Background: Thyroid toxicity is common following treatment with CTLA-4 and PD-1 immune checkpoint inhibitors (ICIs). Published studies estimate the incidence at 10-20%, although rates vary widely between different ICIs. The aetiology of ICI-associated thyroid immune related adverse events (irAEs) is unknown and onset of thyroid dysfunction is highly variable with not all patients developing the classic presentation of transient hyperthyroidism followed by a hypothyroid phase. The current study aimed to fully characterize thyroid irAEs in a large cohort of patients with melanoma.
Methods: We reviewed outcomes in 1246 adult patients undergoing ICI treatment for advanced or metastatic melanoma from a prospectively maintained database.
Results: Immune related adverse events (irAEs) affecting the thyroid occurred in 518 (42%) patients. Over a median follow-up of 11.3 months, multiple patterns of thyroid-irAEs were observed. Primary hyperthyroidism developed in 31% of treated patients and comprised 75% of total thyroid-irAE cases. Primary hypothyroidism occurred in 8% of subjects, with euthyroid hyperthyroxinemia and hypothyroxinemia observed in 10 (<1%) and 6 (<1%) subjects respectively. Non-thyroidal illness (isolated low FT3) occurred in 14 (1%) participants. Thyroid irAEs were most frequent following combination CTLA-4/PD-1 inhibitor treatment (56%). CTLA-4 and PD-1 inhibitor monotherapy resulted in lower rates of thyroid irAEs, 25% and 38% respectively. Severity of thyroid irAEs differed by ICI, with higher rates of overt thyroid dysfunction following combination ICI treatment (45%) relative to PD-1 inhibitor (34%) and CTLA-4 inhibitor (17%) monotherapies.
Conclusions: Thyroid irAEs affect >40% of ICI-treated patients and multiple clinical phenotypes of thyroid dysfunction occur. Higher incidence and more severe thyroid irAEs occur following combination CTLA-4 + PD-1 inhibitor treatment relative to either CTLA-4 or PD-1 inhibitor monotherapy.