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FDA Grants Priority Review to Keytruda Plus Padcev for Urothelial Carcinoma


The FDA previously granted accelerated approval to the Keytruda plus Padcev combination for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy.

The FDA has granted priority review status to a supplemental Biologics License Application (sBLA) for Keytruda (pembrolizumab; Merck) with Padcev (enfortumab vedotin-ejfv; Astellas Pharma and Seagen Inc) for the treatment of adults with locally advanced or metastatic urothelial carcinoma (la/mUC). The sBLA was given a Prescription Drug User Fee Act (PDUFA) date of May 9, 2024.1

Image credit: pikovit | stock.adobe.com

Image credit: pikovit | stock.adobe.com

“The FDA’s acceptance of this application for priority review, as well as under the [Real-Time Oncology Review] program, underscores the urgency to bring this treatment option that has demonstrated an [overall survival (OS)] benefit over chemotherapy to more patients with locally advanced or metastatic urothelial carcinoma,” Eliav Barr, MD, Merck Research Laboratories senior vice president, head of global clinical development, and chief medical officer said in a press release.1 “We look forward to working closely with the FDA to provide this important option to patients as quickly as possible.”

An estimated 81,108 individuals in the United States were diagnosed with bladder cancer in 2022. Urothelial cancer accounts for approximately 90% of all bladder cancers and can also be found in the renal pelvis, ureter, and urethra. Approximately 12% of cases are locally advanced or metastatic urothelial cancer at diagnosis.2

Keytruda is an anti-programed death receptor-1 (PD-1) therapy that improves the immune system's ability to detect and fight tumor cells. The humanized monoclonal antibody blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, which leads to the activation of T lymphocytes that could affect tumor and healthy cells.

Padcev is a first-in-class antibody-drug conjugate (ADC) directed against Nectin-4 with a microtubule disrupter, monomethyl auristatin. The FDA approved Padcev on December 18, 2019, for patients with previously treated locally advanced or metastatic urothelial cancer. In April 2023, the FDA granted accelerated approval to the Keytruda plus Padcev combination for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy.2

The FDA granted accelerated approval based on tumor response rate and durability of response, with continued approval contingent upon verification and description of clinical benefit in confirmatory trials. The approval was the first for an anti-PD-1 therapy plus an ADC in the United States for this indication.

The current sBLA submission was based on data from the Phase 3 KEYNOTE-A39 trial. Investigators found that compared with chemotherapy consisting of gemcitabine plus cisplatin or carboplatin, Keytruda plus Padcev produced a statistically significant and clinically meaningful improvement in OS and progression-free survival (PFS). The combination therapy lowered the risk of morality by 53% vs. chemotherapy, with a median OS of 31.5 months compared with 16.1 months, respectively. This represents an improvement in median OS of more than 15 months.

“We look forward to the FDA’s review of this application, which, if approved, will convert the accelerated approval of the combination based on results from the EV-103 study to standard approval for all first-line locally advanced or metastatic urothelial cancer patients, expanding the indication to cisplatin eligible patients,” said Ahsan Arozullah, MD, MPH, senior vice president, head of Oncology Development, Astellas​, in a press release.3 “These patients have a critical need for innovative new therapies, as chemotherapy has been the standard of care for over 30 years. We are committed to delivering on our goal of helping patients with advanced urothelial cancer live longer.”

For PFS, the Keytruda/Padcev combination lowered the risk of disease progression or mortality by 55%, with median PFS of 12.5 months compared with 6.3 months with chemotherapy. These findings were consistent across all pre-defined subgroups, including individuals who may or may not be eligible for cisplatin-based chemotherapy and patients whose tumors expressed both high and low levels of PD-L1, as well as those with or without liver metastases.

Merck, Seagen, and Astellas are currently evaluating the Keytruda/Padcev combination as part of a development program across multiple stages of urothelial cancer, which includes Phase 3 clinical trials for muscle-invasive bladder cancer in KEYNOTE-B15 (NCT04700124) and KEYNOTE-905 (NCT03924895).

“Through our clinical development program, data have consistently shown the impact of combining enfortumab vedotin with pembrolizumab for advanced bladder cancer,” Roger Dansey, MD​, president, Research and Development, Seagen​.3 “The FDA’s acceptance of our application is a critical step in our work as we seek to deliver this combination to more patients who currently have few treatment options at the advanced stage.”


1. FDA Grants Priority Review to Merck’s Application for KEYTRUDA® (pembrolizumab) Plus Padcev® (enfortumab vedotin-ejfv) for the First-Line Treatment of Patients With Locally Advanced or Metastatic Urothelial Cancer. Merck. News release. November 30, 2023. https://www.merck.com/news/fda-grants-priority-review-to-mercks-application-for-keytruda-pembrolizumab-plus-padcev-enfortumab-vedotin-ejfv-for-the-first-line-treatment-of-patients-with-locally-advanced/

2. FDA Approves Merck’s KEYTRUDA® (pembrolizumab) in Combination With Padcev® (enfortumab vedotin-ejfv) for First-Line Treatment of Certain Patients With Locally Advanced or Metastatic Urothelial Cancer. Merck. News release. April 3, 2023. https://www.merck.com/news/fda-approves-mercks-keytruda-pembrolizumab-in-combination-with-padcev-enfortumab-vedotin-ejfv-for-first-line-treatment-of-certain-patients-with-locally-advanced-or-metastatic/

3. FDA Grants Priority Review for Supplemental Biologics License Application (sBLA) of PADCEV® (enfortumab vedotin-ejfv) with KEYTRUDA® (pembrolizumab) for First-Line Treatment of Advanced Bladder Cancer

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