Enfortumab vedotin plus pembrolizumab approved in Europe for urothelial carcinoma

The European Commission (EC) has approved the combination of enfortumab vedotin-ejfv (EV, Padcev) and pembrolizumab (Keytruda) for the first-line treatment of patients with unresectable or metastatic urothelial carcinoma who are eligible for platinum-containing chemotherapy.¹

The combination of EV and pembrolizumab was approved in the US in December 2023 for patients with locally advanced or metastatic urothelial carcinoma.

The European Marketing Authorization is valid in all 27 European Union member states as well as in Iceland, Liechtenstein, and Norway.
"Having an effective new first-line treatment for advanced urothelial cancer is opening a long-awaited new chapter in the management of this usually fatal disease,” said Thomas Powles, MBBS, MRCP, MD, of Barts Cancer Institute Biomedical Research Centre, London, United Kingdom, in a news release on the approval.¹ “The impressive effects of the treatment combination were clearly seen during the phase 3 clinical trial program, with enfortumab vedotin in combination with pembrolizumab significantly extending overall survival and progression-free survival compared to platinum-containing chemotherapy. I look forward to seeing the treatment combination implemented as a first-line regimen in the clinical setting."

The approval is based on findings from the first interim analysis of the phase 3 EV-302 trial (KEYNOTE-A39 trial; NCT04223856), in which the combination of EV plus pembrolizumab significantly extended overall survival (OS) and progression-free survival (PFS) vs platinum-based chemotherapy (gemcitabine plus cisplatin or carboplatin) in patients with previously untreated locally advanced or metastatic urothelial carcinoma.²

Specifically, at a median follow-up of 17.2 months, treatment with EV plus pembrolizumab reduced the rate of death by 53% vs chemotherapy. Patients in the combination arm demonstrated a median OS of 31.5 months compared with 16.1 months among patients treated with chemotherapy (HR, 0.47; 95% CI, 0.38 to 0.58; P < .001).

Additionally, the median PFS was 12.5 months with EV/pembrolizumab vs 6.3 months with chemotherapy, translating to a 55% reduction in the rate of disease progression or death (HR, 0.45; 95% CI, 0.38 to 0.54; P < .001).

The combination of EV plus pembrolizumab also demonstrated significant improvements on the trial’s secondary end points of objective response rate (ORR) and duration of response (DOR). In the combination arm, the confirmed ORR by blinded independent central review was 67.7% (95% CI, 63.1%-72.1%), vs 44.4% (95% CI, 39.7%-49.2%) in the chemotherapy arm (P < .00001). At the time of data analysis, the median DOR had not yet been reached in the combination arm; in the chemotherapy arm, the median DOR was 7 months.

The safety profile for the combination was consistent with previously reported safety findings from the phase 1/2 EV-103 trial (NCT03288545). In EV-302, treatment-related adverse events of grade 3 or higher were experienced by 55.9% of patients in the combination arm and 69.5% of those in the chemotherapy arm.

In total, the open-label EV-302 trial enrolled 886 patients with previously untreated locally advanced or metastatic urothelial carcinoma. Patients were eligible for enrollment in the trial regardless of eligibility for cisplatin-based chemotherapy or PD-L1 status. Those included in the trial were randomly assigned 1:1 to receive EV plus pembrolizumab (n = 442) or to chemotherapy (n = 444). Patients in the EV plus pembrolizumab cohort received a median of 12 cycles (range, 1-46) of treatment vs 6 cycles (range, 1-6) in the chemotherapy cohort.

The dual primary end points for the trial were PFS per blinded independent central review and OS. Secondary outcome measures included ORR, DOR, time to pain progression, and the incidence of adverse events.

The EV-302 trial remains ongoing to assess long-term outcomes. Final completion of the trial is anticipated for November 2027.³

In the United States, the combination of EV and pembrolizumab was approved by the FDA in December 2023 for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma.

References

1. European Commission approves Astellas' PADCEV (enfortumab vedotin) in combination with KEYTRUDA (pembrolizumab) for first-line treatment of advanced urothelial cancer. News release. Astellas Pharma, Inc. August 27, 2024. Accessed August 28, 2024. https://www.astellas.com/en/news/29371?utm_source=linkedin&utm_medium=organic&utm_campaign=patientvalueandaccess&utm_content=24-PR-021

2. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial carcinoma. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117

3. Enfortumab vedotin and pembrolizumab vs. chemotherapy alone in untreated locally advanced or metastatic urothelial cancer (EV-302). ClinicalTrials.gov. Last updated July 26, 2024. Accessed August 28, 2024. https://clinicaltrials.gov/study/NCT04223856