Enfortumab vedotin-related cutaneous toxicity: Clinical features, pathogenesis and management

Therapeutic strategies for malignant tumors have advanced substantially, and antibody-drug conjugates (ADCs) now enable selective delivery of cytotoxic payloads to tumor cells. Enfortumab vedotin (EV) is a nectin-4-directed ADC composed of a fully human monoclonal antibody against nectin-4 conjugated, via a protease-cleavable linker, to the microtubule-disrupting agent monomethyl auristatin E. EV has demonstrated robust antitumor activity in urothelial carcinoma and is being investigated in other nectin-4-expressing tumors. Because nectin-4 is expressed in keratinocytes and cutaneous appendages, cutaneous adverse events are among the most frequent toxicities. EV-related cutaneous toxicity represents an on-target, mechanism-based toxicity that is distinct from the cutaneous adverse events associated with conventional cytotoxic chemotherapy. This review summarizes the molecular structure and function of nectin-4 and the clinical and histopathologic features of EV-related cutaneous toxicity and discusses current approaches to management. By integrating mechanistic insights from experimental studies with clinical and histopathologic observations, this review provides a translational framework to support optimal recognition and management of EV-related cutaneous toxicity.