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Crizotinib

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]

Medical uses

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]

Mechanism of action

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

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.[12]

Crizotinib is thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells.[6][13] Other studies suggest that crizotinib might also act via inhibition of angiogenesis in malignant tumors.[14]

Society and culture

Legal status

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.[15]

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][16]

Research

Lung cancer

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. [17] 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 had at least one side effect, such as nausea, vomiting, or diarrhea. Some responses to crizotinib have lasted up to 15 months.

A Phase III trial, PROFILE 1007,[18] 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.

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.[19] These results were confirmed in a 2017 analysis.[20]

Lymphomas

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.[21][22][23]

Other cancers

Crizotinib is also being tested in clinical trials of advanced disseminated neuroblastoma.[24]

External links

References

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  2. Xalkori- crizotinib capsule DailyMed, retrieved 18 April 2021^
  3. Xalkori EPAR European Medicines Agency (EMA), 17 September 2018, retrieved 18 April 2021^
  4. Drug Approval Package: Xalkori Capsules (crizotinib) NDA #202570 U.S. Food and Drug Administration (FDA), 27 September 2011, retrieved 18 April 2021^
  5. Summary Review for Regulatory Action U.S. Food and Drug Administration (FDA), 26 August 2011, retrieved 19 April 2021^
  6. {{ClinicalTrialsGov|NCT00585195|A Study Of Oral PF-02341066, A c-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer}}^
  7. Crizotinib in the treatment of non-small-cell lung cancer Expert Opinion on Pharmacotherapy, June 2012^
  8. Clinical use of crizotinib for the treatment of non-small cell lung cancer Biologics: Targets and Therapy, 2013^
  9. Crizotinib: A comprehensive review South Asian Journal of Cancer, April 2013^
  10. FDA approves crizotinib for ALK-positive inflammatory myofibroblastic tumor U.S. Food and Drug Administration (FDA), 14 July 2022, retrieved 14 July 2022^
  11. 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) Journal of Medicinal Chemistry, September 2011^
  12. Molecular pathogenesis of peripheral neuroblastic tumors Oncogene, March 2010^
  13. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma Molecular Cancer Therapeutics, December 2007^
  14. An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms Cancer Research, May 2007^
  15. NICE backs Pfizer's Xalkori after squeezing out a new discount – FiercePharma 18 August 2016, retrieved 18 August 2016^
  16. Xalkori - EMEA/H/C/002489 - T/0059 European Medicines Agency, 2012, retrieved 22 October 2018^
  17. NB Fig 1. Helwick. Novel Agent Demonstrates Striking Activity in ALK-positive NSCLC 2010^
  18. Crizotinib Clinical Trials – Currently Ongoing and/or Enrolling Fact Sheet, Pfizer, retrieved 16 August 2014^
  19. Chugai's ALK Inhibitor "Alecensa" Trial Stopped Early for Benefit Roche, February 2016, retrieved 8 December 2017^
  20. FDA approves Alecensa for ALK-positive metastatic non-small cell lung cancer Healio, November 2017, retrieved 8 December 2017^
  21. Clinical Activity of Crizotinib In Advanced, Chemoresistant ALK+ Lymphoma Patients Annual Meeting of the American Society of Hematology, 2010^
  22. Crizotinib in anaplastic large-cell lymphoma The New England Journal of Medicine, February 2011^
  23. Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase-positive lymphoma patients Journal of the National Cancer Institute, February 2014^
  24. Inhibition of ALK mutated neuroblastomas by the selective inhibitor PF-02341066 J Clin Oncol, 2009^
  25. <ref name=ClinicalTrial1>^
  26. Maintenance Therapy for Non-Small Cell Lung Cancer MedscapeCME, 12 May 2010, retrieved 7 June 2010^
  27. ALK inhibitor crizotinib has high response rate in patients with ALK-positive NSCLC HemOncToday, 5 June 2010, retrieved 7 June 2010^
  28. Advances Come in War on Cancer The Wall Street Journal, 7 June 2010, retrieved 7 June 2010^
  29. Pfizer Oncology To Present New Clinical Data From Ten Molecules Across Multiple Tumor Types Pfizer Oncology, 20 May 2010, retrieved 7 June 2010^
  30. Gene-based lung cancer drug shows promise NBC News, 7 May 2010, retrieved 7 June 2010^
  31. {{ClinicalTrialsGov|NCT00932893|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}}^