Incidence and Phenotypes of Endocrinopathies in Association With Immune Checkpoint Inhibitors: The Experience of Integrated Health Network

Abstract

Introduction: Since 2011 FDA has approved several immune checkpoint inhibitors (ICI) as antineoplastic agents with very promising results. The side effects profile of ICI is different from that of conventional cancer therapies and predominated by immune-related adverse effects (IRAEs). Autoimmune endocrinopathies (AEs), such as disorders of the thyroid, pituitary, and adrenal glands are increasingly recognized IRAEs of ICI. If not diagnosed and treated early, AEs may cause serious harm in an already compromised patient by advanced malignancy. Therefore, it is necessary to recognize the incidence, phenotypes, and time to onset of various AEs in association with ICI. This retrospective study of a large cancer population treated at an integrated health network aims to do so. Methods: We conducted a retrospective chart review of adult patients treated with ICI as cancer therapy at Allegheny Health Network—a major healthcare provider in Western Pennsylvania—between 1/1/2016 and 6/30/2019. Inclusion criteria were ages 18-90 years who received one or more ICI within the study period, laboratory data available for a minimum of 6 months from date of the first ICI dose, and no pre-existing outcome of interest at the time of, or prior to, receiving the first ICI dose. Exclusion criteria were pre-existing thyroid, pituitary, or adrenal diseases. Results: We screened the records of 1200 patients who were treated for 47 different cancers for AEs. Of this sample, 57% were males 92.5% were White. Follow up period ranged between 6-57 months, during which 56% of patient died at a mean age of 67.1 years. The most common cancer diagnoses were non-small cell lung cancer (45.4%), malignant melanoma (11.7%), renal cell carcinoma (6.3%), and small cell lung cancer (6.2%). These patients received one or more agents from the three classes of ICI, including PD-1 (75.86%), PDL-1 (12.57%), and CTLA-4 (11.57%). The overall incidence of AEs was 18%. The distribution of AEs was as follows: primary hypothyroidism 15.3%, secondary hypothyroidism 0.5%, primary hyperthyroidism 3.5%, primary adrenal insufficiency 0.2%, secondary adrenal insufficiency 2.7%, and type 1 diabetes mellitus 0.2%. Of the 42 patients diagnosed with hyperthyroidism, 28 (66.7%) later developed primary hypothyroidism within a mean time of 9 weeks. There was no statistically significant association between the incidence of AEs and gender (P=0.748) or age (P=0.998). Conclusion: AEs are common sequelae of ICI and primary hypothyroidism is the most prevalent AEs among our study sample. This study should help increase awareness about the importance of routine screening of the AEs in cancer patients receiving ICI.