INTRODUCTION

Enfortumab vedotin (EV) is a novel therapeutic option for untreated metastatic urothelial carcinoma. While it was initially introduced as a second-line therapy for this, recent approvals have expanded its use in combination with pembrolizumab (EV+P) as a first-line treatment for patients with locally advanced or metastatic urothelial carcinoma. This combination has been shown to be superior to platinum-based chemotherapy, demonstrating enhanced tumour suppression and sustained antitumor immunity^[1]. However, post-approval cases of cutaneous adverse events, ranging from mild rashes to severe conditions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported^[2]. Here, we present a case of severe cutaneous toxicity under EV+P therapy, leading to the development of an SJS/TEN overlap affecting 10–30% of body surface area, and its successful management with high-dose intravenous steroids.

CASE PRESENTATION

A 67-year-old male patient was admitted to the general internal medicine ward by his nephrologist due to a deterioration in his general condition over the previous three days. The patient reported fever peaking at 39.4°C, shivers and signs of an upper respiratory tract infection, including a dry cough. Concurrently, the patient developed a highly pruritic rash on his chest.

The patient’s medical history was significant for metastatic urothelial carcinoma with pulmonary metastases. He had been undergoing palliative first-line treatment with EV+P. The treatment was administered at a reduced dose (EV: 87 mg for both the first and second doses) due to the patient’s chronic kidney failure, requiring haemodialysis and liver cirrhosis (Child-Pugh class B). The first dose was administered for ten days and the second dose three days prior to hospitalisation. In addition to his oncological condition, the patient had a history of hypertensive heart failure with preserved ejection fraction, type 2 diabetes and a known type IV allergy to penicillin.

On examination, the patient was febrile with slightly elevated blood pressure but otherwise stable vital signs. Cardiopulmonary examination revealed mild, ubiquitous pulmonary crackles. Dermatological assessment showed extensive blanchable erythroderma and maculopapular exanthema over the torso, upper and lower extremities, with diffuse skin excoriation. The mucous membranes (oral, ocular and genital), face, scalp, hands and feet were initially free of pathologies (Fig. 1 and Table 1). A CT scan of the thorax and abdomen was performed, revealing no infectious foci. The scan confirmed stable to lightly regressive pulmonary metastases from the urothelial carcinoma. Other relevant findings included known pre-existing ascites, hepatosplenomegaly, cirrhotic liver remodelling and a portal vein thrombosis with a transjugular intrahepatic portosystemic shunt.

Given the suspicion of an adverse event related to the oncological treatment, intravenous therapy with high-dose methylprednisolone (1 mg/kg, equivalent to 80 mg/day) was initiated. Due to the unclear condition with possible bacterial infection, empiric antibiotic therapy with ceftriaxone (2 g/day IV) was started. On the second day of hospitalisation, the patient’s rash rapidly worsened, presenting with large areas of dermolysis (20-30% of body surface area), bullae formation and significant skin desquamation, particularly on the torso and upper extremities; he also developed painful oral mucosal erosions. He experienced intractable generalised pain and pruritus accompanied by prolonged states of agitation and anguish, necessitating therapy with opioids and benzodiazepines. Neutropenia (absolute neutrophil count 0.7 ×10⁹/l) was observed, prompting escalation to cefepime (1 g/day IV) and initiation of antifungal prophylaxis with intravenous fluconazole (150 mg three times weekly on dialysis days). Intensive topical therapy included dexpanthenol ointment and clobetasol propionate cream (Fig. 2). Two skin biopsies revealed extensive epidermal necrosis with a well-structured stratum corneum, lymphocytic exocytosis, apoptotic keratinocytes and a mixed cellular infiltrate. The findings confirmed the diagnosis of SJS with potential early-stage TEN (SJS/TEN overlap) (Fig. 3).

The patient received high-dose intravenous steroids for ten days, followed by a tapering course of oral prednisolone. Despite a further temporary decline in neutrophil counts (nadir: 0.5 ×10⁹/l), haematopoietic stimulation was not pursued as monocyte levels remained stable. By day 13, significant re-epithelialisation of the skin was observed and the patient’s condition improved steadily. The antibiotic and antifungal therapies were stopped by day 14, and the patient was discharged on day 15 to continue follow-up care in the outpatient oncology clinic. Although EV+P therapy was discontinued, alternative immunotherapy options are currently under evaluation (Fig. 4).

