Optimizing treatment for patients with anaplastic lymphoma kinase‐positive lung cancer

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Chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene in patients with non‐small cell lung cancer (NSCLC) were first described in 2007.1 After this initial discovery, investigators quickly identified NSCLC patients with ALK rearrangements and enrolled them in an early‐phase trial of a c‐MET (tyrosine‐protein kinase MET), ALK, and ROS1 (ROS proto‐oncogene 1, receptor tyrosine kinase) inhibitor called crizotinib. The antitumor activity of crizotinib seen in this trial helped establish ALK‐positive NSCLC as a new targetable subset of NSCLC. Now, 9 years after the initial description of ALK‐rearranged NSCLC, there are currently three US Food and Drug Administration (FDA)‐approved drugs for patients with advanced ALK‐positive lung cancer, with additional drugs currently in development. This review aims to give an overview of the initial development of ALK‐directed therapeutics, describe the clinical activity of approved ALK inhibitors, describe what is currently understood about the mechanisms of resistance to clinically available ALK inhibitors, and highlight the newest ALK inhibitors currently in clinical trials. We will also discuss two important unresolved questions in the treatment of patients with advanced ALK‐positive lung cancer.

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