Thursday 10 June 2010
Pfizer drug crizotinib, PF-02341066, Xalkori
Molecular target: ALK
Definition: Crizotinib (also known as PF-02341066 or 1066), is an ALK (anaplastic lymphoma kinase) inhibitor (see ALK inhibitors) being developed by Pfizer Incorporated.
Crizotinib (Xalkori, Pfizer), is an ALK inhibitor(anaplastic lymphoma kinase) and ROS1 inhibitor (c-ros oncogene1, receptor tyrosine kinase) , approved for treatment of some non-small cell lung carcinoma (NSCLC) in the US.
It is undergoing clinical trials testing its safety and efficacy in anaplastic large cell lymphoma, neuroblastoma, and other advanced solid tumors in both adults and children
Crizotinib is currently undergoing clinical trials for its potential to treat advanced non-small cell lung carcinoma (NSCLC), a type of lung cancer.
Crizotinib is an oral ALK (anaplastic lymphoma kinase) inhibitor under study in patients with advanced NSCLC carrying the echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) fusion gene.
The protein product of this fusion has constitutive kinase activity that is carcinogenic. Crizotinib competes with ATP for the ALK kinase domain of this fusion protein.
Crizotinib (Xalkori, Pfizer), 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.
Mechanism of action and patient population
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, 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.
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.
The ELM4-ALK fusion transcript was first described in a 2007 study published in Nature. Not all patients with lung cancer or NSCLC carry the ELM4-ALK fusion.
Patients with this gene inversion are typically non-smokers who do not have mutations in the epidermal growth factor receptor gene (EGFR) or mutations in the KRAS gene.
Approximately 4% of the 220,000 Americans diagnosed with lung cancer each year have the ALK fusion gene, and 45,000 newly diagnosed NSCLC patients are ALK positive worldwide.