Life-threatening Pneumonitis Induced by Osimertinib Monotherapy as a First-line Treatment for Epidermal Growth Factor Receptor Mutation-positive Non-small-cell Lung Cancer: A Retrospective Case-series Study

Background/Aim: Drug-related pneumonitis is a recognized adverse event associated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small-cell lung cancer (NSCLC). Osimertinib, a third-generation EGFR-TKI, has demonstrated favorable efficacy and safety as a first-line therapy for advanced EGFR-mutated NSCLC. However, osimertinib-induced pneumonitis can be fatal, and the clinical characteristics of patients who develop fatal pneumonitis remain poorly characterized.

Patients and Methods: Using a prospective database, we analyzed 55 patients with EGFR-mutated NSCLC who received osimertinib monotherapy as first-line treatment between January 2019 and May 2025. The clinical course of patients who developed fatal pneumonitis was reviewed in detail. Patient characteristics and survival outcomes were retrospectively compared between the patients with and without fatal pneumonitis.

Results: Among the 55 patients, five (9%) died from osimertinib-related pneumonitis. Of these five patients, four were men and all had a history of heavy smoking. Most cases of fatal pneumonitis occurred within six months of osimertinib initiation. In comparisons based on the occurrence of fatal pneumonitis, smoking history was the only variable that differed between the groups, although the difference did not reach statistical significance. Patients who developed fatal pneumonitis tended to have shorter progression-free survival and a lower overall rate.

Conclusion: In this retrospective case series study, all patients with EGFR-mutated NSCLC who developed fatal pneumonitis during first-line osimertinib monotherapy had a history of heavy smoking. These findings suggest that patients with a substantial smoking history may require closer monitoring to reduce the risk of Grade 5 pneumonitis.