FDA Approves Enfortumab Vedotin/Pembrolizumab Combo for Advanced Urothelial Cancer


Enfortumab vedotin plus pembrolizumab is now an FDA approved treatment based on positive phase 1b/2 findings.

The FDA has granted approval to the combination of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) for the treatment of patients with locally advanced or metastatic urothelial cancer (UC) who are not eligible to receive cisplatin-containing chemotherapy.1

The approval is supported by efficacy and safety data from cohort A and cohort K of the phase 1b/2 EV-103 trial (NCT03288545; KEYNOTE-869) where investigators evaluated the combination of enfortumab vedotin and pembrolizumab in this patient population.2,3

Key findings from the trial showed that enfortumab and pembrolizumab showed encouraging safety and efficacy activity with a response rate of 73.3%. The confirmed overall response rate (ORR; 95% CI) for the combination of enfortumab vedotin plus pembrolizumab was 64.5%, and the median duration of response (DOR) was not reached. For enfortumab vedotin alone, the confirmed ORR was 45.2%, with a median DOR of 13.2 months.

Previously in February 2020, this combination therapy was granted breakthrough therapy designation by the FDA. Then in December 2022, the FDA accepted for priority review supplemental biologics license applications (sBLAs) for this combination for patients with locally advanced or metastatic urothelial cancer who are not eligible to receive cisplatin-containing chemotherapy.

The ongoing, multi-cohort, open-label, multicenter, phase 1b/2 EV-103 trial evaluating enfortumab vedotin as a monotherapy or in combination with pembrolizumab and/or chemotherapy in first- or second-line settings enrolled patients aged 18 years and older with locally advanced or metastatic UC or muscle-invasive bladder cancer. Patients were required to have an ECOG performance status of 0-2 and be eligible for pembrolizumab.

In the dose-escalation cohorts of the trial, patients must have been ineligible for first-line cisplatin-based chemotherapy, have received no prior treatment for locally advanced metastatic UC, and must not have had disease progression following at least 1 platinum-containing treatment.

Urinary bladder cancer with organs and tumors or cancerous cells 3D rendering illustration with male body. Anatomy, oncology, biomedical, disease, medical, biology, science, healthcare concepts. | Image Credt: © Matthieu -  [stock.adobe.com]

Image Credt: © Matthieu [stock.adobe.com]

Patients who were first-line cisplatin-ineligible with locally advanced metastatic UC were administered enfortumab vedotin at a dose of 1.25 mg/kg once a day on days 1 and 8 and intravenous pembrolizumab at 200 mg on day 1 and once daily in 3-week cycles.

Investigators studied the primary end points of safety, objective response rate (ORR), and pathological complete response rate along with the secondary end points of incidence of dose-limiting toxicities, confirmed ORR, disease control rate, DOR, progression-free survival, event-free survival, overall survival, pharmacokinetics, and adverse events (AEs).

Those included in the study were predominantly male, and approximately 60% had impaired performance status. Visceral disease was seen in over 80% of patients. Approximately 40% were PD-L1 high, and a proportion of patients were not evaluable for the study as they did not have a tumor to be submitted.3

A total of 149 patients were included in the study, 76 of whom were treated with enfortumab vedotin plus pembrolizumab and 73 who were treated with enfortumab vedotin alone.

A total of 15.6% of patients in the combination arm stopped treatment due to an AE vs 24.3% of patients receiving enfortumab vedotin alone. AEs which were the most common in the combination arm were fatigue, peripheral sensory neuropathy, alopecia, and maculo-papular rash. Additionally, 18 patients (23.7%) had serious treatment-related AEs (TRAEs) in the combination group vs 11 patients (15.1%) in the monotherapy group. Three (3.9%) TRAEs led to death in the combination group vs 2 (2.7%) in the monotherapy group, and while skin reactions were more frequent in the combination arm, none were serious.

Additional findings published in the Journal of Clinical Oncology demonstrated that for the 45 patients given enfortumab vedotin plus pembrolizumab, the confirmed ORR after a median of 9 cycles of 73.3% and the complete response rate of 15.6%. The median DOR was 25.6 months, and the median OS was 26.1 months, respectively.4


1. FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. FDA.gov. Accessed April 3, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic

2. A study of enfortumab vedotin alone or with other therapies for treatment of urothelial cancer (EV-103). ClinicalTrials.gov. Updated December 20, 2022. Accessed December 20, 2022. https://clinicaltrials.gov/ct2/show/NCT03288545

3. Rosenberg JE, Milowsky M, Ramamurthy C, et al. Study EV-103 Cohort K: Antitumor activity of enfortumab vedotin (EV) monotherapy or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC). Ann Oncol. 2022;33(suppl 7):LBA73. doi:10.1016/annonc/annonc1089

4. Hoimes CJ, Flaig TW, Milowsky MI, et al. Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer [published online ahead of print, 2022 Aug 30]. J Clin Oncol. 2022;JCO2201643. doi:10.1200/JCO.22.01643

Related Videos
Related Content