Real-world incidences and risk factors of immune-related adverse events in patients treated with immune checkpoint inhibitors: A nationwide retrospective cohort study

Immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) are rare but fatal, requiring systemic steroid use. Therefore, to examine the outcomes, incidence, timing, and risk factors of ICIassociated steroid-requiring severe irAEs, we conducted a nationwide, retrospective, cohort study utilizing the Korean Health Insurance and Review Assessment database. We identified 357,010 patients with lung cancer, bladder cancer, or skin melanoma, eligible for ICI reimbursement in Korea between January 2012 to June 2020. Steroid-requiring severe irAEs following ICI treatment or treatment-emergent AEs following cytotoxic chemotherapy were defined as moderate- or high-dose steroid administration for over 2 consecutive days, along with corresponding ICD-10 codes indicating affected organ systems. The ICI-exposed group (N = 10,118) was compared to a matched cohort of 55,436 ICI-unexposed patients treated with cytotoxic chemotherapy. Incidences of acute severe irAEs requiring moderate- and high-dose steroids were higher in the ICI-exposed group (1.95% and 6.42%, respectively). The ICI-exposed group also had a higher risk of developing delayed severe irAEs requiring moderate- and high-dose steroid use (3.89% and 7.39%). Male sex, high comorbidity index, or previously diagnosed autoimmune diseases were associated with an increased risk of severe irAEs. Notably, 27.4-38.8% of the patients experienced recurrent severe irAEs after re-challenge with ICIs following moderateor high-dose steroid use, with the severity matching the initial episode. Steroid-requiring severe irAEs were significantly more prevalent among patients exposed to ICIs than among those treated with chemotherapy in acute and delayed periods.