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

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.