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ALK inhibitor for treatment of non-small-cell lung cancer From Wikipedia, the free encyclopedia
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).[2][3][4][5] Crizotinib 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.[6] It also acts as an ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor.[7][8][9]
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| Trade names | Xalkori, others |
| Other names | PF-02341066 1066 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a612018 |
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| Routes of administration | By mouth |
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| Pharmacokinetic data | |
| Bioavailability | 43% |
| Protein binding | 91% |
| Metabolism | Liver (CYP3A4/CYP3A5-mediated) |
| Elimination half-life | 42 hours |
| Excretion | Faeces (63%), urine (22%) |
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| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.166.440 |
| Chemical and physical data | |
| Formula | C21H22Cl2FN5O |
| Molar mass | 450.34 g·mol−1 |
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Crizotinib is indicated 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.[2][3]
It is also indicated for the treatment of unresectable, recurrent, or refractory inflammatory anaplastic lymphoma kinase (ALK)-positive myofibroblastic tumors (IMT).[2][10]
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.[12] The kinase activity of the fusion protein is inhibited by crizotinib.[12] 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.[12][13] The number of new cases of ALK-fusion NSLC is about 9,000 per year in the U.S. and about 45,000 worldwide.[14][15]
ALK mutations are 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.[16]
Crizotinib is thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells.[6][17] Other studies suggest that crizotinib might also act via inhibition of angiogenesis in malignant tumors.[18]
In August 2011, the US Food and Drug Administration (FDA) approved crizotinib to treat certain late-stage (locally advanced or metastatic) non-small cell lung cancers that express the abnormal anaplastic lymphoma kinase (ALK) gene.[4] Approval required a companion molecular test for the EML4-ALK fusion. In March 2016, the FDA approved crizotinib in ROS1-positive non-small cell lung cancer.[19]
In October 2012, the European Medicines Agency (EMA) approved the use of crizotinib to treat non-small cell lung cancers that express the abnormal anaplastic lymphoma kinase (ALK) gene.[3][20]
Crizotinib caused tumors to shrink or stabilize in 90% of 82 patients carrying the ALK fusion gene.[13][14] Tumors shrank at least 30% in 57% of people treated.[14] [21] Most had adenocarcinoma, and had never smoked or were former smokers.[13] 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.[13][22] They were given 250 mg crizotinib twice daily for a median duration of six months.[13] Approximately 50% of these patients had at least one side effect, such as nausea, vomiting, or diarrhea.[22] Some responses to crizotinib have lasted up to 15 months.[22]
A Phase III trial, PROFILE 1007,[23] compares crizotinib to standard second line chemotherapy (pemetrexed or taxotere) in the treatment of ALK-positive NSCLC.[24][15][25] Additionally, a phase 2 trial, PROFILE 1005, studies patients meeting similar criteria who have received more than one line of prior chemotherapy.[15]
In February 2016, the J-ALEX phase III study comparing alectinib with crizotinib ALK-positive metastatic NSCLC was terminated early because an interim analysis showed that progression-free survival was longer with alectinib.[26] These results were confirmed in a 2017 analysis.[27]
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.[28][29][30]
Crizotinib is also being tested in clinical trials of advanced disseminated neuroblastoma.[31]
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