Enfortumab Vedotin Plus Pembrolizumab Approved in Europe for Metastatic Urothelial Cancer

Thomas Powles, MD

The European Commission (EC) has granted marketing authorization to enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) for the frontline treatment of adult patients with unresectable or metastatic urothelial cancer who are eligible for platinum-containing chemotherapy.¹

This regulatory decision was supported by findings from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856), in which enfortumab vedotin plus pembrolizumab (n = 442) led to a median overall survival (OS) of 31.5 months (95% CI, 25.4-not reached [NR]) vs 16.1 months (95% CI, 13.9-18.3) with platinum-containing chemotherapy (n = 444), translating to a 53% reduction in the risk of death (HR, 0.47; 95% CI, 0.38-0.58; P < .001).1,2 The combination also resulted in a median progression-free survival (PFS) of 12.5 months (95% CI, 10.4-16.6) vs 6.3 months (95% CI, 6.2-6.5) with platinum-containing chemotherapy, translating to a 55% reduction in the risk of disease progression or death (HR, 0.45; 95% CI, 0.38-0.54; P < .001).

“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,” Dr Thomas Powles, of the Barts Cancer Institute Biomedical Research Centre in London, United Kingdom, stated in a news release.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 OS and PFS compared with platinum-containing chemotherapy. I look forward to seeing the treatment combination implemented as a first-line regimen in the clinical setting.”

EV-302 randomized patients with previously untreated, unresectable, locally advanced or metastatic urothelial cancer 1:1 to the doublet or chemotherapy, which could have been cisplatin or carboplatin plus gemcitabine.^2,3 Participants had a glomerular filtration rate of at least 30 mL/min and an ECOG performance status of 0 to 2. They needed to be candidates for platinum, enfortumab vedotin, and pembrolizumab; they could not have previously received a PD-(L)1 inhibitor. PFS by blinded independent central review and OS served as the trial’s primary end points. Secondary end points included objective response rate (ORR) by BICR and investigator assessment, as well as safety. During the trial, approximately 30% of patients completed treatment with chemotherapy and subsequently received standard-of-care avelumab (Bavencio) maintenance therapy.

Additional efficacy data showed that enfortumab plus pembrolizumab elicited an ORR of 67.7% (95% CI, 63.1%-72.1%) compared with 44.4% (95% CI, 39.7%-49.2%; P < .00001). Among responders in the doublet and chemotherapy arms, the complete response rates were 29.1% and 12.5%; the respective partial response rates were 38.7% and 32.0%. The median duration of response in these respective arms was NR (95% CI, 20.2-NR) and 7.0 months (95% CI, 6.2-10.2).

Grade 3 or higher treatment-related adverse effects (AEs) occurred in 55.9% of patients in the enfortumab vedotin arm vs 69.5% of those in the chemotherapy arm.² The most common grade 3 or higher AEs related to treatment with the combination included maculo-papular rash, hyperglycemia, neutropenia, peripheral sensory neuropathy, diarrhea, and anemia.¹

“Despite Europe having the highest reported rates of new bladder cancer cases in the world, awareness remains low, resulting in many patients only being correctly diagnosed at the stage of advanced disease,” Alex Filicevas, executive director of the World Bladder Cancer Patient Coalition, added in the news release. “New treatment options are desperately needed to improve disease outcomes for these patients and provide hope for a better future for the whole bladder cancer patient community.”

This approval follows the December 2023 FDA approval of this combination for this indication, as well as the April 2022 EC approval of enfortumab vedotin monotherapy for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received platinum-containing chemotherapy and a PD-1/PD-L1 inhibitor. This month, Health Canada also approved enfortumab vedotin plus pembrolizumab for patients with unresectable locally advanced or metastatic urothelial cancer who had no prior systemic therapy for metastatic disease.⁴

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 28, 2024. Accessed August 28, 2024. https://www.astellas.com/en/news/29371
2. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117
3. Powles TB, Valderrama BP, Gupta S, et al. LBA6 EV-302/KEYNOTE-A39: Open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). Ann Oncol. 2023;34(suppl 2):S1340. doi:10.1016/j.annonc.2023.10.106
4. Padcev (enfortumab vedotin) in combination with pembrolizumab approved by Health Canada to treat advanced bladder cancer. News release. Pfizer Canada. August 22, 2024. Accessed August 28, 2024. https://www.newswire.ca/news-releases/padcev-r-enfortumab-vedotin-in-combination-with-pembrolizumab-approved-by-health-canada-to-treat-advanced-bladder-cancer-862646661.html