Central nervous system activity of first-line osimertinib in epidermal growth factor receptor-mutant advanced non-small cell lung cancer

Although the majority of patients with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-sensitizing mutations experience good initial response to first-generation (erlotinib, gefitinib) and second-generation (afatinib, dacomitinib) EGFR-TKIs, they invariably suffer disease progression either due to a pharmacodynamic resistance to the EGFR-TKI or a pharmacokinetic failure resulting in central nervous system (CNS) progression (1-3). Despite the efficacy and superiority of first- and second-generation EGFR-TKIs in the treatment of extracranial EGFR-mutant non-small cell lung cancer (NSCLC) compared to conventional chemotherapy, treating and preventing the development of CNS metastases is a challenge because of the limited ability of first-generation and second-generation EGFR-TKIs to cross the blood-brain barrier (BBB) as shown by preclinical and clinical studies leading to the emergence of the CNS as a sanctuary site for metastasis (4-7). Accordingly, the CNS is not an uncommon site of disease progression following initial response to targeted therapy with EGFR-TKIs (2,3). The high incidence of brain metastases (BMs) in patients with EGFR-mutated disease is not only reflective of the pharmacokinetic failure of EGFR-TKIs to penetrate the brain but also the increased likelihood of developing BMs with their long survival on EGFR-TKI therapy (8-10). In fact, up to two-fifths of EGFR-mutant NSCLC patients develop CNS metastases over the course of their treatment with EGFR-TKIs (11)