Lorlatinib atypical safety profile in ALK-positive aNSCLC: tips for management from an Italian expert panel

Lorlatinib is a third-generation tyrosine kinase inhibitor approved for first- and second-line treatment of ALK-positive advanced non-small cell lung cancer. The CROWN study demonstrated that first-line lorlatinib significantly improves progression-free survival and intracranial control compared to crizotinib, with sustained benefits observed over a follow-up period of up to 5 years. As lorlatinib is associated with a distinct adverse event (AE) profile, we aim to analyze lorlatinib's safety profile, focusing on AEs incidence, severity, timing and management. A comprehensive safety management framework is also outlined to address lorlatinib-associated toxicity, drawing on evidence from the literature and the clinical expertise of an Italian expert panel. The most frequent AEs associated with lorlatinib are hypercholesterolemia and hypertriglyceridemia, which emerge early after treatment initiation. The 5-year analysis of the CROWN study revealed minimal changes in most AE rates over time. Pharmacological and non-pharmacological approaches effectively resolved most AEs; lorlatinib dose reduction did not affect its efficacy. The proposed safety management framework emphasizes patient preparation and regular monitoring to predict AE occurrence, indicating AE-specific interventions, mitigation strategies and multidisciplinary collaboration to optimize outcomes. Lorlatinib's toxicity appears generally predictable and manageable; the safety framework offers pragmatic guidance to clinicians for appropriate management in clinical practice.