Comparison of the Efficacy of Different First‐Line Therapies for <scp>EGFR L858R</scp> ‐Mutated <scp>NSCLC</scp> Patients With Brain Metastases

Compared to exon 19 deletions, the epidermal growth factor receptor (EGFR) exon 21 L858R (21L858R) mutation is associated with a poorer prognosis in non-small cell lung cancer (NSCLC), particularly in patients with brain metastases (BMs). However, there is a notable lack of prospective or retrospective clinical studies focusing on this specific population. This study aims to evaluate the efficacy of different first-line treatment strategies using EGFR-tyrosine kinase inhibitors (TKIs) in NSCLC patients harboring the 21L858R mutation and BMs while providing insights into concurrent mutations and resistance mechanisms. We analyzed clinical data from 331 patients diagnosed with the EGFR 21L858R mutation and BMs who received first-line EGFR-TKI treatment at Sun Yat-sen University Cancer Center between April 2014 and June 2023 (ID: GASTO-1027). The efficacy was evaluated through intracranial progression-free survival (iPFS), PFS, and overall survival (OS). Compared to the first-generation and second-generation cohorts, the third-generation EGFR-TKI cohort demonstrated significant improvements in iPFS (p = 0.002), PFS (p < 0.001), and OS (p = 0.016). Within the third-generation EGFR-TKI group, the combination chemotherapy cohort exhibited the most favorable outcomes, with marked extensions in both iPFS (p = 0.037) and PFS (p = 0.049). Multivariate analyses identified the treatment regimen of third-generation TKIs combined with chemotherapy as an independent prognostic factor for improved iPFS. Compared to treatment regimens containing first-generation or second-generation EGFR-TKIs, patients with TP53 mutations derived greater benefit from treatment regimens containing third-generation EGFR-TKIs. The combination of third-generation EGFR-TKIs with chemotherapy shows enhanced efficacy in patients with EGFR 21L858R mutations and BMs compared to other treatments. Future prospective clinical trials are essential to assess this combination's effects in this population.