The FDA will be evaluating findings from cohorts A and K from the phase 1b/2 EV-103 trial.
The FDA has granted a priority review designation to supplemental Biologics License Applications (sBLAs) for the combination of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) for the frontline treatment of cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer.1
The combination of pembrolizumab and enfortumab vedotin was previously granted an FDA breakthrough therapy designation.
The sBLAs are supported by findings from cohorts A and K from the phase 1b/2 EV-103 trial (KEYNOTE-869; NCT03288545). Under the Prescription Drug User Fee Act, the FDA is scheduled to make a final decision on the sBLAs by April 21, 2023.
“Despite advancements in treatment options, approximately half of advanced bladder cancer patients in the United Sates are ineligible for cisplatin-based chemotherapy, and these patients need new options. We are encouraged by the investigational results of the combination of Padcev and Keytruda for this patient population and are fully committed to work to bring this new approach forward to patients,” Eliav Barr, MD, senior vice president, head of Global Clinical Development and chief medical officer, Merck Research Laboratories, the developer of pembrolizumab, stated in a press release.1
Overall, the multicohort, open-label, multicenter EV-103 trial evaluated the antibody-drug conjugate enfortumab vedotin alone and with different combinations of anticancer therapies as a first- and second-line treatment for patients with locally advanced or metastatic urothelial cancer.
The dose-escalation and dose-expansion cohort A of the trialenrolled 45 patients with locally advanced or metastatic urothelial cancer who were not eligible for cisplatin-based chemotherapy.2 All patients received enfortumab vedotin plus the immune checkpoint inhibitor pembrolizumab.
The median patient age was 69 years. Men accounted for 80% (n = 36) of the study population and the primary tumor location was lower tract in 69% (n = 31) of patients. Sites of metastasis included lymph nodes only in 4 patients and visceral disease in the remaining 41 patients, including liver metastases in 15 patients. PD-L1 expression status by combined composite score was less than 10 in 19 patients, 10 or higher in 13 patients, and was not evaluable/available in 13 patients.
Results from this cohort showed that the combination led to an objective response rate (ORR) of 73.3% (n = 33), comprising a 15.6% complete response rate and a 57.8% partial response rate. The median duration of response was 25.6 months and the median overall survival was 26.1 months.
In cohort K of EV-103, patients were randomized to either monotherapy with enfortumab vedotin or combination therapy with enfortumab vedotin plus pembrolizumab.3 There were 149 patients in cohort K, 76 of whom were treated with enfortumab vedotin plus pembrolizumab and 73 who were treated with enfortumab vedotin alone.
The patient population was predominantly male, and approximately 60% had impaired performance status. Visceral disease was presented more than 80% of patients, and approximately 40% were PD-L1 high; a proportion of patients were not evaluable because they did not have tumor to be submitted.
The confirmed ORR (for enfortumab vedotin plus pembrolizumab was 64.5%, and median DOR was not reached. The confirmed ORR for enfortumab vedotin alone was 45.2%, with a median DOR of 13.2 months.
Regarding adverse events (AEs), 15.6% of patients receiving enfortumab vedotin plus pembrolizumab stopped treatment due to an AE, and 24.3% of patients receiving enfortumab vedotin alone stopped treatment due to an AE. The most common AEs seen in patients receiving enfortumab vedotin plus pembrolizumab included fatigue, peripheral sensory neuropathy, alopecia, and maculo-papular rash.
Eighteen (23.7%) serious treatment-related adverse events (TRAEs) were seen in the combination therapy group and 11 (15.1%) were seen in the monotherapy group. Three TRAEs leading to death (3.9%) were seen in the combination group and 2 (2.7%) were seen in the monotherapy group. Rosenberg reported that skin reactions were more frequent with patients receiving enfortumab vedotin plus pembrolizumab, although none were serious.
The combination of pembrolizumab and enfortumab vedotin was previously granted an FDA breakthrough therapy designation based on the results of cohort A. Also of note, the ongoing phase 3 EV-302 trial is comparing the combination with chemotherapy in the frontline setting for patients with locally advanced or metastatic urothelial cancer (NCT04223856).
“Urothelial cancer, the most common type of bladder cancer, is associated with poor survival in the advanced stage,” Marjorie Green, MD, senior vice president and head of Late-Stage Development at Seagen, which co-develops enfortumab vedotin with Astellas, stated in the press release.1 “The investigational results from our clinical development program support the combination of Padcev and Keytruda as a potential treatment for this patient population.”
1. Astellas, Seagen and Merck Announce FDA Acceptance of Supplemental Biologics License Applications for PADCEV® (enfortumab vedotin-ejfv) with KEYTRUDA® (pembrolizumab) for the First-Line Treatment of Certain Patients With Locally Advanced or Metastatic Urothelial Cancer. Published online and accessed December 20, 2022. https://prn.to/3FJNpLf
2. Hoimes CJ, Flaig TW, Milowsky MI, et al. Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer [published online ahead of print August 30, 2022]. J Clin Oncol. doi: 10.1200/JCO.22.01643
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