Crizotinib

Crizotinib

Systematic (IUPAC) name
3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine
Clinical data
Licence data	US FDA:link
Pregnancy cat.	D(US)
Legal status	℞-only (US)
Routes	Oral
Pharmacokinetic data
Half-life	46 hours
Identifiers
CAS number	877399-52-5 N
ATC code	None
PubChem	CID 11626560
DrugBank	DB08700
ChemSpider	9801307 Y
UNII	53AH36668S Y
ChEMBL	CHEMBL601719 Y
Synonyms	PF-02341066 1066
Chemical data
Formula	C21H22Cl2FN5O
Mol. mass	450.337 g/mol
SMILES	eMolecules & PubChem
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
N(what is this?)  (verify)

Crizotinib (Xalkori,^[1] 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.^[2]

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. ^[3] The kinase activity of the fusion protein is also inhibited by crizotinib. ^[3]. 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.^[3][4] The number of new cases of ALK-fusion NSLC is about 9,000 per year in the US and about 45,000 worldwide.^[5][6]

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.^[7]

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.^[8]

Crizotinib is currently thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells.^[8][9] Other studies suggest that Crizotinib may also act via inhibition of angiogenesis in malignant tumors.^[10]

Clinical trials

Crizotinib caused tumors to shrink or stabilize in 90% of 82 patients carrying the ALK fusion gene.^[4][5] Tumors shrank at least 30% in 57% of people treated.^{[5] [11]} Most had adenocarcinoma, and had never smoked or were former smokers.^[4] 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.^[4][12] They were given 250 mg crizotinib twice daily for a median duration of six months.^[4] Approximately 50% of these patients suffered at least one side effect, such as nausea, vomiting, or diarrhea.^[12] Some responses to crizotinib have lasted up to 15 months.^[12]

A phase 3 trial, PROFILE 1007^[13], compares crizotinib to standard second line chemotherapy (pemetrexed or taxotere) in the treatment of ALK-positive NSCLC.^[2][6][14] Additionally, a phase 2 trial, PROFILE 1005, studies patients meeting similar criteria who have received more than one line of prior chemotherapy.^[6]

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.^[1] 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,^[8] and neuroblastoma.^[15]

References

1. ^ ^{a b} FDA approves Xalkori with companion diagnostic for a type of late-stage lung cancer. U.S. Food and Drug Administration.http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm269856.htm
2. ^ ^{a b} ClinicalTrials.gov NCT00932451 An Investigational Drug, PF-02341066, Is Being Studied In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene
3. ^ ^{a b c} "Maintenance Therapy for Non-Small Cell Lung Cancer". MedscapeCME. 2010-05-12. http://cme.medscape.com/viewarticle/720896_transcript. Retrieved 2010-06-07. 
4. ^ ^{a b c d e} "ALK inhibitor crizotinib has high response rate in patients with ALK-positive NSCLC". HemOncToday. 2010-06-05. http://www.hemonctoday.com/article.aspx?rid=65251. Retrieved 2010-06-07. 
5. ^ ^{a b c} Winslow, Ron (2010-06-07). "Advances Come in War on Cancer". The Wall Street Journal. http://online.wsj.com/article/SB10001424052748704002104575291103764336126.html?mod=WSJ_WSJ_US_News_3. Retrieved 2010-06-07. 
6. ^ ^{a b c} "Pfizer Oncology To Present New Clinical Data From Ten Molecules Across Multiple Tumor Types" (Press release). Pfizer Oncology. 2010-05-20. http://media.pfizer.com/files/news/press_releases/2010/asco_curtain_raiser_052010.pdf. Retrieved 2010-06-07. 
7. ^ Janoueix-Lerosey I, Schleiermacher G, Delattre O. Molecular pathogenesis of peripheral neuroblastic tumors. Oncogene 2010;29:1566-79.
8. ^ ^{a b c} http://clinicaltrials.gov/ct2/show/NCT00585195 A Study Of Oral PF-02341066, A c-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer
9. ^ Christensen JG, Zou HY, Arango ME, Li Q, Lee JH, McDonnell SR, Yamazaki S, Alton GR, Mroczkowski B, Los G. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther 2007;6:3314-22.
10. ^ Zou HY, Li Q, Lee JH, Arango ME, et al. (2007). "An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms.". Cancer Res 67 (9): 4408–17. http://cancerres.aacrjournals.org/content/67/9/4408.abstract. 
11. ^ Helwick (2010). "Novel Agent Demonstrates Striking Activity in ALK-positive NSCLC". http://www.ascopost.com/articles/july-2010/novel-agent-demonstrates-striking-activity-in-alk-positive-nsclc.  NB Fig 1.
12. ^ ^{a b c} "Gene-based lung cancer drug shows promise". MSNBC.com. 2010-05-07. http://www.msnbc.msn.com/id/37527542/ns/health-cancer/. Retrieved 2010-06-07. 
13. ^ http://www.pfizer.com/files/news/asco/crizotinib_pf_02341066_1007_trial_bkgder_2010.pdf
14. ^ ClinicalTrials.gov NCT00932893
15. ^ "Inhibition of ALK mutated neuroblastomas by the selective inhibitor PF-02341066.". 2009. http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=35242.