Central nervous system efficacy of third generation vs. first generation EGFR-TKIs in the first line treatment for EGFR-mutated non-small cell lung cancer with central nervous system metastases: a systematic review and meta-analysis of phase 3 randomized controlled trials

Abstract

Background Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) with central nervous system (CNS) metastases poses significant treatment challenges, as first-generation EGFR-tyrosine kinase inhibitors (TKIs) (FGET) show limited CNS efficacy. Although third-generation EGFR-TKIs (TGET) exhibit superior CNS penetration, the optimal choice for first-line treatment remains debated. This meta-analysis aims to resolve this controversy by directly comparing the CNS efficacy of TGET vs. FGET in patients with EGFR-mutant NSCLC and CNS metastases. Methods A thorough literature search was performed for phase 3 randomized controlled trials (RCTs) comparing TGET and FGET in patients with EGFR-mutated NSCLC and CNS metastases. The primary outcome was CNS-progression-free survival (PFS), and secondary outcomes included overall survival (OS), PFS, CNS response rates, and adverse events (AEs). The study was registered in PROSPERO (ID: CRD42024629581). Results A total of 5 phase 3 RCTs (AENEAS, FLAURA, FURLONG, IBIO-103, and LASER301) met the inclusion criteria. TGET demonstrated superior efficacy in CNS-PFS [hazard ratio (HR): 0.44 (0.33, 0.58), P<0.001], PFS [HR: 0.44 (0.35, 0.54), P<0.001], CNS-objective response rate (ORR) [risk ratio (RR): 1.32 (1.15, 1.52), P<0.001], CNS-complete response (CR) [RR: 3.40 (1.39, 8.28), P=0.007], and CNS-duration of response (DOR) [HR: 0.39 (0.21, 0.73), P=0.003]. The CNS-PFS rate at 4–24 months and PFS at 10–24 months were significantly higher in the TGET group. OS data were available from only 2 of the 5 included phase 3 RCTs. In this analysis, OS numerically favored the TGET group but did not reach statistical significance [HR: 0.79 (0.55, 1.13), P=0.20]. At the cutoff time, more CNS progressions were found in the FGET [RR: 0.59 (0.44, 0.80), P=0.001]. Additionally, less grade 3–5 treatment-related AEs (TRAEs) were found in the TGET group [RR: 0.67 (0.46, 0.98), P=0.04]. Conclusions TGET appeared to be better than FGET for patients with EGFR-mutated NSCLC and CNS metastases, showing improved survival, CNS efficacy, and safety.