Safety evaluation of epidermal growth factor receptor tyrosine kinase inhibitors in patients with interstitial pneumonia: a study using a Japanese nationwide database

INTRODUCTION: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard first-line therapies for EGFR mutation-positive non-small cell lung cancer (NSCLC) but can cause rare, potentially fatal drug-induced interstitial lung disease (ILD). Patients with preexisting interstitial pneumonia (IP) are considered at increased risk; however, most prior studies excluded these patients, limiting real-world comparative evidence. MATERIALS & METHODS: We identified patients with NSCLC who initiated first-line EGFR-TKI therapy between August 2018 and December 2024, using a nationwide Japanese claims database. Preexisting IP was defined using diagnosis codes combined with chest computed tomography records. Severe drug-induced ILD was defined as initiation of high-dose intravenous steroid pulse therapy. Cumulative incidence was estimated, and differences according to IP status were assessed using Fine-Gray models. RESULTS: Among 13,092 eligible patients, 481 (3.7%) had preexisting IP. The 2-year cumulative incidence of severe drug-induced ILD was 3.2% in patients with IP and 1.7% in those without IP. Preexisting IP was associated with a higher risk of severe drug-induced ILD (subdistribution hazard ratio, 1.85; 95% confidence interval, 1.06-3.24). CONCLUSIONS: Preexisting IP was associated with an approximately twofold higher risk of severe drug-induced ILD during first-line EGFR-TKI therapy, supporting careful risk assessment and monitoring.