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.
Keywords:
Loratinib in phase II clinical trial; Lorlatinib third generation ALK/ROS1 inhibitor; Macrocyclic ALK inhibitor.
Copyright © 2017 Elsevier Masson SAS. All rights reserved.
MeSH terms
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Aminopyridines
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Anaplastic Lymphoma Kinase
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Carcinoma, Non-Small-Cell Lung / drug therapy*
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / pathology
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Clinical Trials, Phase I as Topic
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Clinical Trials, Phase II as Topic
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Drug Evaluation, Preclinical
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Humans
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Lactams
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Lactams, Macrocyclic / chemistry
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Lactams, Macrocyclic / pharmacology
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Lactams, Macrocyclic / therapeutic use*
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Lung / drug effects*
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Lung / metabolism
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Lung / pathology
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Pyrazoles
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism
Substances
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Aminopyridines
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Antineoplastic Agents
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Lactams
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Lactams, Macrocyclic
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Pyrazoles
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ALK protein, human
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Anaplastic Lymphoma Kinase
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Protein-Tyrosine Kinases
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ROS1 protein, human
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Receptor Protein-Tyrosine Kinases
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lorlatinib