Focused ultrasound enhances lazertinib delivery in an EGFR-mutant brain metastasis rat model

Abstract Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective against EGFR-mutant non-small cell lung cancer (NSCLC) but show limited efficacy in brain metastases due to poor blood–brain barrier (BBB) permeability. While third-generation TKIs like lazertinib improve central nervous system penetration, their therapeutic impact remains suboptimal. Focused ultrasound (FUS) can transiently disrupt the BBB to enhance drug delivery. Here, we evaluated whether FUS improves the efficacy of lazertinib in an EGFR-mutant NSCLC brain metastasis model. H-1975 cells were implanted into rat brains. Animals received either no treatment, lazertinib alone, or lazertinib with FUS. Tumor progression was monitored via MRI. Drug concentration was measured using LC–MS/MS, and transcriptomic profiling was performed. FUS enhanced intratumoral lazertinib delivery (2.19-fold), reduced tumor volume, and modulated gene expression toward reduced tumor burden and immunogenicity. These results support FUS as a noninvasive strategy to improve lazertinib delivery and efficacy in NSCLC brain metastases.