Predictors of severe immune-related adverse events during first-line immune checkpoint inhibitor therapy for advanced non-small cell lung cancer

Immune checkpoint inhibitors (ICIs) have transformed treatment for advanced non-small cell lung cancer (NSCLC) treatment but can trigger immune-related adverse events (irAEs). Evidence on clinically meaningful irAEs in first-line ICI settings is limited. Using the SEER-Medicare data (2010–2019), we conducted a population-based retrospective study of adults aged ≥ 66 years with advanced NSCLC initiating first-line nivolumab, pembrolizumab, or atezolizumab. Severe irAEs were defined as immune-related events requiring systemic immunosuppressants and resulting in ICI delay or discontinuation occurring after treatment initiation. Fine-Gray competing risks models were used to identify predictors of irAE, and model performance was evaluated using bootstrap and ten-fold cross-validation. Among 2,729 patients, 14.2% developed severe irAEs (median onset = 1.4 months; IQR = 0.5–4); mostly within 3 months. Common organ systems affected were pulmonary (14.2%), hematologic (14.0%), gastrointestinal (13.4%), and musculoskeletal (13.3%). Higher risk of severe irAEs was associated with pre-existing autoimmune disease (HR = 1.25, 95% CI = 1.17–1.32), chemoimmunotherapy (HR = 2.35, 95% CI = 1.39–3.96), and longer diagnosis-to-treatment interval (HR = 1.50, 95% CI = 1.31–1.60). Lower risks occurred among Black patients (HR = 0.56, 95%CI = 0.34–0.92), those with baseline metastasis (HR = 0.84, 95% CI = 0.75–0.93), opioid use (HR = 0.68, 95% CI = 0.54–0.87), and with atezolizumab (HR = 0.75, 95% CI = 0.65–0.86) or nivolumab (HR = 0.91, 95% CI = 0.87–0.96) vs. pembrolizumab. The prediction model demonstrated good discrimination and calibration (bootstrap-corrected AUC = 0.85; Brier score = 0.14), supporting risk-stratified monitoring in patients receiving ICIs.