Consolidative Surgery Following Enfortumab Vedotin Plus Pembrolizumab Displays Efficacy in Advanced Urothelial Carcinoma

Enfortumab vedotin-ejfv (Padcev) in combination with pembrolizumab (Keytruda) followed by consolidative surgery was feasible and demonstrated high complete response rates in patients with advanced urothelial carcinoma, according to findings from a retrospective cohort study presented during the 2025 American Urological Association Annual Meeting.¹

A total of 15 patients with advanced bladder cancer or high-risk upper tract urothelial carcinoma (UTUC) who underwent consolidative surgery following the EVP regimen were included in the analysis. Complete pathologic response (T0) was observed in 9 patients (60%), 6 with bladder cancer and 3 with UTUC. All surgical margins were negative.

Patient Characteristics

Of the 15 patients included in the analysis, the median age was 69 years, 67% of patients were male, and all had an ECOG performance status of 0 or 1. Five were ineligible for cisplatin due to renal impairment (n = 4) or hearing loss (n = 1).

Five patients presented with T2 disease, 9 with T3, and 1 with T4. Of the 9 patients who achieved T0 disease, 1 started with T4, 4 started with T3, and 4 started with T2. Two patients downstaged from T3 to T2 disease, and 2 patients went from T3 to T_a-is.

The median number of cycles of EVP before surgery was 4, and the median interval from initiation of EVP to surgery was 16 weeks. The average length of hospital stay was 5 days for radical cystectomy and 4 days for nephroureterectomy or distal ureterectomy.

Safety and Complications

A total of 10 complications were recorded. In patients who underwent cystectomy (n = 9), these included 1 incidence each of Clavien-Dindo grade 1 shortness of breath; grade 2 prolonged ileus, sepsis, urinary tract infection, and wound dehiscence; and grade 3 failure to thrive and ascites. In patients who underwent nephroureterectomy or distal ureterectomy (n = 6), the observed complications were 1 incidence each of grade 1 leg swelling, grade 2 cystitis, and grade 3 obstructive uropathy. Further, there was no 90-day mortality.

About EVP

In April 2023, the FDA granted an accelerated approval to the EVP regimen for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy.² In December 2023, the FDA expanded this indication to all patients with locally advanced or metastatic urothelial carcinoma, regardless of cisplatin eligibility.³

The expanded approval was supported by findings from the EV-302/KN-A39 (NCT04223856) trial.³ Here, EVP demonstrated statistically significant improvements to overall survival (OS) and progression-free survival (PFS) compared with platinum-based chemotherapy. The median OS was 31.5 months (95% CI, 25.4-not estimable) vs 16.1 months (95% CI, 13.9-18.3) with EVP and chemotherapy, respectively (HR, 0.47; 95% CI, 0.38-0.58; P < .0001). The median PFS was 12.5 months (95% CI, 10.4-16.6) with EVP vs 6.3 months (95% CI, 6.2-6.5) with chemotherapy (HR, 0.45; 95% CI, 0.38-0.54; P < .0001).

Recently, at the 2025 Genitourinary Cancers Symposium, updated findings from EV-302/KN-A39 showed that, at a median follow-up of 29.1 months (95% CI, 28.5-29.9), EVP led to a median PFS of 12.5 months (95% CI, 10.4-16.6) compared with 6.3 months (95% CI, 6.2-6.5) with chemotherapy (HR, 0.48; 95% CI, 0.41-0.57; 2-sided P < .00001).⁴ The 12- and 24-month PFS rates were 51.4% and 37.1% with EVP vs 21.7% and 12.6% with chemotherapy, respectively.

References

1. Ghoreifi A, Hoimes C, Ramalingham S, et al. Perioperative outcomes of consolidative surgery following immunotherapy with pembrolizumab plus enfortumab vedotin for advanced urothelial cancer. Presented at: 2025 American Urological Association Annual Meeting. April 26-29, 2025. Las Vegas, NV. Abstract MP05-20.
2. FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. FDA. April 3, 2023. Accessed April 26, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic
3. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed April 26, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer
4. Powles TB, Van der Heijden MS, 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). J Clin Oncol. 2025;43(suppl 5):664. doi:10.1200/JCO.2025.43.5_suppl.658