Enfortumab vedotin-induced cutaneous toxicities and their association with survival in urothelial carcinoma
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Key Points
Question
Among patients with advanced or metastatic urothelial cancer treated with enfortumab vedotin (EV), is development of EV-induced cutaneous adverse events (cAEs) associated with improved survival, and how does this association compare with cutaneous immune-related adverse events (cirAEs)?
Findings
In a multi-institutional retrospective cohort study, EV-induced cAEs were associated with significantly progression-free survival (hazard ratio, 0.60; 95% CI 0.31-0.67, p<0.001) and overall survival (hazard ratio, 0.46; 95% CI 0.31-0.67, p<0.001) across landmark analyses.
Meaning
EV-induced cAEs are independently associated with improved survival in patients, suggesting potential prognostic value during treatment of advanced urothelial cancer.
Importance
Enfortumab vedotin (EV) is an antibody-drug conjugate approved for the treatment of locally advanced or metastatic urothelial cancer (la/mUC). Cutaneous adverse events (cAEs) are common during EV therapy, with prior studies suggesting an association between EV-related cAEs and improved survival; however, there is insufficient data to delineate the survival benefit of EV-induced cAEs from those associated with concurrent immune checkpoint inhibitors (ICIs).
Objective
This study aims to evaluate the association of EV-induced cAEs and survival, and to characterize the timing and morphology of EV-induced cAEs.
Design
We conducted a multi-institutional retrospective study of patients with la/mUC treated with EV between 2020 and 2025.
Setting
Multicenter academic referral center.
Participants
A total of 449 EV-treated patients were included. Patient characteristics were extracted manually, and likelihood scoring was used to attribute cAEs to either EV or other etiologies.
Exposure
EV treatment.
Main Outcomes and Measures
We estimated progression-free (PFS) and overall (OS) survival using Kaplan-Meier method. Multivariable time-varying and landmark Cox regression models were used to evaluate associations between EV-induced cAE and survival. Sensitivity analyses were performed at landmarks from 15 to 105 days.
Results
Of 449 patients, 206 (45.9%) developed a cAE; 39 (18.9%) were high-grade and 127 (61.7%) were attributed to EV. The most common cAEs were pruritus (41.3%), unspecified and desquamating dermatitis (37.3%), and morbilliform dermatitis (27.7%). Across all treatment groups, survival was longer in patients with EV-induced cAEs. Developing an EV-induced cAE was protective across all examined landmark times, with hazard ratio (HR) 0.60 (95% CI: 0.43-0.82, p<0.001) for PFS and HR 0.46 (95% CI: 0.31-0.67, p<0.001) for OS at primary landmark time of 30 days. Early-onset EV-induced cAEs were protective at all landmark times and high-grade EV-induced cAEs were not associated with worse survival.
Conclusions and Relevance
EV-induced cAEs were independently associated with improved PFS and OS in patients with la/mUC, even after accounting for immortal time bias and ICI exposure. Distinguishing EV-induced cAEs from other etiologies in timeline and morphology may help guide oncology and dermatology management.
