Optimal Care for Patients with Anaplastic Lymphoma Kinase (ALK)-Positive Non-Small Cell Lung Cancer: A Review on the Role and Utility of ALK Inhibitors

The treatment of advanced non-small-cell lung cancer (NSCLC) has undergone a paradigm shift in the last decade. Molecular characterization of the disease has led to the rapid development of personalized medicine and swift delivery of targeted therapies to patients. The discovery of the anaplastic lymphoma kinase (ALK) gene in patients with NSCLC has resulted in rapid bench-bedside transition of several active drugs, with several others currently in clinical trials. After the first-generation ALK inhibitor crizotinib, next-generation ALK inhibitors have entered clinical applications for ALK-rearranged NSCLC. Ceritinib, alectinib, and brigatinib have all received approval for ALK-positive patients who have failed prior crizotinib, as well as first-line therapy in treatment-naïve patients based on favorable efficacy. Most recently, lorlatinib, a potent, newer-generation ALK inhibitor, has been approved as second- or third-line treatment. These advances have led to better patient outcomes, but concurrently have led to several crucial unanswered questions about optimal care for ALK-positive NSCLC patients. The ultimate acquisition of resistance to ALK-inhibitor therapy poses a challenge to ongoing research efforts, in addition to the routine management of these patients in the clinic. This review provides a summary of the clinical development of crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib and highlights current management paradigms, current and evolving clinical information, emerging clinical decision-making and sequencing of therapy in advanced, metastatic, or recurrent ALK-positive NSCLC.

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S8229 Brigatinib (AP26113) Brigatinib (AP26113) is a potent and selective ALK (IC50, 0.6 nM) and ROS1 (IC50, 0.9 nM) inhibitor. It also inhibits IGF-1R, FLT3, and mutant variants of FLT3 (D835Y) and EGFR with lower potentcy.

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