Vortioxetine for Cognitive Function in ALK-positive NSCLC Treated With Lorlatinib

Potential Effect of Vortioxetine on Cognitive Functioning of Patients With ALK-positive Non-Small Cell Lung Cancer Treated With Lorlatinib

This observational study evaluates whether vortioxetine - an antidepressant medication with cognitive-enhancing properties - can reduce the neurological and cognitive side effects associated with lorlatinib treatment in patients with non-small cell lung cancer (NSCLC) harboring ALK or ROS1 gene rearrangements.

Lorlatinib is a highly effective third-generation tyrosine kinase inhibitor, but it causes neuropsychological adverse events (NAEs) in approximately 42% of patients, including cognitive impairment, mood changes, and speech disturbances. Vortioxetine has demonstrated cognitive improvement in depressed patients and in preclinical models of androgen deprivation therapy-induced cognitive impairment.

Twenty-four adult patients with ALK/ROS1-positive NSCLC receiving lorlatinib as standard care and prescribed vortioxetine (10-20 mg/day) for NAE management will be enrolled. Comprehensive neuropsychological assessments and quality-of-life questionnaires will be conducted at baseline, week 6, week 12, and month 6 to document changes in cognitive function, depressive symptoms, and quality of life.

Inclusion Criteria:

• Histologically confirmed diagnosis of ALK/ROS1-positive non-small cell lung cancer (NSCLC), stage IIIB/IV.
• Currently receiving lorlatinib as part of the standard therapeutic regimen.
• Documented neurocognitive adverse events (NAEs) attributable to lorlatinib.
• Age >= 18 years.
• ECOG performance status 0-2.
• Ability to understand and sign informed consent.
• Expected survival >= 6 months.
• Planned initiation of vortioxetine as part of standard care.
• Ability to complete neuropsychological tests and questionnaires in Spanish.

Exclusion Criteria:

• Prior diagnosis of major cognitive impairment unrelated to cancer treatment.
• Current use of another antidepressant that cannot be discontinued.
• Uncontrolled major psychiatric disorder.
• History of uncontrolled epilepsy or recent seizures.
• Severe hepatic or renal impairment.
• Known hypersensitivity to vortioxetine.
• Participation in another clinical trial within the past 30 days.
• Inability to provide informed consent.
• Life expectancy < 3 months.
• Contraindications to vortioxetine (e.g., concomitant MAOI use).
• Prior vortioxetine use.
• Severe psychiatric disorders or significant cognitive impairment unrelated to lorlatinib.