Crizotinib

Crizotinib (trade name Xalkori,[1] among others) is an anti-cancer drug acting as an ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor,[2][3][4] approved for treatment of some non-small cell lung carcinoma (NSCLC) in the US and some other countries, 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.[5]

Crizotinib
Clinical data
Trade namesXalkori, Crizonix
Other namesPF-02341066
1066
AHFS/Drugs.comMonograph
MedlinePlusa612018
License data
Pregnancy
category
  • AU: D
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability43%
Protein binding91%
MetabolismHepatic (CYP3A4/CYP3A5-mediated)
Elimination half-life42 hours
ExcretionFaeces (63%), urine (22%)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.166.440
Chemical and physical data
FormulaC21H22Cl2FN5O
Molar mass450.34 g·mol−1
3D model (JSmol)
 NY (what is this?)  (verify)

Mechanism of action
Human anaplastic lymphoma kinase in complex with crizotinib. PDB 2xp2[6]

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.[7] The kinase activity of the fusion protein is inhibited by crizotinib.[7] 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.[7][8] The number of new cases of ALK-fusion NSLC is about 9,000 per year in the U.S. and about 45,000 worldwide.[9][10]

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.[11]

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.[12]

Crizotinib is currently thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells.[12][13] Other studies suggest that crizotinib might also act via inhibition of angiogenesis in malignant tumors.[14]

Approvals and indications

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. In March 2016, the U.S. Food and Drug Administration approved crizotinib in ROS1-positive non-small cell lung cancer.[15]

In October 2012, the European Medicines Agency approved the use of crizotinib (Xalkori) to treat non-small cell lung cancers that express the abnormal anaplastic lymphoma kinase (ALK) gene[16]

Clinical trials

Crizotinib caused tumors to shrink or stabilize in 90% of 82 patients carrying the ALK fusion gene.[8][9] Tumors shrank at least 30% in 57% of people treated.[9] [17] Most had adenocarcinoma, and had never smoked or were former smokers.[8] 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.[8][18] They were given 250 mg crizotinib twice daily for a median duration of six months.[8] Approximately 50% of these patients suffered at least one side effect, such as nausea, vomiting, or diarrhea.[18] Some responses to crizotinib have lasted up to 15 months.[18]

A phase 3 trial, PROFILE 1007,[19] compares crizotinib to standard second line chemotherapy (pemetrexed or taxotere) in the treatment of ALK-positive NSCLC.[5][10][20] Additionally, a phase 2 trial, PROFILE 1005, studies patients meeting similar criteria who have received more than one line of prior chemotherapy.[10]

Crizotinib is also being tested in clinical trials of advanced disseminated anaplastic large-cell lymphoma,[12] and neuroblastoma.[21]

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.[22] These results were confirmed in a 2017 analysis.[23]

Brand names

In Bangladesh it is under the trade name Crizonix.

