ABSTRACT
The central nervous system (CNS) is a dominant place of metastasis in patients with non-small cell lung cancer (NSCLC). The tendency to spread to the CNS is even more pronounced in patients presenting with an oncogenic driver mutation in EGFR. While the first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) are associated with a limited intracranial activity, the third generation EGFR TKI osimertinib passes the blood-brain-barrier (BBB) much more effectively, leading to a markedly higher activity in the CNS. Based on the compelling intra- and extracranial activity of osimertinib compared to earlier EGFR TKIs in the pivotal FLAURA trial, this agent has become the standard of care first line treatment for patients with EGFR-mutant NSCLC, including those who present with baseline CNS metastases. More recently, results of the FLAURA2 trial showed that combining osimertinib with chemotherapy in first line results in a more pronounced clinical activity, especially in the CNS. In addition, also the upfront use of local therapy prior to the start of osimertinib is being explored as a way to improve the CNS activity of this agent. Osimertinib does not only target existing brain metastases, it also prevents the development of new brain lesions. This CNS protective effect is now also being leveraged in the adjuvant treatment of patients with earlier stage, EGFR-mutant NSCLC.
