Baylor College of Medicine Houston, Texas, United States
Introduction: Enfortumab Vedotin (EV) is an antibody drug conjugate (ADC) used as third line agent for adult patients with metastatic urothelial cancer (mUC) who have previously failed platinum-based therapy and a PD-1/PD-L1 inhibitor. While there have been other reports of refractory DKA in the setting of Enfortumab therapy this is the unique first reported case to show that dialysis may offer some improvement for severe hyperglycemia if initiated earlier in the course of presentation.
Case Description: This is a case of a 72-year-old male with metastatic urothelial cancer treated with Enfortumab Vedotin (EV), with no known history of diabetes mellitus, who presented with altered mental status, flu-like symptoms, rash, and refractory DKA five days after his second infusion of EV. Despite requiring up to 80 units/hour of insulin via infusion, with continued titration per institution DKA protocol, the patient had persistent hyperglycemia ranging from 200-300 mg/dL. The patient showed some signs of clinical improvement with improvement in hyperglycemia after initiation of continuous renal replacement therapy (CRRT), however he ultimately passed away due to his underlying illness fifteen days later from initial presentation.
Discussion: Treatment related toxicities of EV were seen in clinical trials and now are being reported in clinical practice that include diabetic ketoacidosis and acute kidney injury. Three adverse drug events during clinical trials required special attention: hyperglycemia (6%), peripheral neuropathy (34%), and rash (47%). Our patient had two of the three toxicities. Bringing awareness of these adverse drug events to healthcare providers using EV is critical to improvement in clinical outcomes and patient care.
The importance of screening appropriate patients prior to EV use is necessary. In our patient case, the patient did not have a history of diabetes mellitus at baseline HbA1c of 5.3%, but still developed DKA (grade 4 toxicity). He completed the screening process and was appropriate for EV therapy. Perhaps his elevated BMI, history of hypertension, history of tobacco use, known risk factors for diabetes mellitus made him more susceptible to hyperglycemia. These same factors could have made him more susceptible to insulin resistance. Still, this finding for our patient was unexpected considering the clinical trial data showed that a majority of patients that initially developed hyperglycemia did not worsen during the course of treatment (68%). The mechanism behind this toxicity is not well understood. It was likely not due to insulin deficiency, but rather insulin resistance as our patient had markedly elevated serum C-peptide and insulin levels.
In our patient, his insulin rate decreased from 9 units/hour to 1.5 units/hour upon initiation of CRRT. This was significant as the half-life of EV is 1.5 to 2 days and pharmacokinetic studies showed time-dependence of clearance had no effect beyond the first dosing cycle. Clearance is not enhanced with time. If toxicity is suspected, especially in a critically ill patient, then exogenous rapid removal of EV is necessary.