Brain radiotherapy synergizes with first-line, third-generation EGFR-TKIs in patients with EGFR-mutant NSCLC and treatment-naïve brain metastases: a multicenter real-world study

First-line third generation (3rd-gen) epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the standard of care for patients with EGFR-mutant advanced non-small-cell lung cancer (NSCLC) and brain metastases. However, the optimal timing of brain radiotherapy (BRT) in combination with third-generation EGFR-TKIs remains uncertain. This multicenter real-world study evaluated outcomes associated with concurrent versus salvage BRT in patients receiving first-line third-generation EGFR-TKIs. This multicenter retrospective study included 465 patients with NSCLC who presented with brain metastases at initial diagnosis and received first-line, 3rd-gen EGFR-TKIs. Patients were classified into three cohorts: 3rd-gen TKI alone ( n = 92), 3rd-gen concurrent TKI-BRT ( n = 229), and 3rd-gen salvage TKI-BRT ( n = 144). Inverse probability of treatment weighting (IPTW) was used to balance baseline characteristics. Overall survival (OS) was the primary endpoint; intracranial progression-free survival (iPFS) and progression-free survival (PFS) were secondary endpoints. Treatment-related adverse events (TRAEs) were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, with particular attention to Grade ≥ 3 TRAEs. In the IPTW analysis, both 3rd-gen concurrent TKI-BRT (OS HR = 0.36, 95% CI 0.26–0.51) and 3rd-gen salvage TKI-BRT (OS HR = 0.29, 95% CI 0.20–0.42) were associated with lower mortality than 3rd-gen TKI alone. After propensity score matching (PSM) between the two radiotherapy cohorts, OS was comparable (31.2 vs. 35.7 months; HR = 1.198, 95% CI 0.8583–1.671; P = 0.284), whereas iPFS was significantly longer with 3rd-gen concurrent TKI-BRT (22.4 vs. 14.5 months; HR = 0.5083, 95% CI 0.3383–0.7638; P < 0.001). Extracranial metastatic status was the only factor showing a significant interaction with OS benefit ( P for interaction = 0.031). The incidence of Grade ≥ 3 TRAEs did not differ significantly according to whether EGFR-TKI therapy was continued or temporarily interrupted during BRT. Among patients with EGFR-mutant NSCLC presenting with treatment-naïve brain metastases and receiving first-line 3rd-gen EGFR-TKIs, the addition of BRT was associated with longer survival than EGFR-TKI alone. Compared with salvage BRT, concurrent BRT was associated with longer iPFS while maintaining comparable OS, supporting concurrent BRT as a reasonable strategy for selected patients, particularly those without extracranial metastases.