MON-628 Enfortumab Vedotin-Mediated Severe Insulin Resistance and Fatal Ketoacidosis

Abstract Disclosure: M. Gonzalez: None. R. Florian: None. A.L. Morvant: None. C.D. Hendrickson: None. Introduction: Enfortumab vedotin-ejfv (EV) is a monoclonal antibody approved in locally advanced or metastatic urothelial carcinoma with previous PD1/PD-L1 inhibitor and platinum-based chemotherapy use. Enfortumab targets nectin-4 and, after endocytosis and payload delivery, vedotin inhibits microtubules leading to cytotoxicity. Our case adds to the growing body of literature demonstrating a rare, often fatal side effect of severe insulin resistance and diabetic ketoacidosis (DKA). Case description: A 61-year-old male presented with lethargy and nausea. Medical history included metastatic urothelial carcinoma, hypertension, diabetes mellitus type 2 and obesity. Cancer treatment history included ddMVAC, GC and adjuvant nivolumab. With biopsy proven lymph node recurrence, he started EV (1.25mg/kg) and pembrolizumab. His diabetes was diet-controlled, not on antihyperglycemics at admission with an A1c of 6.1%.He presented on cycle 1 day 15 of therapy and was found to be hypotensive and acidemic. Volume resuscitation failed, and he was started on broad-spectrum antibiotics and vasopressors in the ICU. With escalating pressors, stress dose steroids were given, worsening his hyperglycemia (glucose 721 mg/dL) and acidemia (pH 7.17, P CO2 14 mmHg). Insulin requirements rose on continuous infusion, and he was transferred to a tertiary academic center and intubated. He required three pressors and maxed insulin infusion at 450 units/hr. Labs confirmed ketoacidosis (anion gap 28 mmol/L, beta-hydroxybutyrate 3.1 mmol/L) and elevated C peptide (61.6 ng/mL). Due to significant renal dysfunction, hemodialysis was started. Multidisciplinary discussions were held where previous cases of EV-mediated DKA were reviewed, and a trial of plasma exchange (PLEX) was agreed upon. One session was completed, with improvement in glucose and acidemia, but he clinically declined with refractory hypotension and tachyarrhythmias requiring cardioversions. His family decided to pursue comfort care, and he expired within 84 hours of admission. Discussion: This case is the 10th instance of EV-mediated DKA reported in the literature. Mechanisms behind high insulin resistance are unclear, but the leading theory suggests vedotin/monomethyl auristatin E (MMAE) to be the cause, and similar events have been noted in other drugs using the same payload. Across 10 cases, there is a 70% associated mortality rate, with 40% expiring in 96 hours and only three patients surviving hospitalization. Late and limited PLEX did not provide meaningful benefit in our case. A sample was stored to test for residual drug but no commercial or research lab assay was found. Our case adds to the reported events of EV-mediated severe DKA and its high mortality risk. Reporting to manufacturers remains a key step in post-marketing safety data, and publishing can promote education and awareness of this rare but severe adverse effect. Presentation: Monday, July 14, 2025