Enfortumab Vedotin Combo Gains European Approval for Urothelial Cancer

The decision follows phase 3 EV-302 trial findings showing improved survival with enfortumab vedotin plus pembrolizumab vs chemotherapy in urothelial cancer.

The European Commission (EC) has granted marketing authorization for the use of enfortumab vedotin-ejfv (Pedcev) plus pembrolizumab (Keytruda) as a first-line treatment in patients with unresectable or metastatic urothelial cancer eligible for platinum-based chemotherapy, according to a press release from the drug’s developer, Astellas Pharma Inc.¹

Support for the approval follows updated findings from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856)published in the New England Journal of Medicine, wherein the efficacy and safety of the combination therapy was evaluated against platinum-containing chemotherapy (cisplatin or carboplatin) with gemcitabine in patients with previously untreated locally advanced or metastatic urothelial carcinoma.²

Results from the study revealed a progression free-survival (PFS) benefit of 12.5 months (95% CI, 10.4-16.6) for the combination therapy vs 6.3 months (95% CI, 6.2-6.5) with chemotherapy (HR, 0.45; 95% CI, 0.38-0.54; P < .001). Additionally, an overall survival (OS) benefit was reported at 31.5 months (95% CI, 25.4-not reached [NR]) with enfortumab vedotin plus pembrolizumab vs 16.1 months (95% CI, 13.9-18.3) in chemotherapy with gemcitabine (HR, 0.47; 95% CI, 0.38-0.58; 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,” Thomas Powles, MD, MBBS, MRCP, a professor of genitourinary oncology and the director of Barts Cancer Centre in the United Kingdom, said in the news release.1 “The impressive effects of the treatment combination were seen during the phase 3 clinical trial program, with enfortumab vedotin in combination with pembrolizumab significantly extending overall survival and progression-free survival compared with platinum-containing chemotherapy. I look forward to seeing the treatment combination implemented as a first-line regimen in the clinical setting."

Based on the phase 3 EV-302 findings, the FDA approved the combination of enfortumab vedotin plus pembrolizumab for use in this patient population in December 2023.³

The international, open-label phase 3 EV-302 trial randomly assigned patients 1:1. Of 866 patients enrolled for the study, 442 patients received 3-week cycles of intravenous (IV) enfortumab vedotin at 1.25 mg/kg on days 1 and 8 plus IV pembrolizumab at 200 mg on day 1 and 444 patients received chemotherapy with IV gemcitabine at 1000 mg/m2 plus IV cisplatin at 70 mg/m2 or carboplatin at area under the curve of 4.5 to 5 mg/mL/minute.

The dual primary end points for the study were PFS per RECIST v 1.1 criteria and OS. Secondary end points included overall response rate (ORR), duration of response (DOR), time to pain progression, and safety.

Additional findings reported an ORR benefit in the combination therapy of 67.7% (95% CI, 63.1%-72.1%) vs 44.4% (95% CI, 39.7%-49.2%) in the chemotherapy arm (P <.001). Complete responses were reported in 29.1% and 12.5% of patients in each cohort, respectively.

Estimated 12-month OS rates were 78.2% (95% CI, 73.9%-81.9%) and 61.4% (95% CI, 56.6%-65.9%) in each cohort, respectively. Median DOR was NR in the combination therapy arm, with 67.3% and 59.6% ongoing response rates at 12 and 18 months; median DOR was 7 months with chemotherapy, with 35.2% and 19.3% ongoing response rates, respectively.

Any-grade treatment-related adverse effects (TRAES) were reported in 97.0% and 95.6% of the combination therapy and chemotherapy groups. Grade 3 or higher TRAEs occurrence was 55.9% and 69.5% in each arm, respectively. Dose reductions because of TRAEs occurred in 40.7% and 37.9% of each cohort, with 4 deaths in the combination therapy arm related to individual instances of multiple organ dysfunction syndrome, immune-mediated lung disease, diarrhea, and asthenia.

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://tinyurl.com/3e77bw2x
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. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. News release. FDA. December 15, 2023. Accessed April 2, 2024. https://bit.ly/48ls9bi