FRI610 Phosphatidylinositol 3-kinase Inhibition With Alpelisib Is Safe And Effective In Treating Refractory Hypoglycemia Associated With Malignant Insulinoma
Authors: Mi Kang Yu , Rubinson Douglas A , Odintsov Igor , Vaidya Anand , Williams Jonathan S , Kurr Adler Gail , Elizabeth McDonnell Marie , Patti Mary-Elizabeth , Palermo Nadine E 
Published: October 2023

Abstract
Disclosure: Y. Kang: None. D.A. Rubinson: None. I. Odintsov: None. A. Vaidya: None. J.S. Williams: None. G.K. Adler: None. M.E. McDonnell: None. M. Patti: Advisory Board Member; Self; Fractyl Laboratories. Consulting Fee; Self; AstraZeneca, Hanmi Pharmaceuticals, MBX. Grant Recipient; Self; Dexcom. N.E. Palermo: None.
Background: Nonfunctioning malignant pancreatic neuroendocrine tumors (PNETs) can transform to functional PNETs. Transformation into insulin-secreting PNET (ISPNET) is associated with poor overall survival and refractory hypoglycemia, often requiring ICU care. We present a case of refractory hypoglycemia due to ISPNET, which was successfully treated with alpelisib, an inhibitor of phosphatidylinositol 3-kinase (PI3K) currently approved for breast cancer. Clinical Case: A 79-year-old man with a 5-year history of type 2 diabetes and 10-year history of grade II, well-differentiated, non-functioning PNET (Ki67 15%) with hepatic metastasis presented with worsening symptomatic hypoglycemia. He discontinued his antidiabetic agent 3 months ago due to hypoglycemia and was on lanreotide and everolimus as PNET treatment. Evaluation revealed plasma glucose 29 mg/dL, proinsulin &gt;700 pmol/L (reference: 3.6-22), insulin 116 uIU/mL (2.6-24.9), C-peptide 12.0 ng/mL (1.1-4.4), beta-hydroxybutyrate 0.1 mmol/L (&lt;0.3), and negative sulfonylurea panel. Imaging showed extensive progression of hepatic metastases, and debulking hepatectomy was performed. Pathology showed grade III PNET with positive insulin staining and mib-1 index of 22%. After 2 months of euglycemia post-surgery, he was readmitted to the ICU with refractory hypoglycemia. Evaluation showed plasma glucose 91 mg/dL, proinsulin, and insulin levels above-assay (&gt;700 pmol/L and &gt;930.0 uIU/mL, respectively) and C-peptide 71.8 ng/mL; imaging revealed hepatic tumor progression. Severe hypoglycemia as low as 34 mg/dL was noted despite therapy with IV dextrose (30%, up to 100 cc/hr), glucagon infusion (0.6 mg/hr), dexamethasone 20 mg QD, and diazoxide 30 mg TID. Debilitating anasarca developed despite aggressive diuresis, attributed to high-volume IV dextrose, diazoxide, and renal dysfunction. Two hours after 300 mg alpelisib administration, patient exhibited hyperglycemia, allowing discontinuation of dextrose infusion 8 hours later. Glucagon infusion was subsequently discontinued, and he was discharged to home. Within 20 days, the patient was able to discontinue all diuretics, dexamethasone, and cornstarch. Patient had no side effects related to alpelisib and performance status returned to baseline. Glucose ranged between 160-300 mg/dL without any hypoglycemia. On week 4 of alpelisib, plasma glucose was 340 mg/dL, proinsulin &gt;700 pmol/L, insulin 181 uIU/mL, and C-peptide 20.2 ng/mL. Conclusion: To our knowledge, this is the first case demonstrating alpelisib as a safe and effective option in refractory hypoglycemia associated with insulinoma. While it is unclear whether this is mediated by anti-tumor effects or solely by blockade of insulin action, PI3-K inhibition should be considered as a treatment option in patients with ISPNET in whom hypoglycemia has failed to improve with conventional approaches.
Presentation: Friday, June 16, 2023