FDA Accepts sBLAs for Enfortumab Vedotin and Pembrolizumab in Locally Advanced or Metastatic UC

The FDA has accepted for priority review supplemental biologics license applications (sBLAs) for the combination of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) in patients with locally advanced or metastatic urothelial cancer (UC) who are not eligible to receive cisplatin-containing chemotherapy, according to Astellas Pharma Inc.¹

Previously in February 2020, this combination therapy was granted breakthrough therapy designation by the FDA. These sBLAs are supported by efficacy and safety data from cohort A and cohort K of the phase 1b/2 EV-103 trial (NCT03288545; KEYNOTE-869).

The combination of these 2 agents has the potential to be the first treatment option combining an antibody-drug conjugate plus an immunotherapy for this patient population.

“We look forward to working closely with the FDA as we seek potential accelerated approval for this combination in the hopes that it can be another treatment option for patients with locally advanced or metastatic urothelial cancer who are not eligible for cisplatin-containing chemotherapy,” said Ahsan Arozullah, MD, MPH, senior vice president and head of development therapeutic areas, Astellas Pharma Inc, in the press release.

In the ongoing, multi-cohort, open-label, multicenter, phase 1b/2 EV-103 trial, investigators are evaluating enfortumab vedotin as a monotherapy or in combination with pembrolizumab and/or chemotherapy in first- or second-line settings in patients with locally advanced or metastatic UC and in patients with muscle-invasive bladder cancer.²

Enrollment in the trial is open to patients aged 18 years and older with locally advanced or metastatic UC with an ECOG performance status of 0-2, and be eligible for pembrolizumab. For the dose-escalation cohorts of the trial, patients must be ineligible for first-line cisplatin-based chemotherapy, have received no prior treatment for locally advanced metastatic UC, or have disease progression following at least 1 platinum-containing treatment.

First-line cisplatin-ineligible patients 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.

The primary end points of the trial include safety by evaluating adverse events (AEs), laboratory abnormalities, objective response rate (ORR), and pathological complete response rate. Secondary end points include incidence of dose-limiting toxicities, confirmed ORR, disease control rate, duration of response, progression-free survival, event-free survival, overall survival, pharmacokinetics, and AEs.

According to recent findings published in the Journal of Clinical Oncology, a total of 45 patients have received enfortumab vedotin in combination with pembrolizumab.³ The confirmed ORR after a median of 9 cycles was 73.3% with a complete response rate of 15.6%. The median DOR was 25.6 months and the median OS was 26.1 months, respectively.

Investigators also found that the most common treatment-related AEs were peripheral sensory neuropathy (55.6%), fatigue (51.1%), and alopecia (48.9%). A total of 29 patients (64.4%) had grade 3 of higher treatment-related AEs, including increased lipase (17.8%), maculopapular rash (11.1%), and fatigue (11.1%). Further, 1 death (2.2%) was classified as a treatment-related AE.

Each of the respective applications are intended to expand both labels for enfortumab vedotin-ejfv and pembrolizumab with a prescription drug user fee act goal date of April 21, 2023 for each application.

The combination of enfortumab vedotin and pembrolizumab is also being investigated in the ongoing phase 3 EV-302 study (NCT04223856) which is looking at the clinical benefit of this treatment in patients with previously untreated advanced urothelial cancer. This trial is intended to serve as the confirmatory trial for the potential accelerated approval in the United States as well as for the basis for its global registration.

These studies are part of an extensive program evaluating this investigational treatment in multiple stages of urothelial cancer. This includes 2 phase 3 clinical trials in muscle-invasive bladder cancer: EV-304 (NCT04700124) and EV-303 (NCT03924895).

“Despite advancements in treatment options, approximately half of advanced bladder cancer patients in the United States are ineligible for cisplatin-based chemotherapy, and these patients need new options. We are encouraged by the investigational results of the combination of [enfortumab vedotin-ejfv] and [pembrolizumab] for this patient population and are fully committed to work to bring this new approach forward to patients,” said Eliav Barr, MD, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories, in the press release.

REFERENCES:

1. Seagen, Astellas and Merck announce FDA acceptance of sBLAs for PADCEV® (enfortumab vedotin-ejfv) with KEYTRUDA® (pembrolizumab) for the first-line treatment of certain patients with locally advanced or metastatic urothelial cancer. News release. Astellas Pharma Inc. https://bit.ly/3BR3UnL

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. 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