrophils decreased (32%), urinary tract infection (30%), constipation (27%), potassium increased (27%), calcium increased (27%), peripheral edema (26%), dry eye (25%), dizziness (23%), arthralgia (23%), and dry skin (21%).¹

Results from Cohort K were presented in a late-breaking session at the 2022 European Society for Medical Oncology (ESMO) Congress. Additionally, results from Dose Escalation/Cohort A were published in the Journal of Clinical Oncology in August 2022.

The combination therapy was granted Breakthrough Therapy designation by the FDA in February 2020 based on Dose Escalation/Cohort A data. The combination therapy was also granted Priority Review in December 2022. The accelerated approval granted to the combination therapy today is part of the FDA's Accelerated Approval Program, which allows approval of a medicine based on a surrogate endpoint if the medicine fills an unmet medical need for a serious condition. 

The ongoing phase 3 EV-302 trial (NCT04223856, also known as KEYNOTE-A39) evaluating the clinical benefit of PADCEV in combination with pembrolizumab in patients with previously untreated advanced urothelial cancer is intended to serve as the pivotal confirmatory trial for the U.S. accelerated approval. It is also intended to serve as the basis for global registrations. The trial has completed global enrollment, with the China extension of the study currently enrolling patients.