FRI603 Treatment Of Severe Refractory Hypoglycemia Due To Malignant Insulinoma With A Novel Anti-insulin Receptor Antibody
Authors: Osataphan Soravis , Vamvini Maria , Rosen Evan D , Pei Lei , Erlikh Natanie , Singh Gurcharan , Dhorajiya Poojaben , Parker J Anthony , Dreyfuss Jonathan M , Rattani Ahmed , Patti Mary-Elizabeth 
Published: October 2023

Abstract
Disclosure: S. Osataphan: None. M. Vamvini: None. E.D. Rosen: Consulting Fee; Self; Novartis Pharmaceuticals. L. Pei: None. N. Erlikh: None. G. Singh: None. P. Dhorajiya: None. J. Parker: None. J.M. Dreyfuss: None. A. Rattani: Stock Owner; Self; Vertex Pharmaceuticals, Provention Bio, Bluebird Bio, Agenus, MacroGenics, Immunity Bio, Mirati Therapeutics, Actinium Pharmaceuticals, Bausch Health Companies, Compass Therapeutics, Magenta Therapeutics. M. Patti: Advisory Board Member; Self; Fractyl Laboratories. Consulting Fee; Self; AstraZeneca, Hanmi Pharmaceuticals, MBX. Grant Recipient; Self; Dexcom.
Severe hypoglycemia caused by malignant insulinoma is often resistant to medical therapy targeting both tumor burden and insulin secretion. We report a patient who developed severe, treatment-resistant hypoglycemia after receiving 177lutetium-DOTATATE (Lu-177). Hypoglycemia was completely ameliorated after treatment with RZ358, a human monoclonal antibody that functions as a negative allosteric modulator of the insulin receptor, reducing insulin signaling. This 55 year old man presented with abdominal pain, fatigue, and weight loss; imaging showed a 1.8 cm pancreatic tail mass and numerous hepatic lesions. Liver biopsy demonstrated well-differentiated pancreatic neuroendocrine tumor, WHO Grade 2, and pathogenic MEN1 mutation. Following one year of octreotide therapy, both pancreatic and hepatic tumors increased in size, prompting Lu-177 therapy. Two days after the first dose, the patient became unresponsive, with capillary glucose 20 mg/dL. He developed recurrent neuroglycopenia on day 8, with venous glucose 41 mg/dL, insulin 45 µIU/mL, C-peptide 6.5 ng/mL and proinsulin 453 pmol/L, requiring intensive care unit admission for for intravenous glucose. High-dose diazoxide, everolimus, dexamethasone, glucagon, pasireotide, or enteral feeding did not produce a response. Despite multiple therapies, neuroglycopenia required frequent dextrose boluses and continuous intravenous glucose (up to 30 g/hr of 50% dextrose); up to 58% of sensor glucose was below 70 mg/dL and 19% below 54 mg/dL over 24 hours. CT imaging 1 month after Lu-177 showed significant reduction in liver metastases size. Given the severity of hypoglycemia despite tumor regression, we considered treatment with RZ358, a human monoclonal antibody that acts as a negative allosteric modulator of the insulin receptor, inducing insulin resistance. We obtained emergency use authorization from the FDA, approval from the local Institutional Review Board, and written informed consent. Following a 6 mg/kg dose of RZ358, there was transient worsening of hypoglycemia accompanied by an 8-fold increase in insulin, potentially due to reduced insulin clearance. After dose increase to 9 mg/kg weekly, glucose infusion was weaned. Metabolic stability was achieved after 6 doses, allowing a second dose of Lu-177 and eventual discharge. Diazoxide was discontinued, steroid doses were reduced, and RZ358 dosing was reduced to every 3-4 weeks. A third dose of Lu-177 was administered without complications. Despite elevated insulin (537 uIU/mL), C-peptide (10.1 ng/mL), and proinsulin (634.0 pmol/L), he remains free of level 3 hypoglycemia. No adverse effects have been observed. In summary, the anti-insulin receptor monoclonal antibody RZ358 effectively controlled hypoglycemia refractory to multiple other therapies, allowing restoration of normoglycemia and enabling additional successful cancer therapy.
Presentation: Friday, June 16, 2023