Introduction: Immune checkpoint inhibitor-related pneumonitis (ICI-P) is a life-threatening complication, limiting immune checkpoint inhibitors (ICIs) clinical application in non-small cell lung cancer (NSCLC). But risk factors for developing ICI-P have not been well defined. Methods: This study employed a retrospective analysis method. Following approval from the Ethics Committee of Chinese PLA General Hospital, we retrieved patient information on NSCLC registered in the hospital’s PRIDE workstation, selecting patients who received treatment with ICIs from January 1, 2018, to September 30, 2023. Complete medical records of patients were collected and verified. Logistic regression analysis was used to identify independent high-risk factors for the occurrence of ICI-P. Results: A total of 753 patients with NSCLC who received treatment with ICIs were included, with a mean age of (63 ± 9.5) years. A total of 102 patients diagnosed with ICI-P were identified, resulting in an incidence rate of 13.5%. Development of ICI-P was independently associated with history of interstitial lung disease (ILD) (OR, 3.85; CI, 1.99–7.46; p < 0.001), prior thoracic radiotherapy (OR, 2.65; CI, 1.56–4.48; p < 0.001), concurrent thoracic radiotherapy (OR, 3.56; CI, 1.69–7.47; p < 0.001) and treatment with programmed cell death 1 (PD-1) inhibitors compared with programmed death-ligand 1 (PD-L1) inhibitors (OR, 3.54; CI, 1.05–11.98; p = 0.04). Conclusion: Independent risk factors for ICI-P occurrence included the history of ILD, previous chest radiotherapy, concurrent chest radiotherapy, and the use of PD-1 inhibitors (compared to non-PD-1 inhibitors). Specialty assessment of ILD before treatment and cautious use of ICIs in radiotherapy patients, represent feasible strategies to prevent the occurrence of ICI-P.

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