3693 - Reassessing the Incidence and Risk Factors of Radiation Pneumonitis in Treatment-Naive EGFR-Mutant NSCLC with Concurrent Third-Generation EGFR-TKI and Thoracic Radiotherapy

Purpose/Objective(s): The incidence, risk factors, and drug-specific toxicity differences of radiation pneumonitis (RP) induced by first-line third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and thoracic radiotherapy (TRT) in non-small-cell lung cancer (NSCLC) patients remain unclear, excluding concurrent chemotherapy/antiangiogenics. This study aims to clarify their relationship with RP and identify safer treatment regimens.

Materials/Methods: The study was a single-institution retrospective cohort conducted from January 2019 to September 2024. RP diagnosis was based on chest CT, clinical symptoms, post-radiotherapy time window, and concordance with irradiated fields, supported by standardized interventions (e.g., corticosteroids and oxygen). Inflammatory markers and microbiological tests excluded infectious pneumonia. Serial imaging, tumor marker changes, prior tumor burden, and treatment response assessments helped rule out tumor progression or metastasis. CT images were assessed by two senior radiologists, with discrepancies resolved by a third and graded according to CTCAE v5.0. ROC-derived cutoffs were applied. Predictors of grade =2 RP and grade 3 RP were analyzed using multivariable logistic regression; PFS was estimated by Kaplan–Meier.

Results: Among 209 patients, grade =2 RP occurred in 91 (43.54%): grade 2 in 46 (22.01%) and grade 3 in 45 (21.53%); no grade 4 or 5 RP was observed. Grade =2 RP incidence by TKI was 54.25% (51/94) for osimertinib, 36.36% (32/88) for aumolertinib, and 29.63% (8/27) for furmonertinib; grade 3 RP rates were 25.53% (24/94), 20.45% (18/88), and 11.11% (3/27), respectively. For grade =2 RP, compared with osimertinib, aumolertinib (OR=0.42, 95% CI 0.21–0.86, P=0.017) and furmonertinib (OR=0.24, 95% CI 0.08–0.69, P =0.008) were associated with lower risk, while ipsilateral lung V5 =35.93% (OR=3.78, 95% CI 1.47–9.72, P =0.006) and GTV =12.62 mL (OR=3.64, 95% CI 1.65–8.02, P =0.001) increased risk. For grade 3 RP, smoking was protective (OR=0.07, 95% CI 0.01–0.55, P =0.012) While ipsilateral lung V30 =24.61% increased risk (OR=6.57, 95% CI 2.47–17.49, P <0.001) and GTV=14.56 mL (OR=3.56 95% CI=1.53-9.37, P=0.010) emerged as a risk factor. Median PFS for EGFR-TKI and TRT was 26.70 months (median follow-up 21.11 months); median PFS was 26.24, 29.26, and 21.86 months for osimertinib, aumolertinib, and furmonertinib, respectively (P =0.376).

Conclusion: First-line third-generation EGFR-TKI plus TRT showed no grade 4–5 RP. RP risk was independently associated with TKI selection, ipsilateral lung V5/V30, and GTV. Risk appeared to increase when ipsilateral lung V5 exceeded approximately 35% and when V30 exceeded approximately 25% (data-driven thresholds), together with larger GTV. These findings support dose optimization and may inform TKI selection when clinically appropriate; however, the proposed thresholds are exploratory and require external validation.