Approval Sought for Keytruda/Padcev Combination for First-Line Treatment of Urothelial Cancer


FDA to evaluate Padcev (enfortumab vedotin) with Merck’s Keytruda (pembrolizumab) for the first-line treatment of adults with previously untreated locally advanced or metastatic urothelial cancer.

Image credit: pikovit |

Image credit: pikovit |

Astellas Pharma announced the submission of a Supplemental New Drug Application (sNDA) in the United States and Japan for the combination of Padcev (enfortumab vedotin) plus Merck’s Keytruda (pembrolizumab) for the first-line treatment of adults with previously untreated locally advanced or metastatic urothelial cancer (la/mUC). If approved, this would be the first combination to offer a therapeutic alternative to platinum-containing chemotherapy, which is currently the standard of care for first-line la/mUC.1
“The initiation of [Japan's Ministry of Health, Labour and Welfare’s] review of our application for enfortumab vedotin and pembrolizumab is encouraging, as we are working to improve upon current treatment options for patients in Japan with advanced stage urothelial cancer, who face poor outcomes at the advanced stage,” Ahsan Arozullah, MD, MPH, Astellas senior vice president and head of Oncology Development, in a press release. “This submission brings us one step closer to the possibility of offering these patients a treatment that demonstrated improved survival and slowed disease progression compared to platinum-containing chemotherapy.”1

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. In December 2023, the Padcev/Keytruda combination was approved by the FDA for the treatment of adults with la/mUC.2

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/Padcev combination for patients with la/mUC who are ineligible for cisplatin-containing chemotherapy.3

The sNDA for the first-line indication of the Padcev/Keytruda combination was based on findings from the open-label, randomized, controlled Phase III EV-302/KEYNOTE-A39 (NCT04223856) trial. Investigators enrolled 886 patients with previously untreated la/mUC who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status.

Patients were randomly assigned to either Padcev in combination with Keytruda or platinum-containing chemotherapy. The trial’s primary endpoints are overall survival (OS) and progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints included ORR per RECIST v1.1 by BICR, DOR per RECIST v1.1 by BICR, and safety.

Investigators found the combination produced statistically significant and clinically meaningful improvements to OS and PFS compared to platinum-containing chemotherapy. In terms of safety, the findings were consistent with what was previously reported in treatment with the combination, with no new safety issues reported.

To date, more than 1600 trials are evaluating Keytruda across a range of cancer types and treatment settings. Keytruda also has approved indications in melanoma; non-small cell lung cancer; head and neck squamous cell cancer; classical Hodgkin lymphoma; primary mediastinal large B-cell lymphoma; urothelial carcinoma; gastric cancer; microsatellite instability-high or mismatch repair deficient cancer; microsatellite instability-high or mismatch repair deficient colorectal cancer; esophageal cancer; cervical cancer; hepatocellular carcinoma; Merkel cell carcinoma; renal cell carcinoma; endometrial carcinoma; tumor mutational burden-high cancer; cutaneous squamous cell carcinoma; and triple-negative breast cancer.


1. Astellas Submits Supplemental New Drug Application in Japan for PADCEV™ (enfortumab vedotin (genetical recombination)) with KEYTRUDA® (pembrolizumab (genetical recombination)) for First-Line Treatment of Advanced Bladder Cancer. Astellas. News release. January 31, 2024.

2. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. News release. December 15, 2023. Accessed January 31, 2024.

3. 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. Accessed January 31, 2024.

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