Risk of immune-related adverse events from checkpoint inhibitors in cancer patients with autoimmune disease: An emulated target trial.

11120 Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by activating the immune system to target and eliminate cancer cells, leading to durable responses and improved survival. However, patients with preexisting autoimmune diseases are excluded from ICI clinical trials due to concerns about triggering immune-related adverse events (irAEs). Consequently, there is limited real-world data comparing the risk of irAEs between ICIs and other systemic cancer therapies in this high-risk population. Methods: We conducted a target trial emulation using a new-user, active-comparator design to compare the risk of developing de novo irAEs following ICI initiation compared to chemotherapy or targeted therapy. Using Merative MarketScan data (2014–2023), we identified adults with cancer and a preexisting autoimmune disease who initiated treatment with ICIs, chemotherapy, or targeted therapy. Propensity score matching (1:1) was performed for two comparisons: ICI versus chemotherapy and ICI versus targeted therapy. The primary outcome was de novo irAEs affecting organ systems distinct from the patient’s baseline autoimmune disease. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), with subgroup analyses by age, sex, cancer type, preexisting autoimmune disease category, and ICI class. Results: A total of 3,601 matched patient pairs were included in the ICI–chemotherapy comparison and 1,479 matched pairs in the ICI–targeted therapy comparison. Patients receiving ICI had a significantly higher risk of developing de novo irAEs compared to those receiving chemotherapy (HR=1.71; 95% CI, 1.49–1.97) or targeted therapy (HR=1.43; 95% CI, 1.20–1.70). This increased risk was consistent across age and sex. By ICI class, CTLA-4 inhibitors were associated with the highest risk (HR=2.64; 95% CI, 1.97–3.53 vs chemotherapy; HR=1.72; 95% CI, 1.18–2.50 vs targeted therapy), followed by ICI combination therapy (HR=2.46; 95% CI, 1.80–3.37 vs chemotherapy). By cancer type, patients with liver cancer had the greatest risk (HR=2.75; 95% CI, 1.96–3.85 vs chemotherapy; HR=2.67; 95% CI, 1.68–4.24 vs targeted therapy), followed by breast cancer (HR=2.11; 95% CI, 1.31–3.42 vs chemotherapy; HR=1.97; 95% CI, 1.06–3.68 vs targeted therapy). By baseline autoimmune disease category, patients with endocrine autoimmune diseases consistently showed elevated risk across both comparisons (HR=1.74; 95% CI, 1.42–2.14 vs chemotherapy; HR=1.92; 95% CI, 1.43–2.58 vs targeted therapy). Conclusions: ICI use in cancer patients with preexisting autoimmune diseases is associated with a higher risk of de novo irAEs than chemotherapy or targeted therapy, with risk varying by ICI type, cancer type, and underlying autoimmune condition, highlighting the need for individualized risk assessment and close monitoring.