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Case Reports

Abstract

Enfortumab vedotin (EV) is an antibody-drug conjugate approved for locally advanced or metastatic urothelial carcinoma. EV combines an anti-nectin-4 antibody with monomethyl auristatin E, a microtubule disruptor, and is frequently associated with low-grade cutaneous adverse events.

A 69-year-old male with metastatic urothelial carcinoma presented with fever, abdominal pain, and shock. He was found to have norovirus and received empiric broad-spectrum antibiotics, vasopressors, and stress-dose hydrocortisone. Four days later when his shock had resolved and hydrocortisone was discontinued, he developed tender erythematous patches with vesicobullae in flexural areas. Pembrolizumab and EV had been initiated 12 days prior, and he received his second EV infusion 5 days before rash onset. Skin biopsy demonstrated subepidermal clefting with scattered keratinocyte necrosis. Adjacent to the split, there was keratinocyte dyskeratosis at all levels of the epidermis with associated dysmaturation. Eosinophils were present in the superficial dermis. Direct immunofluorescence studies were negative. He subsequently experienced multisystem organ failure and skin detachment predominantly in the intertriginous areas that progressed to involve 30% body surface area. He had mild superficial erosions of the oral mucosa and otherwise lacked mucosal involvement. Despite treatment with methylprednisolone 2 mg/kg/day, he died 1 week following rash onset.

Nectin-4 is expressed in adherens junctions of epidermal keratinocytes and adnexal structures, potentially explaining EV-associated cutaneous toxicity. This eruption resembles toxic epidermal necrolysis but appears histopathologically distinct given the absence of full thickness necrosis. Importantly, it is associated with minimal mucosal involvement and potentially fatal extracutaneous manifestations.