ABSTRACT: Lorlatinib is a novel, highly potent, brain-penetrant, third-generation ALK/ROS1 tyrosine kinase inhibitor (TKI), which has broad-spectrum potency against most known resistance mutations that can develop during treatment with crizotinib and second-generation ALK TKIs. The safety profile of lorlatinib was established based on 295 patients who had received the recommended dose of lorlatinib 100?mg once daily. Adverse events associated with lorlatinib are primarily mild to moderate in severity, with hypercholesterolemia (82.4%), hypertriglyceridemia (60.7%), edema (51.2%), peripheral neuropathy (43.7%), and central nervous system effects (39.7%) among the most frequently reported. These can be effectively managed with dose modification and/or standard supportive medical therapy, as indicated by a low incidence of permanent discontinuations due to adverse reactions. Most patients (81.0%) received at least one lipid-lowering agent. Prescription of supportive therapy should also consider the potential for drug-drug interactions with lorlatinib via engagement of specific CYP450 enzymes. This article summarizes the clinical experience from lorlatinib phase I investigators and was generated from discussion and review of the clinical study protocol and database to provide an expert consensus opinion on the management of the key adverse reactions reported with lorlatinib, including hyperlipidemia, central nervous system effects, weight increase, edema, peripheral neuropathy, and gastrointestinal effects. Overall, lorlatinib 100?mg once daily has a unique safety profile to be considered when prescribed, based on the recent U.S. Food and Drug Administration approval, for the treatment of patients with ALK-positive metastatic non-small cell lung cancer previously treated with a second-generation ALK TKI. IMPLICATIONS FOR PRACTICE: Despite the advancement of second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs), the emergence of resistance and progression of central nervous system metastases remain clinically significant problems in ALK-positive non-small cell lung cancer. Lorlatinib is a potent, brain-penetrant, third-generation, macrocyclic ALK/ROS1 TKI, with broad-spectrum potency against most known resistance mutations that can develop during treatment with existing first- and second-generation ALK TKIs. This article provides recommendations for the clinical management of key adverse reactions reported with lorlatinib.
