FDA Grants Accelerated Approval to Enfortumab Vedotin-ejfv Plus Pembrolizumab for Urothelial Carcinoma


Enfortumab vedotin-ejfv (Padcev, Astellas Pharma and Seagen Inc) with pembrolizumab (Keytruda, Merck) approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy.

The FDA has granted accelerated approval to enfortumab vedotin-ejfv (Padcev, Astellas Pharma and Seagen Inc) with pembrolizumab (Keytruda, Merck) for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy.1

The accelerated approval was 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 is the first for an anti-PD-1 therapy in combination with an antibody-drug conjugate (ADC) in the United States for this patient population.

“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.1 “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.”

Enfortumab vedotin-ejfv is a first-in-class ADC directed against Nectin-4 with a microtubule disrupter, monomethyl auristatin. The FDA approved enfortumab vedotin-ejfv on December 18, 2019, for patients with previously treated locally advanced or metastatic urothelial cancer.

The approval was based on objective response rate (ORR) and median duration of response (DOR) data from the phase 1b/2 EV-103, trial also known as KEYNOTE-869 (NCT03288545). In the dose escalation cohorts, Cohort A and Cohort K, the median follow-up time for the dose escalation cohort plus Cohort A was 44.7 months (range, 0.7 to 52.4 months) and for Cohort K was 14.8 months (range, 0.6 to 26.2 months).

Combined efficacy analysis of Cohort A and Cohort K (n=121) showed that the combination produced an ORR of 68% (95% CI: 58.7, 76.0) per RECIST v1.1 by blinded independent central review, with complete and partial response rates of 12% and 55%, respectively. The median DOR was 22.1 months (range, 1.0+ to 46.3+ months) for the dose escalation cohort plus Cohort A, whereas it was not reached (range, 1.2 to 24.1+ months) for Cohort K.

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.

“Advanced-stage urothelial cancer is aggressive and associated with devastating outcomes,” said David R. Epstein, chief executive officer, Seagen, in a press release.2 “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.”

Immune-mediated adverse events (AEs) may occur at any time during or after treatment with pembrolizumab, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Early identification and management of immune-mediated AEs are vital for optimal use of pembrolizumab.

The most common AEs (≥20%), including laboratory abnormalities, in patients administered enfortumab vedotin-ejfv 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%).2

In December, the FDA granted Priority Review to the combination of enfortumab vedotin-ejfv and pembrolizumab for this indication, with a Prescription Drug User Fee Act goal date of April 21, 2023.

“The accelerated approval for the combination of Padcev and pembrolizumab marks an important milestone for the approximately 8000 to 9000 patients in the United States with locally advanced or metastatic urothelial cancer who are not eligible for cisplatin-containing chemotherapy,” said Ahsan Arozullah, MD, MPH, senior vice president, head of Oncology Development, Astellas, in a press release.2 “This patient population now has an additional treatment option to treat advanced bladder cancer at first diagnosis of metastatic disease.”


1. 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/

2. FDA Grants Accelerated Approval for PADCEV® (enfortumab vedotin-ejfv) with KEYTRUDA® (pembrolizumab) for First-Line Treatment of Locally Advanced or Metastatic Urothelial Cancer. Seagen Inc. April 3, 2023. https://investor.seagen.com/press-releases/news-details/2023/FDA-Grants-Accelerated-Approval-for-PADCEV-enfortumab-vedotin-ejfv-with-KEYTRUDA-pembrolizumab-for-First-Line-Treatment-of-Locally-Advanced-or-Metastatic-Urothelial-Cancer/default.aspx

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