Abstract
BACKGROUND: ROS1 inhibitors play a critical role in the treatment of ROS1 fusion-positive non-small cell lung cancer (NSCLC). Although agents such as Crizotinib, Ceritinib, Lorlatinib, Entrectinib, and Repotrectinib have demonstrated strong efficacy and intracranial activity, their neurological safety profiles remain insufficiently characterized in real-world settings. This study aimed to evaluate the neurological adverse events (AEs) of ROS1 inhibitors using the FDA Adverse Event Reporting System (FAERS) database. METHODS: We conducted a pharmacovigilance analysis of FAERS reports from 2011Q4 to 2024Q4. Disproportionality analysis was used to detect potential AE signals, followed by time-to-onset and logistic regression analyses to assess the onset timing and mortality risk associated with neurological AEs. RESULTS: A total of 7,296 AE reports related to ROS1 inhibitors were identified. Neurological AEs were prominent, with distinct patterns across drug generations. Common events included dysgeusia, dysarthria, cognitive disorder, and taste disturbance. Novel inhibitors such as Lorlatinib, Entrectinib, and Repotrectinib showed earlier onset of neurotoxicity, whereas older agents (Crizotinib and Ceritinib) were associated with delayed or cumulative neurological events. Despite stronger neurotoxicity signals, Entrectinib demonstrated a relatively favorable safety profile with fewer fatal outcomes. CONCLUSION: This study provides real-world evidence that newer ROS1 inhibitors exhibit earlier but generally manageable neurological AEs. Clinicians should implement early neurotoxicity monitoring and individualized risk assessment to ensure safe and effective targeted therapy for ROS1-positive NSCLC.