One Man’s Meat Is Another Man’s Poison: High Incidence of Severe Cutaneous Drug Reactions Induced by Enfortumab Vedotin

Our study investigates the incidence, onset timing, and risk factors of severe cutaneous adverse events (AEs) associated with enfortumab vedotin (EV) using data from the U.S. Food and Drug Administration Adverse Event Reporting System. We found a high incidence of skin-related AEs, particularly Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN); with most skin reactions occurring within the first cycle of treatment, the most common time to onset of SJS/TEN is 14 d. Associate factors for skin-limited AEs included prior immunotherapy, male gender, and chemotherapy. We believe that our findings highlight the need for vigilant monitoring of these serious AEs in patients receiving EV, especially in high-risk populations. We hope that our study will contribute to improving patient safety and management. Enfortumab vedotin (EV), an antibody-drug conjugate targeting nectin-4 and linked to monomethyl auristatin E, has shown efficacy in metastatic urothelial carcinoma. However, emerging evidence has identified severe cutaneous adverse events (cAEs), particularly Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). To date, no comprehensive analysis of cAEs associated with EV has been reported. This study aims to investigate the incidence, onset time, and factors associated with cAEs, particularly SJS/TEN, in patients treated with EV, using data from the U.S. Food and Drug Administration’s Adverse Event Reporting System. This retrospective study analyzed data from January 1, 2020 to November 1, 2024, covering 2736 patients. A disproportionality analysis and positive signal detection were used to assess the correlation between EV and adverse events (AEs). Logistic regression was employed to evaluate the factors associated with the occurrence of AEs. Among the 2736 patients analyzed, a total of 6520 AEs were reported. Skin-related AEs were most frequent, accounting for 1027 cases (37.54%), with SJS/TEN occurring in 8.59% of cases. Our analysis shows that most cAEs occurred within 30 d of starting EV treatment, with SJS/TEN onset peaking at 14 d. Within the category of skin and subcutaneous tissue disorders, 54 skin-related AEs had one or more positive signals, and 43 cases had three or more positive signals. The factors associated with skin-limited AEs included prior immunotherapy (adjusted odds ratio aOR 1.90, 95% confidence interval CI 1.15–3.15; p = 0.013), male gender (aOR 1.51, 95% CI 1.19–1.91; p 80 yr: aOR 2.17, 95% CI 1.04–4.53; p = 0.038) and hypertension (aOR 1.65, 95% CI 1.03–2.65; p = 0.038). Our study highlights a higher incidence of cAEs during EV treatment, particularly severe cAEs such as SJS/TEN. These findings underscore the need for vigilant monitoring and proactive management of these AEs in clinical practice, especially in high-risk populations. Our study shows that a significant number of patients treated with enfortumab vedotin experienced serious skin reactions. We found that certain factors, such as previous immunotherapy and being male, increased the risk of these reactions. These imply that doctors need to watch patients closely when using this drug.