FDA Approves Padcev/Keytruda Combo for Locally Advanced, Metastatic Urothelial Cancer

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In clinical trials, Padcev (enfortumab vedotin-ejfv) plus Keytruda (pembrolizumab) produced a statistically significant improvement in survival compared to platinum-based chemotherapy alone in patients with locally advanced or metastatic urothelial cancer.

The FDA has approved Padcev (enfortumab vedotin-ejfv; Astellas Pharma and Seagen [now owned by Pfizer]) plus Keytruda (pembrolizumab; Merck) for patients with locally advanced or metastatic urothelial cancer (la/mUC).1 The FDA previously granted the application with priority review and breakthrough designation.

The efficacy of the combination was evaluated in the open-label, randomized EV-302/KN-A39 (NCT04223856) trial, which enrolled 886 patients with la/mUC who received no prior systemic therapy for advanced disease. Patients were randomly assigned 1:1 to receive either Padcev with Keytruda or platinum-based chemotherapy consisting of gemcitabine with either cisplatin or carboplatin.

The trial’s major efficacy outcomes were overall survival (OS) and progression-free survival (PFS) as assessed by blinded independent central review. The combination produced a statistically significant improvement in PFS and OS compared to platinum-based chemotherapy alone.1

Median OS was 31.5 months with the Padcev and Keytruda combination compared to 16.1 months with platinum-based chemotherapy. Median PFS was 12.5 months in the Padcev and Keytruda cohort compared with 6.3 months in the platinum-based chemotherapy arm.1

In the dose escalation patient cohorts A and K, the median follow-up time was 44.7 months and 14.8 months, respectively. In the combined analysis, the objective response rate was 68%, with complete and partial responses of 12% and 55%, respectively. The median DOR was 22.1 months in cohort A and not reached in cohort K.2

The most common adverse effects (AEs) reported in at least 20% of patients administered Padcev and Keytruda included laboratory abnormalities, increased aspartate aminotransferase, increased creatinine, rash, increased glucose, peripheral neuropathy, increased lipase, decreased lymphocytes, increased alanine aminotransferase, decreased hemoglobin, fatigue, decreased sodium, decreased phosphate, decreased albumin, pruritus, and diarrhea. Other common AEs observed in the trial were alopecia, decreased weight, decreased appetite, increased urate, decreased neutrophils, decreased potassium, dry eye, nausea, constipation, increased potassium, dysgeusia, urinary tract infection, and decreased platelets.1

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 la/mUC.

Approximately 81,108 US patients 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 la/mUC at diagnosis.2

In April, the FDA granted accelerated approval to the combination for patients with la/mUC who are ineligible for cisplatin-containing chemotherapy. The action marked the first approval for an anti-PD-1 therapy in combination with an ADC in the United States for this patient population.2

“This approval is a major milestone in the treatment of patients with locally advanced or metastatic urothelial carcinoma because it is the first approved combination of an immunotherapy and an antibody-drug conjugate for these patients,” said Dr. Eliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories, in a press release.2 “This expands the use of Keytruda-based regimens to more patients with advanced urothelial carcinoma and demonstrates the value of collaboration in creating new combination approaches for patients in need of more options.”


1. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. News release. December 15, 2023. Accessed December 15, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer

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/

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