<p>The management of central nervous system (CNS) metastases can be a significant challenge in non–small cell lung cancer (NSCLC), particularly when oncogenic drivers such as ROS1 fusions are present. Fortunately, several ROS1-targeted therapies offer effective systemic disease control with the added benefit of having CNS activity.</p>

In patients with NSCLC who have oncogenic drivers such as EGFR mutations, ALK fusions, and ROS1 fusions, there seems to be a higher risk of brain metastases at the time of diagnosis and throughout the disease duration vs in patients with wild-type disease. Many times, these are small, asymptomatic brain metastases that are seen on magnetic resonance imaging scans at the time of a patient’s NSCLC diagnosis, with characteristic radiologic findings. Often, these patients are symptomatic from their systemic disease and will present with shortness of breath, a cough, and fatigue, which are related to a greater burden of disease outside the CNS than inside the CNS.

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If a patient has a targetable molecular alteration such as ROS1, ROS1-targeted therapies are typically the best choice for management, and you can usually assume that the driver at the time of diagnosis is consistent across disease sites. Newer ROS1-targeted agents are orally administered, are highly effective, and cross the blood-brain barrier, demonstrating CNS activity. I will repeat a brain magnetic resonance imaging scan 4 weeks after starting a targeted therapy to be sure that the disease in the brain is responding, as brain metastases can have devastating consequences. Often, patients do not resolve the neurologic deficits that they develop due to the cancer.

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In individuals without brain metastases at the time of diagnosis, TKIs with CNS activity can have a protective effect on their development. Entrectinib, repotrectinib, and taletrectinib seem to have much better CNS activity than crizotinib, so I have not used crizotinib in patients with ROS1-positive disease in a while. I would like to prevent patients from developing brain metastases for as long as possible. In my opinion, crizotinib is now of historic interest only.

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Fortunately, ROS1-targeted therapies are generally well tolerated, with toxicities typically of grade 1 or 2; discontinuations due to side effects are uncommon. However, patients with advanced ROS1-positive NSCLC can live with their disease for years, and their quality of life may be impacted if they are experiencing low-grade adverse events frequently. It is not clear how these low-grade (ie, grade 1 or 2) toxicities may impact people’s day-to-day living.

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Sometimes we have a situation in which a patient has a great response to a TKI for several years but then develops oligometastatic disease. If there are a limited number of sites in the brain that seem to be escaping the TKI effect, we often use targeted radiotherapy.