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Neuropsychiatric adverse events associated with lorlatinib in ALK-positive NSCLC

Eleonora Castellana1, Maria Rachele Chiappetta1

  • 1Hospital Pharmacy, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.

The International Journal of Risk & Safety in Medicine
|April 13, 2026
PubMed

Insights

Lorlatinib, an ALK/ROS1 inhibitor for non-small-cell lung cancer, shows a distinct neuropsychiatric profile. Analysis of post-marketing data reveals cognitive, mood, speech, and psychotic adverse events, necessitating proactive patient monitoring.

Area of Science:

  • Oncology
  • Pharmacovigilance
  • Neuroscience

Background:

  • Lorlatinib is a third-generation ALK/ROS1 inhibitor effective for ALK-positive non-small-cell lung cancer (NSCLC), including brain metastases.
  • Lorlatinib is associated with a unique profile of neuropsychiatric adverse events (AEs).

Purpose of the Study:

  • To characterize the neuropsychiatric adverse events (AEs) associated with lorlatinib.
  • To analyze lorlatinib's neuropsychiatric toxicity using post-marketing surveillance data.

Main Methods:

  • Utilized the FDA Adverse Event Reporting System (FAERS) database from November 2018 to December 2024.
  • Analyzed lorlatinib as the primary suspect drug using OpenVigil 2.1 software.
  • Categorized neuropsychiatric AEs into cognitive, mood, speech, and psychotic domains, assessing disproportionality with Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR).

Main Results:

  • Cognitive effects were most frequent, including cognitive disorder (ROR: 16.68) and memory impairment (ROR: 4.07).
  • Mood alterations such as affective disorder (ROR: 13.13) and personality change (ROR: 10.32) were observed.
  • Psychiatric events, particularly olfactory hallucinations (ROR: 91.44), auditory hallucinations (ROR: 22.0), and acute psychosis (ROR: 22.12), were pronounced.

Conclusions:

  • Lorlatinib presents a complex neuropsychiatric safety profile with specific, albeit rare, events.
  • Clinical practice should involve proactive monitoring of patients for cognitive, mood, speech, and psychotic disturbances during lorlatinib treatment.
Keywords:
ALK-positive non–small-cell lung cancerFAERSlorlatinibneuropsychiatric adverse eventspharmacovigilance

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