Value and significance of brain radiation therapy during first-line EGFR-TKI treatment in lung adenocarcinoma with EGFR sensitive mutation and synchronous brain metastasis: Appropriate timing and technique.

Background: For lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) sensitive mutation and synchronous brain metastasis (syn-BM), when and how to apply radiotherapy (RT) during first-line tyrosine kinase inhibitor (TKI) treatment remains debatable.

Methods: From a real-world multicenter database, EGFR-mutant patients with syn-BM diagnosed between 2010-2020 and treated with first-line TKIs were enrolled and divided into upfront TKI + RT and upfront TKI groups. Median intracranial progression-free survival (mIC-PFS), median overall survival (mOS), and their risk factors were estimated.

Results: There were 60 and 186 patients in the upfront TKI + RT group and upfront TKI group, respectively. Their mIC-PFS were 28.9 months (m) and 17.5 m (p = 0.023), and mOS were 42.7 m and 40.1 m (p = 0.51). Upfront brain RT improved mIC-PFS in patients ≤60-year-old (p = 0.035), with symptomatic BM (p = 0.002), and treated with first-generation TKIs (p = 0.012). There was no significant difference in mOS in any subgroup. Upfront brain stereotactic radiosurgery (SRS) showed a trend of better mIC-PFS and mOS. mIC-PFS was independently correlated with symptomatic BM (HR = 1.54, p = 0.030), EGFR L858R mutation (HR = 1.57, p = 0.019), and upfront brain RT (HR = 0.47, p = 0.001). mOS was independently correlated with being female (HR = 0.54, p = 0.007), ECOG 3-4 (HR = 10.47, p < 0.001), BM number>3 (HR = 2.19, p = 0.002), and third-generation TKI (HR = 0.54, p = 0.044) or antiangiogenic drugs (HR = 0.11, p = 0.005) as first/second-line therapy.

Conclusions: Upfront brain RT based on first-line EGFR-TKI might improve IC-PFS but not OS in EGFR-mutant lung adenocarcinoma patients, indicating potential survival benefit from brain SRS and early application of drugs with higher intracranial activity.