Neuropsychiatric adverse events associated with lorlatinib in ALK-positive NSCLC

Background Lorlatinib, a third-generation ALK/ROS1 inhibitor, is highly effective in ALK-positive non–small-cell lung cancer (NSCLC), particularly for intracranial disease. It is associated with a distinctive neuropsychiatric toxicity profile. Objective To characterize neuropsychiatric adverse events (AEs) of lorlatinib using FAERS post-marketing data. Methods FAERS reports listing lorlatinib as the primary suspect (November 2018–December 2024) were analyzed via OpenVigil 2.1. Neuropsychiatric AEs were grouped into four domains: cognitive, mood, speech, and psychotic. Disproportionality was assessed using Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR). Results Among 3452 reports, cognitive effects predominated: cognitive disorder (2.95%, ROR: 16.68, PRR: 16.22), memory impairment (2.35%, ROR: 4.07, PRR: 3.99), and confusional state (1.77%, ROR: 3.22, PRR: 3.18). Mood alterations included affective disorder (0.43%, ROR: 13.13, PRR: 13.08) and personality change (0.32%, ROR: 10.32, PRR: 10.29). Speech disturbances included slow speech (0.2%, ROR: 18.49, PRR: 18.45) and speech disorder (1.22%, ROR: 6.47, PRR: 6.40). Psychiatric manifestations were most pronounced: olfactory hallucinations (0.14%, ROR: 91.44, PRR: 91.31), auditory hallucinations (1.3%, ROR: 22.0, PRR: 21.7), and acute psychosis (0.2%, ROR: 22.12, PRR: 22.07). Conclusions Lorlatinib exhibits a multidimensional neuropsychiatric profile with rare but highly specific events. Proactive monitoring of cognitive, mood, speech, and psychotic domains is recommended in clinical practice.