Crizotinib

Crizotinib

File:Crizotinib structure.svg
Clinical data
Trade names	Xalkori
Synonyms	PF-02341066 1066
MedlinePlus	a612018
[[Regulation of therapeutic goods |Template:Engvar data]]	US FDA: Crizotinib
Pregnancy category	US: D (Evidence of risk)
Routes of administration	Oral
ATC code	L01XE16 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Elimination half-life	46 hours
Identifiers
IUPAC name 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine
CAS Number	877399-52-5 N
PubChem CID	11626560
DrugBank	DB08700 Y
ChemSpider	9801307 Y
UNII	53AH36668S
KEGG	D09731 Y
ChEMBL	ChEMBL601719 Y
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C21H22Cl2FN5O
Molar mass	450.337 g/mol
3D model (JSmol)	Interactive image
SMILES C1(=C(C=CC(=C1[C@H](OC2=C(N=CC(=C2)C3=C[N](N=C3)C4CCNCC4)N)C)Cl)F)Cl
InChI InChI=1S/C21H22Cl2FN5O/c1-12(19-16(22)2-3-17(24)20(19)23)30-18-8-13(9-27-21(18)25)14-10-28-29(11-14)15-4-6-26-7-5-15/h2-3,8-12,15,26H,4-7H2,1H3,(H2,25,27)/t12-/m1/s1 Y Key:KTEIFNKAUNYNJU-GFCCVEGCSA-N Y
NY (what is this?)  (verify)

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Clinical Trials
Ongoing Trials on Crizotinib at Clinical Trials.gov Trial results on Crizotinib Clinical Trials on Crizotinib at Google
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US National Guidelines Clearinghouse on Crizotinib NICE Guidance on Crizotinib NHS PRODIGY Guidance FDA on Crizotinib CDC on Crizotinib
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Crizotinib (Xalkori, Pfizer), is an ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene1, receptor tyrosine kinase) inhibitor, approved for treatment of some non-small cell lung carcinoma (NSCLC) in the US and some other countries, and undergoing clinical trials testing its safety and efficacy in anaplastic large cell lymphoma, neuroblastoma, and other advanced solid tumors in both adults and children.

Mechanism of action

File:2xp2.png

Human anaplastic lymphoma kinase in complex with crizotinib. PDB 2xp2

Crizotinib has an aminopyridine structure, and functions as a protein kinase inhibitor by competitive binding within the ATP-binding pocket of target kinases. About 4% of patients with non-small cell lung carcinoma have a chromosomal rearrangement that generates a fusion gene between EML4 ('echinoderm microtubule-associated protein-like 4') and ALK ('anaplastic lymphoma kinase'), which results in constitutive kinase activity that contributes to carcinogenesis and seems to drive the malignant phenotype. The kinase activity of the fusion protein is also inhibited by crizotinib. Patients with this gene fusion are typically younger non-smokers who do not have mutations in either the epidermal growth factor receptor gene (EGFR) or in the K-ras gene. The number of new cases of ALK-fusion NSLC is about 9,000 per year in the U.S. and about 45,000 worldwide.

ALK mutations are also thought to be important in driving the malignant phenotype in about 15% of cases of neuroblastoma, a rare form of peripheral nervous system cancer that occurs almost exclusively in very young children.

Crizotinib also inhibits the c-Met/Hepatocyte growth factor receptor (HGFR) tyrosine kinase, which is involved in the oncogenesis of a number of other histological forms of malignant neoplasms.

Crizotinib is currently thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells. Other studies suggest that crizotinib may also act via inhibition of angiogenesis in malignant tumors.

Clinical trials

Crizotinib caused tumors to shrink or stabilize in 90% of 82 patients carrying the ALK fusion gene. Tumors shrank at least 30% in 57% of people treated. Most had adenocarcinoma, and had never smoked or were former smokers. They had undergone treatment with an average of three other drugs prior to receiving crizotinib, and only 10% were expected to respond to standard therapy. They were given 250 mg crizotinib twice daily for a median duration of six months. Approximately 50% of these patients suffered at least one side effect, such as nausea, vomiting, or diarrhea. Some responses to crizotinib have lasted up to 15 months.

A phase 3 trial, PROFILE 1007, compares crizotinib to standard second line chemotherapy (pemetrexed or taxotere) in the treatment of ALK-positive NSCLC. Additionally, a phase 2 trial, PROFILE 1005, studies patients meeting similar criteria who have received more than one line of prior chemotherapy.

On August 26, 2011, the U.S. Food and Drug Administration approved crizotinib (Xalkori) to treat certain late-stage (locally advanced or metastatic) non-small cell lung cancers that express the abnormal anaplastic lymphoma kinase (ALK) gene. Approval required a companion molecular test for the EML4-ALK fusion.

Crizotinib is also being tested in clinical trials of advanced disseminated anaplastic large-cell lymphoma, and neuroblastoma.