Thoracic radiotherapy synergizes with first‐line EGFR ‐ TKIs in advanced EGFR ‐mutant NSCLC : A dual‐center real‐world study

Abstract First‐line thoracic radiotherapy (TRT) with epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) shows promising efficacy in advanced EGFR‐mutated non‐small‐cell lung cancer (NSCLC), yet clinical evidence remains limited. This dual‐center retrospective study evaluated 322 patients receiving first‐line EGFR‐TKIs (197 first‐/second‐generation; 125 third‐generation) between May 2017 and May 2024, categorized by treatment sequence: TKI alone, salvage TKI‐TRT (salvage TRT at local progression after EGFR‐TKI maintenance), or upfront concurrent TKI‐TRT initiated before disease progression. Survival analysis revealed concurrent TKI‐TRT achieved median progression‐free survival (PFS) of 23.8 months (vs. 11.9 months, TKI alone) with first‐/second‐generation TKIs and 43.1 months (vs. 17.2 months, TKI alone) with third‐generation TKIs. Survival benefits were mutation‐independent, with concurrent third‐generation TKI‐TRT reducing progression risk by 81% for exon 19 deletions (HR 0.19; 95% CI 0.09–0.42) and 56% for L858R mutations (HR 0.44; 95% CI 0.19–0.99). Notably, both oligometastatic and non‐oligometastatic disease benefited, especially in the brain metastasis subgroup where concurrent first/second generation TKI‐TRT improved PFS by 72% (HR 0.28; 95% CI 0.12–0.64). Concurrent TKI‐TRT therapy also altered progression patterns, reducing primary tumor progression risk by 63–74% and distant progression risk (with third‐generation TKI‐TRT) by 53%. Concurrent TRT showed favorable safety, with grade ≥3 radiation pneumonitis in <5% of patients and no increase in severe TKI‐related toxicities. These findings suggest concurrent TKI‐TRT as a disease‐modifying strategy redefining treatment expectations in advanced EGFR‐mutant NSCLC.