Enfortumab Vedotin Plus Pembrolizumab Outperforms Chemotherapy in Advanced Urothelial Carcinoma

Enfortumab vedotin (Padcev; Pfizer Inc.) in combination with pembrolizumab (Keytruda; Milliman, Inc.) demonstrated superior efficacy to chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC). The data from the EV-302/KEYNOTE-A39 study (NCT04223856) are to be presented at the 2025 ASCO Genitourinary Cancers Symposium.¹

Man with hands over bladder | Image Credit: © eddows - stock.adobe.com

Despite the fact that most UC cases are superficial, 11% are diagnosed as la/mUC, and 25% are thought to be muscle-invasive. Patients with la/mUC have a poor prognosis, with less than 15% surviving for more than 5 years. Metastatic disease is regarded as incurable, and the 5-year survival rate in the US is 4.6%. The standard, first-line treatment for patients with la/mUC is cisplatin (Platinol; Bristol-Myers Squibb)-based chemotherapy. However, between 30% and 50% of patients are not suitable for chemotherapy that contains cisplatin.^2-4

Immunotherapy has revolutionized cancer treatment across various malignancies. Enfortumab vedotin is an antibody drug conjugate that targets and binds to nectin-4, a commonly found protein on bladder cancer cells. In 2019, it received accelerated approval from the FDA for adult patients with locally advanced or mUC, making it the second approved targeted therapy for bladder cancer.^3,4

In the open-label, randomized, controlled phase 3 EV-302/KEYNOTE-A39 study, enfortumab vedotin with pembrolizumab demonstrated meaningful improvements in progression-free survival (PFS) and overall survival (OS) in the first line compared with chemotherapy. The trial enrolled 886 patients with previously untreated la/mUC who were randomized 1:1 to receive either enfortumab vedotin (1.25 mg/kg; Days 1 and 8; IV) and pembrolizumab (200 mg; Day 1; IV) or gemcitabine (Gemzar; Eli Lilly and Company) with cisplatin or carboplatin (Paraplatin; Bristol-Myers Squibb) every 3 weeks.^1,5

The primary end points were PFS and OS, with secondary end points of confirmed objective response rate (cORR), duration of response (DOR), and safety. The median follow-up was 29.1 months (95% CI, 28.5-29.9).⁵

The data showed that enfortumab vedotin with pembrolizumab yielded superior PFS (HR, 0.48 [95% CI, 0.41-0.57]) and OS (HR, 0.51 [95% CI, 0.43-0.61]) to chemotherapy. In the response-evaluable population, the cORR was 67.5% and 44.2% in patients receiving the combination treatment compared with chemotherapy, respectively. The median DOR was 23.3 months (95% CI, 17.8-NE) for enfortumab vedotin with pembrolizumab compared with 7.0 months (95% CI, 6.2-9.0) for chemotherapy. A complete confirmed response (cCCR) was achieved by 30.4% of patients in the combination arm versus 14.5% in the chemotherapy arm. The median duration of cCR was not reached for enfortumab vedotin plus pembrolizumab and was 15.2 months (95% CI, 10.3-NE) for the chemotherapy group.⁵

Grade greater than or equal to 3 treatment-related adverse events (AEs) were reported in 57.3% of patients in the combination arm compared with 69.5% in the chemotherapy arm in the safety analysis set, and in 61.7% versus 71.9% within the cCR subgroup, respectively. Treatment-related deaths occurred in 1.1% of patients receiving enfortumab vedotin with pembrolizumab and 0.9% of chemotherapy patients in the safety analysis set, with no treatment-related deaths reported in the cCR subgroup.⁵

Given that a substantial proportion of patients with la/mUC are ineligible for cisplatin-based regimens, the success of enfortumab vedotin plus pembrolizumab suggests a promising new standard of care that extends beyond traditional chemotherapy constraints. While metastatic urothelial carcinoma remains a highly aggressive disease, the durability of response and survival benefits observed in this trial highlight the potential for long-term disease control in a setting where prognosis has historically been poor.

REFERENCES

1. Enfortumab vedotin and pembrolizumab vs. chemotherapy alone in untreated locally advanced or metastatic urothelial cancer (EV-302). Updated September 27, 2024. Accessed February 11, 2025. https://clinicaltrials.gov/study/NCT04223856

2. Hepp Z, Shah SN, Smoyer K, Vadagam P. Epidemiology and treatment patterns for locally advanced or metastatic urothelial carcinoma: a systematic literature review and gap analysis. J Manag Care Spec Pharm. February 2021. doi: 10.18553/jmcp.2020.20285

3. Enfortumab vedotin approved for recurrent bladder cancer. National Cancer Institute. January 14, 2020. Accessed February 11, 2025. https://www.cancer.gov/news-events/cancer-currents-blog/2020/enfortumab-vedotin-bladder-cancer-fda-approval

4. FDA grants accelerated approval to enfortumab vedotin-ejfv for metastatic urothelial cancer. FDA. December 18, 2019. Accessed February 11, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-enfortumab-vedotin-ejfv-metastatic-urothelial-cancer

5. Powles T, Van der Heijden M, Loriot Y, et al. EV-302: Updated analysis from the phase 3 global study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC). February 13, 2025. 2025 ASCO Genitourinary Cancers Symposium. San Francisco, CA.