See also

References
  1. "FDA approves Xalkori with companion diagnostic for a type of late-stage lung cancer". U.S. Food and Drug Administration.
  2. Forde PM, Rudin CM (2012). "Crizotinib in the treatment of non-small-cell lung cancer". Expert Opin Pharmacother. 13 (8): 1195–201. doi:10.1517/14656566.2012.688029. PMID 22594847. S2CID 23715951.
  3. Roberts PJ (2013). "Clinical use of crizotinib for the treatment of non-small cell lung cancer". Biologics. 7: 91–101. doi:10.2147/BTT.S29026. PMC 3643289. PMID 23671386.
  4. Sahu A, Prabhash K, Noronha V, Joshi A, Desai S (2013). "Crizotinib: A comprehensive review". South Asian J Cancer. 2 (2): 91–7. doi:10.4103/2278-330X.110506. PMC 3876666. PMID 24455567.
  5. Clinical trial number NCT00932451 for "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" at ClinicalTrials.gov
  6. Cui JJ, Tran-Dubé M, Shen H, Nambu M, Kung PP, Pairish M, Jia L, Meng J, Funk L, Botrous I, McTigue M, Grodsky N, Ryan K, Padrique E, Alton G, Timofeevski S, Yamazaki S, Li Q, Zou H, Christensen J, Mroczkowski B, Bender S, Kania RS, Edwards MP (2011). "Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK)". J. Med. Chem. 54 (18): 6342–63. doi:10.1021/jm2007613. PMID 21812414.
  7. "Maintenance Therapy for Non-Small Cell Lung Cancer". MedscapeCME. 2010-05-12. Retrieved 2010-06-07.
  8. "ALK inhibitor crizotinib has high response rate in patients with ALK-positive NSCLC". HemOncToday. 2010-06-05. Retrieved 2010-06-07.
  9. Winslow, Ron (2010-06-07). "Advances Come in War on Cancer". The Wall Street Journal. Retrieved 2010-06-07.
  10. "Pfizer Oncology To Present New Clinical Data From Ten Molecules Across Multiple Tumor Types" (PDF) (Press release). Pfizer Oncology. 2010-05-20. Archived from the original (PDF) on 2010-06-12. Retrieved 2010-06-07.
  11. Janoueix-Lerosey I, Schleiermacher G, Delattre O (2010). "Molecular pathogenesis of peripheral neuroblastic tumors". Oncogene. 29 (11): 1566–79. doi:10.1038/onc.2009.518. PMID 20101209.
  12. Clinical trial number NCT00585195 for "A Study Of Oral PF-02341066, A c-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer" at ClinicalTrials.gov
  13. Christensen JG, Zou HY, Arango ME, Li Q, Lee JH, McDonnell SR, Yamazaki S, Alton GR, Mroczkowski B, Los G (2007). "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. 6 (12 Pt 1): 3314–22. doi:10.1158/1535-7163.MCT-07-0365. PMID 18089725.
  14. Zou HY, Li Q, Lee JH, Arango ME, McDonnell SR, Yamazaki S, Koudriakova TB, Alton G, Cui JJ, Kung PP, Nambu MD, Los G, Bender SL, Mroczkowski B, Christensen JG (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. doi:10.1158/0008-5472.CAN-06-4443. PMID 17483355.
  15. "NICE backs Pfizer's Xalkori after squeezing out a new discount - FiercePharma".
  16. European Medicines Agency. Xalkori - EMEA/H/C/002489 - T/0059 [Internet]. 2012. Available from: https://www.ema.europa.eu/documents/product-information/xalkori-epar-product-information_en.pdf
  17. Helwick (2010). "Novel Agent Demonstrates Striking Activity in ALK-positive NSCLC". Archived from the original on 2011-01-28. NB Fig 1.
  18. "Gene-based lung cancer drug shows promise". NBC News. 2010-05-07. Retrieved 2010-06-07.
  19. "Crizotinib Clinical Trials – Currently Ongoing and/or Enrolling" (PDF). Fact Sheet. Pfizer.
  20. Clinical trial number NCT00932893 for "An Investigational Drug, PF-02341066 Is Being Studied Versus Standard Of Care In Patients With Advanced Non-Small Cell Lung Cancer With A Specific Gene Profile Involving The Anaplastic Lymphoma Kinase (ALK) Gene" at ClinicalTrials.gov
  21. Wood AC, Laudenslager M, Haglund EA, Attiyeh EF, Pawel B, Courtright J, Plegaria J, Christensen JG, Maris JM, Mosse YP (2009). "Inhibition of ALK mutated neuroblastomas by the selective inhibitor PF-02341066". J Clin Oncol. 27 (15s. suppl, abstr 10008b): 10008b. doi:10.1200/jco.2009.27.15_suppl.10008b. Archived from the original on 2014-08-16.
  22. Chugai's ALK Inhibitor "Alecensa" Trial Stopped Early for Benefit. Feb 2016
  23. FDA approves Alecensa for ALK-positive metastatic non-small cell lung cancer Nov 2017
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.