(986) A Case of Enfortumab Vedotin Toxicity in a Patient With Advanced Urothelial Cell Carcinoma

Introduction: We describe a rare presentation of refractory hyperglycemia caused by enfortumab vedotin (EV) toxicity, which was treated with continuous renal replacement therapy (CRRT). EV is an antinectin-4 antibody that is used in combination or as monotherapy for treatment of metastatic urothelial carcinoma and is associated with hyperglycemia in clinical trials.

Methods: A retrospective review of the medical record, drug pharmacokinetics, and literature associated with the case.

Results: A 72-year-old Caucasian male presented 5 days following cycle 2 of adjuvant EV and was admitted to the medical intensive care unit (ICU) within 24 hours of hospital admission for refractory shock, DKA, AKI, cholestatic liver injury, and acute hypoxic respiratory failure. Admission glucose was 331 mg/dL and beta-hydroxybutyric acid 1.76 mmol/L, for which an insulin infusion was titrated to 90 units/ hour, despite serum glucose remaining in the 200-300 range. An elevated C-peptide >30 ng/ml suggested insulin resistance and not pancreatic beta islet cell destruction. Within 12 hours of CRRT, the patient’s insulin drip requirements significantly decreased, drip stopped on day 6. The patient ultimately left the ICU, returned with complications related to progressive organ failure, and expired on hospital day 28.

Conclusions: EV is an antibody-drug complex designed to deliver the metabolite unconjugated monomethyl auristatin E (MMAE) to the tumor, where it exerts its pharmacologic effect. MMAE is a highly toxic compound that otherwise would not be safe for human administration. The mechanism of the refractory hyperglycemia is not well characterized. We suspect CRRT benefitted this patient by dialyzing the serum glucose utilizing non-glucose containing replacement fluids, and possible removal of the toxic MMAE metabolite (MW 717 Daltons). It's unlikely CRRT provided any significant removal of EV, as the parent compound has a large molecular weight, (150k Daltons) and volume of distribution. We estimate the refractory hyperglycemia and multi-organ failure to be related to EV as a 7 on the Naranjo scale: probably association. Clinicians need to be aware of this potential for toxicity, and CRRT should be evaluated early on to support patients who develop critical illness associated with refractory hyperglycemia.