Endocrine Abstracts

Introduction: Guidelines recommend enfortumab vedotin as therapy for patients with locally advanced or metastatic urothelial cell carcinoma (UCC) combined with pembrolizumab in first line or as monotherapy in third line. Enfortumab vedotin is an antibody drug conjugate (ADC) directed against nectin-4, a transmembrane protein highly expressed in malignant urothelial cells.

Case description: A 62-year-old man, known with a locally advanced UCC and obesity (BMI 36.2 kg/m²), was hospitalised with complaints of vomiting and diarrhoea. We report severe hyperglycemia after two administrations of enfortumab vedotin, requiring up to 600 units of intravenous insulin per day. The course was complicated with acute renal failure and development of circulatory shock, with suspicion of septic shock. The patient died on day 4 after initiation of palliative sedation.

Discussion: Literature review revealed 16 case reports of enfortumab vedotin – associated hyperglycemia. The underlying mechanism is severe insulin resistance, as evidenced by massive insulin requirement, hypertriglyceridemia, increased C-peptide and negative diabetes autoantibodies. Vedotin (monomethyl auristatin E, MMAE) is suspected to be the causal agent as the complication was also observed with other ADC with MMAE as payload. The mortality rate is high, but the complication is reversible if the patient can clear the medication.

Conclusion: Hyperglycemia as a side effect of enfortumab vedotin occurs frequently, with the possibility of rapid deterioration to refractory diabetic ketoacidosis based on severe insulin resistance. Patients with known risk factors such as obesity or increased hemoglobin A1c should be closely monitored. The treatment requires aggressive escalation in insulin therapy, sometimes necessitating more than 1000 units of insulin per day. Continuous hemodialysis may play a role by exogenously removing MMAE. Additional studies are needed to better understand the pathophysiology of insulin resistance and to safely support treatment with enfortumab vedotin.

References: 1. Powles T, Bellmunt J, Comperat E, De Santis M, Huddart R, Loriot Y, et al. ESMO Clinical Practice Guideline interim update on first-line therapy in advanced urothelial carcinoma. Annals of Oncology: Official Journal of the European Society for Medical Oncology. 35(6), pages 485-490 (2024) 2. Hovelroud R, Goh Xiu Ming S, McLeod DSA, Donovan PJ, Ng G, Mungomery M. A Case of Enfortumab Vedotin-Associated Diabetic Ketoacidosis With Severe Insulin Resistance in a Nondiabetic Woman. JCEM Case Reports. 2(12) (2024) 3. Kapoor AK, Ellis CS, Pandey D, Allison DB, Myint ZW. Case report: Enfortumab vedotin induced refractory DKA and multi organ failure - a rare fatal adverse event. Front Oncol. 14:1332478 (2024)

Keywords: Enfortumab vedotin, hyperglycemia, diabetic ketoacidosis