“ This case illustrates a rare but life-threatening complication of pembrolizumab and enfortumab vedotin therapy, potentially amplified by recent radiotherapy .”
BUFFALO, NY — October 21, 2026 — A new case report was published in Volume 13 of Oncoscience on September 30, 2026, titled “ Stevens–Johnson syndrome following combination therapy with pembrolizumab and enfortumab vedotin in a patient with metastatic urothelial carcinoma: A rare but serious adverse event .”
The report describes a rare, life-threatening skin reaction in a man receiving pembrolizumab and enfortumab vedotin for metastatic urothelial carcinoma. After six treatment cycles, the patient developed toxic epidermal necrolysis (TEN), a severe condition involving extensive skin damage and systemic complications. Despite intensive treatment, he died after 32 days in hospital. The case highlights the importance of recognizing serious skin reactions during cancer therapy, including those that emerge after several treatment cycles.
The report was led by first and corresponding author Aed Banibakr, affiliated with the Sultan Qaboos Comprehensive Cancer Care and Research Centre, University Medical City .
Urothelial carcinoma develops in the lining of the urinary tract, most commonly affecting the bladder but also occurring in the ureters and renal pelvis. Advanced disease can be difficult to treat, prompting the development of therapies that target cancer cells or strengthen immune responses against tumors.
Pembrolizumab is an immune checkpoint inhibitor that blocks programmed cell death protein 1 (PD-1), helping immune cells recognize and attack cancer. Enfortumab vedotin is an antibody-drug conjugate that targets nectin-4, a protein commonly expressed on urothelial cancer cells, to deliver a cytotoxic drug. Their combination has improved treatment outcomes in advanced urothelial cancer, although both agents can cause serious skin reactions.
Stevens–Johnson syndrome (SJS) and TEN belong to a spectrum of severe immune-mediated skin disorders characterized by skin-cell death, blistering and epidermal detachment. SJS typically affects less than 10% of the body's surface area, while TEN involves more than 30%. These reactions can also affect mucous membranes and cause life-threatening systemic complications, particularly in patients with cancer or other underlying illnesses.
The reported patient had high-grade urothelial carcinoma involving the left ureteral stump and a pelvic mass extending around the left iliac blood vessels, with regional lymph node involvement. His medical history included insulin-dependent diabetes, chronic kidney disease, obesity, obstructive sleep apnea and hypothyroidism thought to be related to immunotherapy.
The patient received pelvic radiotherapy in August 2024, followed by pembrolizumab and enfortumab vedotin beginning in October 2024. After the first treatment cycle, he developed a severe generalized rash with blistering. A skin biopsy showed vacuolar interface dermatitis rather than SJS or TEN. The reaction improved with corticosteroids, allowing treatment to continue.
After completing six cycles, however, the patient developed a more severe reaction. In March 2025, he experienced acute skin burning that progressed to extensive blistering and epidermal detachment, accompanied by metabolic acidosis, neutropenia and respiratory distress. Clinicians diagnosed toxic epidermal necrolysis, with a SCORTEN severity score of 5, indicating a high risk of death.
To determine which medication was more likely responsible, the researchers used the Algorithm of Drug Causality for Epidermal Necrolysis (ALDEN), a scoring system that evaluates potential relationships between drug exposure and severe skin reactions.
Pembrolizumab received an ALDEN score of 5, indicating probable causality, while enfortumab vedotin received a score of 2, indicating possible causality. The authors considered pembrolizumab the more likely trigger because the delayed onset was consistent with immune checkpoint inhibitor-related skin toxicity. Enfortumab vedotin-associated SJS/TEN more commonly occurs earlier in treatment.
However, the exact cause could not be established. Both agents have been linked to serious skin reactions, and previous radiotherapy was considered a possible contributing factor through enhanced immune activation. This potential interaction remains unproven.
Following the diagnosis, the cancer treatments were discontinued, and the patient was admitted to the intensive care unit. Initial immunosuppressive treatment with methylprednisolone was later changed to cyclosporine and intravenous immunoglobulin (IVIG), alongside multidisciplinary supportive care.
Cyclosporine suppresses T-cell activity involved in immune-mediated skin damage, while IVIG has been investigated for its ability to interfere with pathways contributing to skin-cell death. Although these treatments may help control disease progression, their effectiveness varies, and optimal management of TEN remains an area of clinical investigation.
Despite aggressive treatment, the patient's condition was complicated by septic shock, bloodstream infections, acute-on-chronic kidney injury requiring continuous renal replacement therapy and respiratory failure requiring mechanical ventilation. Partial skin healing was observed around days seven to eight, but persistent infection and multiple organ failure followed. The patient experienced cardiac arrest and died after 32 days in hospital.
The case also highlights differences in the timing of severe skin reactions associated with newer cancer therapies. Enfortumab vedotin has been linked to early-onset SJS/TEN, while pembrolizumab and other immune checkpoint inhibitors can produce delayed reactions. These patterns may complicate diagnosis when patients receive combination therapy.
“ Early recognition, drug discontinuation, and prompt initiation of immunomodulatory therapy are critical for improving outcomes .”
The authors emphasize that clinicians should remain alert to rapidly worsening skin symptoms, including painful redness, blistering and skin detachment, throughout treatment. Early dermatological assessment and coordinated care involving oncology, critical care and other specialists are particularly important when severe reactions are suspected.
The report has important limitations. As a single-patient case report, it cannot establish the frequency of TEN associated with this combination or determine which medication was definitively responsible. The patient's underlying conditions and previous radiotherapy further complicate causal interpretation. The case also cannot establish the comparative effectiveness of the immunosuppressive treatments administered.
Nevertheless, the findings demonstrate that potentially fatal skin reactions can develop even after an earlier rash has resolved and subsequent treatment cycles have been completed without further dermatological complications. Additional studies and pharmacovigilance monitoring are needed to better understand risk factors, onset patterns and management strategies.
Overall, the report highlights a rare but potentially fatal complication associated with modern urothelial cancer treatment. As pembrolizumab and enfortumab vedotin become more widely used, early recognition of severe skin reactions, timely intervention and multidisciplinary management remain essential for improving patient safety.
DOI: https://doi.org/10.18632/oncoscience.676
Correspondence to: Aed Banibakr - a.banibakr@cccrc.gov.om (ORCID: 0000-0001-9886-9609 )
Keywords: toxic epidermal necrolysis (TEN), immune checkpoint inhibitors, Antibody-Drug conjugates, urothelial carcinoma, Immunomodulatory therapy
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Stevens–Johnson syndrome following combination therapy with pembrolizumab and enfortumab vedotin in a patient with metastatic urothelial carcinoma: A rare but serious adverse event
30-Sep-2026
Authors have no conflicts of interest to declare.