Abstract
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.
Data availability
Access to the SEER-Medicare data requires an approved research protocol and a data-use agreement with the National Cancer Institute. Guidance for requesting these data is available at [https://healthcaredelivery.cancer.gov/seermedicare/obtain](https:/healthcaredelivery.cancer.gov/seermedicare/obtain).
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Acknowledgements
This study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the National Cancer Institute; Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER-Medicare database. The collection of cancer incidence data used in this study was supported by the California Department of Public Health pursuant to California Health and Safety Code Sect. 103885; Centers for Disease Control and Prevention’s (CDC) National Program of Cancer Registries, under cooperative agreement 1NU58DP007156; the National Cancer Institute’s Surveillance, Epidemiology and End Results Program under contract HHSN261201800032I awarded to the University of California, San Francisco, contract HHSN261201800015I awarded to the University of Southern California, and contract HHSN261201800009I awarded to the Public Health Institute. The ideas and opinions expressed herein are those of the author(s) and do not necessarily reflect the opinions of the State of California, Department of Public Health, the National Cancer Institute, and the Centers for Disease Control and Prevention or their Contractors and Subcontractors.
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Conceptualization: O.A. Olateju (lead); M. Patel, J.D. Thornton, R.R. Aparasu (supporting) Methodology: O.A. Olateju Formal analysis: O.A. Olateju Writing – original draft: O.A. Olateju Writing – review & editing: All authors Supervision: J.D. Thornton Approval of final manuscript: All authors.
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Olateju, O.A., Aparasu, R.R., Patel, M. et al. Predictors of severe immune-related adverse events during first-line immune checkpoint inhibitor therapy for advanced non-small cell lung cancer. Sci Rep (2026). https://doi.org/10.1038/s41598-026-42768-6
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DOI: https://doi.org/10.1038/s41598-026-42768-6
