Direct Target : ALK,MET,ROS1,MST1R
Drug Type : Multi-target inhibitor
Alteration : Exon 14 deletion
Indications : Crizotinib inhibits ALK fusions, ROS1 fusions, and MET tyrosine kinases (ie, high-level MET amplification, METex14 skipping mutation). The NCCN NSCLC Panel recommends crizotinib as a first-line therapy or subsequent therapy option (category 2A; useful in certain circumstances) for patients with metastatic NSCLC who are positive for METex14 skipping mutations based on this data. Crizotinib may be used as subsequent therapy if it or capmatinib were not previously given as first-line therapy for METex14 skipping mutation–positive metastatic NSCLC.
Mechanism Of Action :
Crizotinib is an inhibitor of receptor tyrosine kinases including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), ROS1 (c-ros), and Recepteur d’Origine Nantais (RON). Translocations can affect the ALK gene resulting in the expression of oncogenic fusion proteins. The formation of ALK fusion proteins results in activation and dysregulation of the gene’s expression and signaling which can contribute to increased cell proliferation and survival in tumors expressing these proteins. Crizotinib demonstrated concentration-dependent
inhibition of ALK, ROS1, and c-Met phosphorylation in cell-based assays using tumor cell lines and demonstrated antitumor activity in mice bearing tumor xenografts that expressed echinoderm microtubule-associated protein-like 4 (EML4)- or nucleophosmin (NPM)-ALK fusion proteins or c-Met.
Efficacy & Safety : A phase 2 study assessed crizotinib in 69 patients with advanced NSCLC who were positive for METex14 skipping mutations. The objective response rate was 32% (95% CI, 21%–45%). Median PFS was 7.3 months (95% CI, 5.4–9.1 months).
Reference Source : Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Guideline Name V.1.2022.◎ National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed [Dec. 7, 2021]. To view the most recent and complete version of the guideline, go online to NCCN.org.
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