Safety profile of lorlatinib: correction of adverse events

Abstract

Lorlatinib is a new third-generation tyrosine kinase (TKI) inhibitor of ALK/ROS1, which has antitumour activity against most of the known mutations of resistance to crizotinib and second-generation TKI, as well as high intracranial efficacy. The safety of lorlatinib was evaluated in a multi-cohort phase I study involving 295 patients receiving the recommended dose of lorlatinib 100 mg once a day. Adverse events of lorlatinib were mainly mild to moderate severity. The most frequent complications – hypercholesterolemia (82.4%), hypertriglyceridemia (60.7%), edema (51.2%), peripheral neuropathy (43.7%) and side effects from the central nervous system (39.7%), were reversible and well controlled by dose modification and concomitant therapy, as evidenced by the low frequency of discontinuation of therapy due to adverse reactions. The majority of patients (81.0%) required the appointment of at least one hypolipidemic drug. When prescribing concomitant therapy, the possibility of drug interaction with lorlatinib, whose metabolism is carried out with the participation of specific CYP450 enzymes, should also be taken into account. Based on the presented results, an expert consensus opinion was developed on the correction of the main adverse reactions, including hyperlipidemia, complications from the central nervous system, weight gain, edema, peripheral neuropathy and others. No new adverse events were reported in the CROWN Phase III study conducted later. Lorlatinib has a characteristic toxicity profile, which must be taken into account for successful long-term targeted therapy while maintaining a good quality of life for patients. In the Russian Federation, the drug is approved for use in a wide clinical practice both for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) in the first line, and after progression to second-generation TKI. The article presents recommendations for the correction of the main adverse events of lorlatinib, as well as their own experience in managing patients.