A Literature Review and Management Approach for Severe Skin Toxicity Induced by Enfortumab Vedotin Through Sequential Adaptation and Combination With Immune Checkpoint Inhibitors

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In patients with advanced urothelial carcinoma who have progressed after platinum-based chemotherapy, enfortumab vedotin (EV) improves overall survival compared to standard chemotherapy. Additionally, for treatment-naïve patients with locally advanced or metastatic urothelial carcinoma, the combination of pembrolizumab and EV demonstrates superior efficacy over platinum-based chemotherapy. Hence, EV becomes a standard treatment option. Although EV monotherapy is generally well tolerated, with severe skin toxicities occurring in some cases, higher rates have been reported when combined with immune checkpoint inhibitors (ICIs). Severe EV-induced skin toxicities have reportedly occurred. Management of these toxicities remains challenging because of inconsistent recommendations and varied responses to therapies. Hence, to determine the difference in the frequency and severity of skin toxicity induced by EV based on whether ICIs were used concomitantly with or before EV therapy, we searched PubMed, Medical Online, and Cochrane Library for articles published from January 2012 to March 2025. We included clinical trials and cohort studies. To identify data on severe skin toxicity, data were extracted with a focus on grade ≥3 skin toxicities. As a result, a total of 644 articles were identified through the literature search. Of these, 11 publications were included based on predefined eligibility criteria for the literature review. The frequency of EV-related grade ≥3 skin toxicity was higher in patients treated with EV in combination with ICIs or following prior ICI therapy, compared to EV monotherapy. Heterogeneity among studies may involve differences in the duration and method of assessment of adverse events. Specific management is needed because EV-induced skin toxicity can be more severe during concomitant or sequential ICI indications than monotherapy of EV. An inflammatory infiltrate composed of CD4+ and CD8+ T cells was identified as a contributing factor to EV-associated skin toxicity based on histopathological data from prior studies, suggesting that it shares pathologic features with ICI-associated skin toxicity. Allergic reactions were considered a contributing factor to skin toxicity induced by the combination of EV and ICI, as supported by both clinical and histopathological findings. Clinically, affected patients often presented with erythematous, pruritic rashes resembling drug eruptions, while histopathological analysis revealed features such as spongiosis, perivascular lymphocytic infiltrates with eosinophils, and interface dermatitis, consistent with hypersensitivity reactions. Antihistamines and topical steroids have anti-inflammatory effects on the above mechanisms and can be useful for EV-related skin toxicities. Therefore, prophylaxis with antihistamines and early steroid intervention at the onset of skin toxicity are needed.

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