Introduction: 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 treatment complication. The aim of this study is to determine the incidence of IH and characterise clinical presentation and outcomes in these patients.
Patients and methods: We retrospectively evaluated adult patients with melanoma treated between December 2010 and April 2018 at a tertiary referral centre. All patients received ipilimumab (3 mg/kg) monotherapy or in combination with nivolumab. Symptoms, pituitary hormone assessment, pituitary imaging and patient survival were assessed.
Results: Of 120 patients treated with ipilimumab, 11 patients (55% male; age at onset 60.8±8.5 years) presented with hypophysitis. The median onset was at 16.4 weeks (range: 8.464.6 weeks) after treatment start, occurring in 73% after the fourth infusion. The main presenting symptom was lethargy (n=8) followed by headache (n=5). All patients had ACTH deficiency. A fall in TSH prior to cortisol was observed in six patients at a median duration of 10.6 weeks (range: 8.819.2 weeks) after commencing ipilimumab and a median of 3.7 weeks (range: 2.810.1 weeks) before the diagnosis of hypophysitis. Gonadotroph deficiency was detected in two patients. By end of follow-up (median 16.7 months, range: 2.858.4 months), corticotroph deficiency was persistent in all patients; all but one patient recovered thyrotroph function and gonadotroph deficit completely recovered. Additional irAEs were diagnosed in five patients with IH, including one case of autoimmune diabetes. Three patients with hypophysitis died within the first year of immunotherapy.
Conclusion: The incidence of IH was 9.2%, predominantly occurring after the fourth infusion. Usually, hormonal deficits improved, except for corticotroph function. TSH fall may be an early predictor of IH.