Crizotinib
Encyclopedia
Crizotinib is an ALK (anaplastic lymphoma kinase
) inhibitor, approved for treatment of some non-small cell lung carcinoma (NSCLC) in the US, 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.
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, which results in constitutive kinase activity that contributes to carcinogenesis. The kinase activity of the fusion protein is also inhibited by crizotinib. . Patients with this gene fusion are typically non-smokers who do not have mutations in the epidermal growth factor receptor
gene (EGFR) or in the KRAS
gene. The number of new cases of ALK-fusion NSLC is about 9,000 per year in the US 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 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 cancer.
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.
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 cancer
s 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
.
Anaplastic lymphoma kinase
Anaplastic lymphoma kinase also known as ALK tyrosine kinase receptor or CD246 is an enzyme that in humans is encoded by the ALK gene.-Function:...
) inhibitor, approved for treatment of some non-small cell lung carcinoma (NSCLC) in the US, and undergoing clinical trials testing its safety and efficacy in anaplastic large cell lymphoma
Anaplastic large cell lymphoma
Anaplastic large-cell lymphoma is a type of non-Hodgkin lymphoma that features in the World Health Organisation classification of lymphomas.Its name derives from anaplasia and large-cell lymphoma.-Signs and symptoms:...
, neuroblastoma
Neuroblastoma
Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 cases per year in the US , and 100 cases per year in the UK . Close to 50 percent of neuroblastoma cases occur in children younger than two years old...
, and other advanced solid tumors in both adults and children.
Mechanism of action and patient population
Crizotinib has an aminopyridine structure, and functions as a protein kinaseProtein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...
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, which results in constitutive kinase activity that contributes to carcinogenesis. The kinase activity of the fusion protein is also inhibited by crizotinib. . Patients with this gene fusion are typically non-smokers who do not have mutations in the epidermal growth factor receptor
Epidermal growth factor receptor
The epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
gene (EGFR) or in the KRAS
KRAS
GTPase KRas also known as V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog and KRAS, is a protein that in humans is encoded by the KRAS gene. Like other members of the Ras family, the KRAS protein is a GTPase and is an early player in many signal transduction pathways...
gene. The number of new cases of ALK-fusion NSLC is about 9,000 per year in the US 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
Neuroblastoma
Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 cases per year in the US , and 100 cases per year in the UK . Close to 50 percent of neuroblastoma cases occur in children younger than two years old...
, a rare form of nervous system cancer that occurs almost exclusively in very young children.
Crizotinib also inhibits the c-Met
C-MET
c-Met is a proto-oncogene that encodes a protein known as hepatocyte growth factor receptor . The hepatocyte growth factor receptor protein possesses tyrosine-kinase activity...
/Hepatocyte Growth Factor receptor (HGFR) tyrosine kinase, which is involved in the oncogenesis of a number of other histological forms of cancer.
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
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
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
Pemetrexed
Pemetrexed is a chemotherapy drug manufactured and marketed by Eli Lilly and Company. Its indications are the treatment of Pleural Mesothelioma as well as non-small cell lung cancer.-History:...
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
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
approved crizotinib (Xalkori) to treat certain late-stage (locally advanced or metastatic) non-small cell lung cancer
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
s that express the abnormal anaplastic lymphoma kinase
Anaplastic lymphoma kinase
Anaplastic lymphoma kinase also known as ALK tyrosine kinase receptor or CD246 is an enzyme that in humans is encoded by the ALK gene.-Function:...
(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
Neuroblastoma
Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 cases per year in the US , and 100 cases per year in the UK . Close to 50 percent of neuroblastoma cases occur in children younger than two years old...
.