<p>Patients with ROS1-altered non–small cell lung cancer (NSCLC) frequently develop brain metastases. Treatment typically involves the use of ROS1 inhibitors with central nervous system (CNS) penetration and/or radiation therapy. However, optimizing the use of ROS1 inhibitors with CNS penetration while avoiding potential neurologic side effects remains a clinical challenge.</p>

ROS1-altered NSCLC is associated with a relatively high frequency of brain metastases, with an incidence of approximately 35% at baseline (similar to the frequency in patients with ALK-altered NSCLC) and an up to 50% risk during the disease course. Therefore, it is important to surveil the brain in those with and without brain metastases at baseline, although the frequency of surveillance may differ among these patients (eg, perhaps every 6 months for those without baseline brain metastases).

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If a patient with ROS1-altered NSCLC develops brain metastases, your treatment choices will be focused on administering fractionated stereotactic radiation therapy (FSRT) and continuing or switching the TKI, depending on which TKI the patient is receiving. For example, if a patient is receiving crizotinib, this is a great opportunity to upgrade to a CNS-penetrant ROS1 inhibitor. We try to avoid whole-brain radiation therapy (WBRT) as much as possible, and what is considered acceptable for FSRT eligibility has gradually expanded over the years. There was a time when patients with 1 lesion got FSRT but those with 2 or more lesions needed to have WBRT. Fortunately, those days are gone.

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One issue with using the ROS1 inhibitor repotrectinib—and, to some extent, entrectinib—is that they have considerable anti-TRKB activity, which may cause neurologic side effects. These can include dizziness, ataxia, and muscle weakness with repotrectinib, and dizziness and taste disturbances with entrectinib. These neurologic adverse events are not as prominent with taletrectinib, which has less anti-TRKB activity. However, taletrectinib is associated with a higher incidence of gastrointestinal side effects, particularly nausea. Finally, the investigational ROS1 inhibitor zidesamtinib has very little anti-TRKB activity. Assuming that anti-TRKB activity only contributes to neurologic side effects but not to efficacy, taletrectinib may be a little more promising than repotrectinib, and zidesamtinib looks even more promising because of its reduced anti-TRKB activity.