Clinical Presentation of Immune-Related Endocrine Adverse Events during Immune Checkpoint Inhibitor Treatment

Abstract

Simple SummaryWith the growing use of immune checkpoint inhibitors (ICIs), clinicians are increasingly encountering a unique set of adverse events called immune-related adverse events (irAEs) associated with ICIs. In this retrospective study, we tried to analyse the clinical course of endocrine irAEs and determine the factors associated with persistent endocrine dysfunction. We also performed survival analysis of patients with endocrine irAEs compared to those without any irAEs. The clinical course of endocrine irAEs was found to be highly variable. The presentation of some endocrine irAEs could be nonspecific, and sometimes life-threatening if not detected early, e.g., hypocortisolism and diabetic ketoacidosis. Therefore, frequent clinical assessment and laboratory monitoring are recommended. Measuring thyroid antibodies at the start of thyroid dysfunction could be helpful as it was found to be associated with persistent thyroid dysfunction in our study. The presence of endocrine irAEs was found to have survival benefits in our patient population.The exact clinical course and factors associated with persistent endocrine immune-related adverse events (irAEs) are not well-established. Elucidation of these information will aid irAEs screening and follow-up planning for patients on immunotherapy. We analysed the clinical course of endocrine irAEs including thyroid and pituitary dysfunction and insulin-dependent diabetes mellitus (IDDM), identified factors associated with persistent thyroid dysfunction, and determined the association between endocrine irAEs and survival parameters. This retrospective observational study enrolled patients with metastatic cancer who underwent anti-PD-1, anti-PD-L1, and/or anti-CTLA-4 treatment and developed endocrine irAE at the National University Cancer Institute, Singapore, between June 2015 and December 2020. Sixty-six patients with endocrine irAE were evaluated, with a median follow-up time of 15.7 months. The median time to onset of thyroid dysfunction, pituitary dysfunction, and IDDM was 1.8 months (range: 0.3–15.8 months), 6.8 months (range: 1.5–27.3 months), and 7.8 months (range: 1.4–9.1 months), respectively. Positive thyroperoxidase antibodies (TPOAb) and/ or thyroglobulin antibodies (TgAb) status at the time of thyroid dysfunction was associated with persistent thyroid dysfunction (OR 11.6, 95% CI 1.3–570.8, p = 0.02; OR 8.8, 95% CI 1.3–106.9, p = 0.01, respectively). All patients with pituitary irAE had central hypocortisolism. All patients with IDDM had grade 4 irAE. Patients with endocrine irAE had longer median survival times. Endocrine irAEs were associated with non-progressive disease. The screening and follow-up approach for endocrine irAEs should be tailored according to each endocrinopathy’s clinical course. Early screening is imperative given its wide median time to onset.