DISCUSSION

The patient received EV in combination with pembrolizumab as first-line treatment. Approximately 10 days after the first dose and following the second dose, the patient’s condition declined with fever, upper respiratory symptoms and a widespread skin rash. This quickly progressed to extensive cutaneous lesions and absolute neutropenia. These developments were interpreted as the onset of SJS or an SJS-TEN overlap, affecting 20-30% of the total body surface area, which was later confirmed by histopathological findings.

The clinical presentation and histopathological findings of extensive epidermal necrosis and dermolysis are consistent with other cases of SJS and TEN reported in association with EV^[2,3]. While the novel combination of EV+P has significantly improved the prognosis for patients with metastatic urothelial carcinoma, severe dermal off-target toxicity remains a potential limitation of this treatment^[2].

EV is an antibody-drug conjugate that specifically targets the transmembrane protein nectin-4, which is overexpressed in many tumours, including urothelial carcinoma. The specific binding of enfortumab to nectin-4 leads to the internalisation of the cytotoxic component monomethyl auristatin E into the target cell, followed by apoptosis. Nectin-4 is expressed not only in various solid tumour tissues but also, to a lesser extent, in normal human epidermis. This off-target expression in the skin likely contributes to the observed cutaneous toxicity^[3,4].

Other antibody-drug conjugates containing monomethyl auristatin E have also shown skin toxicity as a potential side effect, suggesting the possibility of nectin-4-independent mechanisms of toxicity^[3]. In the context of drug approval, the efficacy and safety of EV were evaluated in the Phase 2 EV-201 study, where a variety of side effects were observed, including mild fatigue (54%), rash (53%), alopecia (48%), peripheral neuropathy (44%), decreased appetite (30%), diarrhoea (28%) and nausea (24%). Grade 3 or higher adverse events included neutropenia (9%), maculopapular rash (8%) and anaemia (6%). In two patients, skin toxicity led to the discontinuation of therapy, with one case progressing to Stevens-Johnson syndrome^[5,6].

In this case, the rapid onset of severe skin toxicity within a few days of EV administration aligns with findings in the EV-201 study. This distinguishes it from immune-related adverse events associated with immune-checkpoint inhibitors, which typically have a time to occurrence of 3-12 weeks for psoriatic rash and 13-80 weeks for bullous pemphigoid^[7,8].

A recent pharmacovigilance study by Yang et al.^[9] analysed 212 cutaneous adverse events associated with EV reported to the US Food and Drug Administration’s Adverse Event Reporting System. Of these cases, 13 were categorised as SJS and 9 as TEN^[9]. SJS is considered to be primarily HLA-linked, involving cytotoxic CD8+ T-cell-mediated keratinocytic necroptosis. The standard treatment for SJS and TEN includes systemic corticosteroids, intravenous immunoglobulins (IVIg), cyclosporine and TNF-alpha antagonists^[10,11]. However, in cases of EV-induced dermolysis, cessation of the causative agent is critical. While there is limited data on whether treatment with EV can be resumed following recovery from SJS/TEN, our patient responded well to high-dose glucocorticoids, and additional treatments such as intravenous immunoglobulin or other immunomodulatory therapies were not required.

The complicating neutropenia observed in our patient has been reported as a side effect of EV in approximately 9% of patients^[6]. The clinical picture of systemic inflammation combined with neutropenia necessitated empirical antibacterial and antifungal therapy, as described in similar cases. Broad-spectrum antibiotics, although not standard in SJS and TEN management, may be justified in the presence of neutropenia and the heightened risk of systemic infection due to extensive skin barrier disruption. The risk factors for developing cutaneous toxicity with EV may include the patient’s pre-existing comorbidities, such as chronic kidney failure and liver cirrhosis, as well as the concurrent use of pembrolizumab^[3,6]. These factors likely contributed to the severity of the cutaneous reaction observed in this case.