Crizotinib, sold under the brand name Xalkori among others, is an
anti-cancer medication used for the treatment of
non-small cell lung carcinoma (NSCLC).
It acts as an ALK (
anaplastic lymphoma kinase) and ROS1 (
c-ros oncogene 1) inhibitor.
Medical uses
Crizotinib is
indicated
In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...
for the treatment of metastatic non-small cell lung cancer (NSCLC) or relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL) that is ALK-positive.
It is also indicated for the treatment of unresectable, recurrent, or refractory inflammatory anaplastic lymphoma kinase (ALK)-positive myofibroblastic tumors (IMT).
Mechanism of action
![2xp2](https://upload.wikimedia.org/wikipedia/commons/b/b9/2xp2.png)
Crizotinib has an
aminopyridine Aminopyridine may refer to any of several chemical compounds:
* 2-Aminopyridine
* 3-Aminopyridine
3-Aminopyridine is an aminopyridine. It is a colorless solid.
Preparation
3-Aminopyridine is prepared by heating nicotinamide with sodium hypobr ...
structure, and functions as a
protein kinase inhibitor by competitive binding within the
ATP
ATP may refer to:
Companies and organizations
* Association of Tennis Professionals, men's professional tennis governing body
* American Technical Publishers, employee-owned publishing company
* ', a Danish pension
* Armenia Tree Project, non ...
-binding pocket of target kinases. About 4% of patients with
non-small cell lung carcinoma have a
chromosomal
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
rearrangement that generates a
fusion gene between ''
EML4
Echinoderm microtubule-associated protein-like 4 is a protein that in humans is encoded by the ''EML4'' gene.
This protein is involved in cancers when spliced with the anaplastic lymphoma kinase
Anaplastic lymphoma kinase (ALK) also known as A ...
'' ('echinoderm microtubule-associated protein-like 4') and
''ALK'' ('anaplastic lymphoma kinase'), which results in constitutive
kinase
In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
activity that contributes to
carcinogenesis
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...
and seems to drive the
malignant phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
.
[ The kinase activity of the fusion protein is 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
The epidermal growth factor receptor (EGFR; ErbB-1; HER1 in humans) is a transmembrane protein that is a receptor for members of the epidermal growth factor family (EGF family) of extracellular protein ligands.
The epidermal growth factor recept ...
'' gene (EGFR) or in the ''K-Ras
''KRAS'' (Kirsten rat sarcoma virus) is a gene that provides instructions for making a protein called K-Ras, a part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell ...
'' 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 thought to be important in driving the malignant phenotype in about 15% of cases of ]neuroblastoma
Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the neck, chest, abdomen, or spine. Symptoms may include bone pain, a lump in the ...
, a rare form of peripheral nervous system cancer that occurs almost exclusively in very young children.
Crizotinib inhibits the c-Met/ Hepatocyte growth factor receptor (HGFR) tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.
Tyrosine kinases belong to a larger cla ...
, which is involved in the oncogenesis of a number of other histological forms of malignant neoplasms.
Crizotinib is thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells. Other studies suggest that crizotinib might also act via inhibition of angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
in malignant tumors.
Society and culture
Legal status
On August 24, 2011, the U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
approved crizotinib to treat certain late-stage (locally advanced or metastatic) non-small cell lung cancer
Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissue (biology), tissues of the lung. Lung carcinomas derive from tran ...
s that express the abnormal anaplastic lymphoma kinase (ALK) gene. Approval required a companion molecular test for the EML4-ALK fusion. In March 2016, the U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
approved crizotinib in ROS1-positive non-small cell lung cancer.
In October 2012, the European Medicines Agency
The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...
(EMA) approved the use of crizotinib to treat non-small cell lung cancer
Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissue (biology), tissues of the lung. Lung carcinomas derive from tran ...
s that express the abnormal anaplastic lymphoma kinase (ALK) gene.
Research
Lung cancer
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 had at least one side effect, such as nausea, vomiting, or diarrhea.][ Some responses to crizotinib have lasted up to 15 months.][
A Phase III trial, PROFILE 1007,] compares crizotinib to standard second line chemotherapy (pemetrexed
Pemetrexed, sold under the brand name Alimta among others, is a chemotherapy medication for the treatment of pleural mesothelioma and non-small cell lung cancer (NSCLC)..
It is available as a generic medication.
Medical use
In February 2004, t ...
or taxotere
Docetaxel (DTX or DXL), sold under the brand name Taxotere among others, is a chemotherapy medication used to treat a number of types of cancer. This includes breast cancer, head and neck cancer, stomach cancer, prostate cancer and non-small-ce ...
) 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.][
In February 2016, the J-ALEX phase III study comparing ]alectinib
Alectinib (INN, marketed as Alecensa) is an oral drug that blocks the activity of anaplastic lymphoma kinase (ALK) and is used to treat non-small-cell lung cancer (NSCLC). It was developed by Chugai Pharmaceutical Co. Japan, which is part of th ...
with crizotinib ALK-positive metastatic NSCLC was terminated early because an interim analysis showed that progression-free survival was longer with alectinib. These results were confirmed in a 2017 analysis.
Lymphomas
In people affected by relapsed or refractory ALK+ anaplastic large cell lymphoma, crizotinib produced objective response rates ranging from 65% to 90% and 3 year progression free survival rates of 60-75%. No relapse of the lymphoma was ever observed after the initial 100 days of treatment. Treatment must be continued indefinitely at present.
Other cancers
Crizotinib is also being tested in clinical trials of advanced disseminated neuroblastoma
Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the neck, chest, abdomen, or spine. Symptoms may include bone pain, a lump in the ...
.
References
External links
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