The spectrum, incidence, kinetics and management of endocrinopathies with immune checkpoint inhibitors for metastatic melanoma.

OBJECTIVE: Endocrine immune-related adverse events (endocrinopathies) are increasingly prevalent with the use of immune checkpoint inhibitors for the treatment of metastatic melanoma and other malignancies. There are no evidence-based guidelines for the screening or management of such patients. To describe the spectrum, incidence, kinetics and management of endocrinopathies with immune checkpoint inhibitors.

DESIGN: A prospective study conducted at Melanoma Institute Australia between April 2014 and October 2015.

METHODS: A total of 177 patients were treated with (a) ipilimumab ( n  = 15), (b) anti-PD-1 (nivolumab, pembrolizumab) ( n  = 103) or (c) combination ipilimumab and anti-PD-1 ( n  = 59) and were screened and managed for the subsequent endocrinopathies. The main outcome measures were the incidence and kinetics of endocrinopathy by immunotherapy drug class.

RESULTS: Thirty-one patients (18%) developed an endocrine immune-related adverse event (thyroid dysfunction: 14%, hypophysitis: 6% and autoimmune diabetes: 0.6%). Combination immunotherapy was more likely to result in a single or multiple endocrinopathy compared to anti-PD-1 monotherapy (27% vs 9% and 7% vs 0% respectively, P  < 0.01). Endocrinopathies occurred after a median of 8 weeks from treatment commencement (range: 12-225 days), with combination immunotherapy resulting in significantly earlier onset compared to ipilimumab (median: 30 vs 76 days, P  = 0.046). The majority of endocrinopathies were identified in asymptomatic patients with hormonal screening. There were no baseline predictors for endocrinopathy.

CONCLUSIONS: Combination immunotherapy has a greater risk of development of endocrinopathy compared to anti-PD-1 monotherapy. Regular biochemical profiling of patients, particularly within the first twelve weeks, results in early detection of endocrinopathy to minimise morbidity.