MON-290 Ipilimumab Immune-Related ACTH Deficiency Is of Acute Onset and Severe

Abstract

IntroductionImmune checkpoint inhibitors (ICIs) are immunomodulatory molecules that downregulate T-cell inhibiting-receptors or ligands to promote an enhanced anti-tumour response. Ipilimumab is a human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4) that has been shown to significantly improve survival in patients with metastatic melanoma. Immune-related adverse events (irAEs) occur in some patients with increased T-cell activation, of which ipilimumab-related hypophysitis (IH) is an important endocrine complication. The aim of this study is to determine the incidence of IH and characterise clinical presentation and outcomes in these patients.Patients and MethodsWe retrospectively evaluated consecutive adult patients with melanoma treated between December 2010 and August 2019 at a tertiary cancer centre. All patients received ipilimumab (3mg/kg) monotherapy or in combination with PD-1 (programmed cell death protein 1) inhibitors (nivolumab or pembrolizumab). Symptoms, pituitary hormone assessment, pituitary imaging and patient survival were assessed.ResultsOf 189 patients, 23 patients (12.2%, 13 male; age 59.2±11.8 years) presented with hypophysitis, two having received ipilimumab monotherapy. The median onset was at 17.3 weeks (range: 6.7-160 weeks) after treatment start, occurring in 57% after the fourth infusion (n=13). Five patients developed late-onset IH (range: 30.1-160 weeks) whilst on treatment with PD-1 inhibitors. Three of the patients developing hypophysitis (13%) received only a single ipilimumab infusion. Additional irAEs were diagnosed in 16 patients (70%) with IH, including six cases of destructive thyroiditis and one of autoimmune diabetes.The main presenting symptom of IH was lethargy (n=18, 78%) followed by headache (n=8, 35%). Corticotroph deficiency with cortisol levels <83 nmol/l (<3μg/dL) at presentation were observed in all patients. At diagnosis, a drop in cortisol level of >70% over a median time of 22 days (range: 3-39 days) was evident in 87% patients. A fall in fT4 level of at least 20% from baseline was observed in ten patients (59%, 10/17 – after excluding patients with thyroiditis) at a median of 4 weeks (range: 0-8 weeks) prior to the diagnosis of IH. Gonadotroph deficiency was detected in three male patients.At the end of follow-up (median 14.3 months, range: 1-61.5 months after IH diagnosis), corticotroph deficiency was persistent in all patients; seven of ten patients recovered thyrotroph function and gonadotroph deficit resolved in one patient. Three patients with hypophysitis died within the first year of immunotherapy.ConclusionThe incidence of IH was 12.2%, predominantly occurring after the fourth infusion. IH is characterised by acute severe drop in cortisol levels to less than 3μg/dL. A falling fT4 may herald development of ACTH deficiency.