Real-World Data Show Enfortumab Vedotin Significantly Improves OS in Urothelial Carcinoma

Administration of third-line enfortumab vedotin (Padcev; EV) significantly improved outcomes for patients with unresectable or metastatic urothelial carcinoma, according to data from from a multicenter, retrospective study presented at the 2025 Genitourinary Cancers Symposium.

“We aimed to investigate the efficacy and safety of EV in patients with unresectable or metastatic urothelial carcinoma in real-world practice,” investigators stated in a poster presented during the meeting. “The retrospective design is a limitation.”

In the study, 419 patients with unresectable or metastatic urothelial carcinoma received treatment from April 2004 to April 2024. Patients who received the following treatments were stratified into 3 treatment groups: first-line chemotherapy and sequential chemotherapy alone (chemo-alone group; n=87), maintenance or second-line immunotherapy after first-line chemotherapy (chemo/ICI group; n=217), and EV after first-line chemotherapy and immunotherapy (chemo/ICI/EV group; n=115).

The primary end point in the trial was the comparison of first-line progression-free survival (PFS) and overall survival (OS) between these 3 treatment groups and secondary end points focused on skin-related adverse events (AEs) regarding efficacy and safety in the chemo/ICI/EV group.

Results

Investigators noted that OS was significantly longer in the chemo/ICI/EV group; however, there was no significant difference in first-line PFS of first-line therapy between the 3 groups. The unadjusted OS from first-line therapy was 36 months in the chemo/ICI/EV group (P=.008), 25 months in the chemo/ICI group (P=.033), and 16 months in the chemo-alone group. Multivariable Cox regression analysis showed that the chemo/ICI/EV group was significantly associated with improved OS, according to the investigators.

Patient Characteristics

The average age in the chemo-alone group was 67 years (range, 23-84), 72 years (range, 31-93) in the chemo/ICI group and 74 years (range, 23-89) in the chemo/ICI/EV group and most patients were male: 73%, 78%, and 72%, respectively. Ten percent of patients in the chemo/ICI/EV group had a ECOG performance status greater than 1; this information was not documented for the other 2 groups.

There were 39% of patients with upper tract urothelial carcinoma (UTUC) in the chemo-alone group, 61% in the chemo/ICI group, and 45% in the chemo/ICI/EV group and percentages of those with T4 TNM staging were 16%, 32%, and 31%, respectively. Lymph node metastases were present in 70% in the chemo-alone group, 60% in the chemo/ICI group, and 47% in the chemo/ICI/EV group, and distant metastases were present in 76%, 67%, and 70%, respectively. In addition, liver metastases were present in 11%, 12%, and 13%, respectively.

Treatment History

In the chemo-alone group, 62% of patients received local therapy (54 underwent surgery, and none received radiation). In the chemo/ICI group, 53% of patients received local therapy (94 underwent surgery, and 18 received radiation). In the chemo/ICI/EV group, 59% of patients received local therapy (55 underwent surgery, and 13 received radiation).

Seventy-six percent of patients in the chemo-alone group received a first-line carboplatin-based regimen, compared with 64% in both the chemo/ICI and chemo/ICI/EV groups. In the chemo/ICI and chemo/ICI/EV groups, 21% of patients each received avelumab (Bavencio), and there were no patients who did in the chemo-alone group.

Skin-Related AEs

Investigators noted that patients with skin-related AEs (n=69) had significantly longer PFS and OS than those without (n=46). In addition, multivariable Cox regression analysis showed a significant association between skin-related AEs and prolonged relapse-free survival and OS.

The median PFS from EV treatment was 9.7 months for those with skin-related AEs and 5.9 months in those without (P=.001). The median OS from EV treatment was 19 months vs 14 months, respectively (P=.019). The number of cycles of EV treatment was 7 for those with skin-related AEs and 4 for those without (P=.001).

EV dose levels varied among patients, (0.75 mg/kg, 0.99mg/kg-0.75 mg/kg, 1.24-1.00 mg/kg, and 1.25 mg/kg) with the majority of patients with skin-related AEs receiving the 1.25 mg/kg dose in cycle 1. In contrast, the majority of patients without skin-related AEs received a dose of 1.25 mg/kg on cycle 10. However, overall patients without skin-related AEs received higher doses of EV throughout the 10 cycles of treatment whereas those with skin-related AEs had higher doses earlier on in the treatment course. Dose reductions occurred in 67% of patients with skin-related AEs and 35% in those without (P=.001).

Patient Characteristics Related to AEs

The average age of patients with and without skin-related AEs was 74 years and most patients were male (67% with skin-related AEs vs 80% without; P=.101). The body mass index for patients with skin-related AEs was 21.9 (range, 15.0-30.9) and 21.3 (range,14.4-29.2) for those without. Those with an ECOG performance score greater than 1 was 7% in those with skin-related AEs and 65% in those without (P<.001).

The percentage of those with UTUC and skin-related AEs was 49% and 39% in those without skin-related AEs. T4 TMN staging was observed in 30% vs 33%, lymph node metastases in 49% vs 50%, and distant metastases in 68% vs 72%, each respectively. In addition, liver metastases were observed in 13% of patients with skin-related AEs and without and 64% vs 76% had chronic kidney disease stage III, respectively.

Treatment History Related to AEs

Fifty-seven percent of patients with skin-related AEs had local therapy (32 patients had surgery and 7 received radiation) and 63% of patients without skin-related AEs (23 patients had surgery and 6 received radiation). Those receiving carboplatin-based regimens were 68% and 59%, respectively. There were 14% of patients with skin-related AEs who received prior avelumab and 77% who received prior pembrolizumab (Keytruda). This percentage was 30% and 74%, respectively, in those without skin-related AEs.

“Although skin AEs often led to dose reductions, dose adjustment of EV may be the key for long-term use and optimizing outcomes,” investigators stated.

Reference

Hatakeyama S, Ozaki K, Yamamoto H, et al Real-world analysis of the efficacy and safety of enfortumab vedotin in patients with locally advanced or metastatic urothelial carcinoma: A multicenter retrospective study. J Clin Oncol 43, 2025 (suppl 5; abstract 712). ASCO Genitourinary Cancers Symposium 2025.February 13-15, 2025, in San Francisco, California. doi:10.1200/JCO.2025.43.5_suppl.712