Central nervous system progression and liquid biopsy in patients with oncogene addicted non-small cell lung cancer treated with ALK/ROS1 inhibitors

Non-small cell lung cancer (NSCLC) driven by ALK or ROS1 rearrangements have an increased risk for developing central nervous system (CNS) metastases, as a result of increased CNS tropism of the tumor cell or insufficient drug penetration of the blood-brain barrier. Novel generation tyrosine kinase inhibitors (TKIs) have increased intracranial activity after failing crizotinib or in the frontline setting. The sequential use of TKIs is effective in controlling CNS disease and patients may attain long-term survival, despite the presence of CNS disease. Disease progression under TKIs is frequently associated with the development of resistance mutations, which need drugs that do not have the same resistance profile. Tailoring treatment according to resistance alterations might increase the chance of obtaining a response, which is essential for patients at risk of rapid clinical deterioration, such as those with CNS disease. Moreover, the molecular portrait of CNS metastases might differ than that of extra-CNS metastases. The molecular characterization of the CNS disease is challenged by the invasive nature of tissue biopsies and the risk of negative liquid biopsies when performed in plasma. The analysis of the cerebro-spinal fluid (CSF) by liquid biopsy has proven to be more sensitive than plasma for the detection of genomic alterations in patients with CNS progression. Here, we discuss the interest and feasibility of performing a liquid biopsy to characterize CNS metastases of NSCLC patients treated with ALK and ROS1 inhibitors.