Endocrine Emergencies in Immune Checkpoint Inhibitor Therapy for Lung Cancer

Introduction: Since the introduction of nivolumab in 2015 for the treatment of non-small cell lung cancer (NSCLC), four other immune checkpoint inhibitors (ICI) have gained FDA approval in advanced stage lung cancer. While efficacious, ICIs can lead to several immune related adverse events (irAEs) attributed to T cell dysfunction. Endocrinopathies account for up to 10% of irAEs. We aimed to characterize endocrine irAEs related to ICI use in patients with NSCLC using a national, multicenter cohort.


Methods: Querying the TriNetX database, an aggregator of approximately 98 million patient records drawn from electronic chart and claim-derived data from across the U.S., we assessed patients with ICD-10-CM diagnostic codes for lung cancer between 03/2015 and 06/2022 who received approved ICI therapies. Establishing a propensity-matched control group (accounting for 19 demographic and comorbidity variables) with lung cancer patients who did not receive ICIs, we then examined the 1-year incidence of endocrine irAE diagnoses, including thyrotoxicosis (TT), hypothyroidism (HT), diabetic ketoacidosis (DKA), adrenal insufficiency (AI), and hypophysitis. Patients with antecedent diagnoses of the relevant outcomes were excluded from analysis.


Results: Of the 97,891,305 patients in the database, 322,246 (0.3%) were diagnosed with lung cancer in the specified time period, of whom 32,087 received ICI therapy. Following propensity matching, the ICI-receiving lung cancer group had a significantly higher 1-year risk of TT (2.4% vs 0.6%, OR 3.8, CI 3.3 – 4.5), as well as HT (12.7% vs 2.8%, OR 4.9, CI 4.5 – 5.3), DKA (0.4% vs 0.2%, OR 1.5, CI 1.2 – 2.1), AI (2.8% vs 0.5%, OR 5.5, CI 4.7 – 6.5), and hypophysitis (1.1% vs 0.1%, OR 7.4, CI 5.4 – 10.0). For all associations, p-value < 0.01.


Conclusions: Lung cancer patients who received ICI therapy since 2015 had markedly increased rates of endocrine irAEs than non-ICI treated patients, especially hypophysitis and adrenal insufficiency. Clinicians caring for patients with lung cancer receiving ICIs should be cognizant of the broad spectrum of endocrine irAEs to facilitate prompt work-up and timely management.