Abstract
Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to 2nd-generation ALK inhibitors. Lorlatinib (PF-06463922) (6) is a 3rd-generation macrocyclic ALK-TKI that demonstrates many advantages over 2nd-generation ALK inhibitors. Lorlatinib has demonstrated decent kinase selectivity, promising pharmacokinetic profile, selective brain-penetration and strong antiproliferative activity in several ALK/ROS1-driven tumor models. The current review describes the activity spectrum, key events from discovery to clinical applications and the evidences that lorlatinib acts as an ALK/ROS1 inhibitor in clinical settings.
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•Lorlatinib (PF-06463922) is 3rd-generation ALK/ROS1 inhibitor with novel macrocyclic scaffold.•Lorlatinib has inhibits ALK mutants resistant to 2nd-generation clinical ALK inhibitors.•Demonstrated high safety margin in preclinical settings and progressing in phase I/II trials.•This review describes the journey of lorlatinib from acylic to macrocyclic scaffold.•Designing, discovery, development strategy and clinical update of loratinib from crizotinib is summarized.