Crizotinib

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Crizotinib
Names
Trade namesXalkori, others
Other namesPF-02341066
1066
  • 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine
Clinical data
Drug classReceptor tyrosine kinase (RTK) inhibitor[1]
Main usesNon-small cell lung carcinoma (NSCLC)[1]
Side effectsVision problems, nausea, diarrhea, swelling, liver problems, dizziness, nerve pain, tiredness[1]
Pregnancy
category
  • AU: D
Routes of
use		By mouth
Typical dose250 mg BID[1]
External links
AHFS/Drugs.comMonograph
MedlinePlusa612018
Legal
License data
Legal status
Pharmacokinetics
Bioavailability43%
Protein binding91%
MetabolismLiver (CYP3A4/CYP3A5-mediated)
Elimination half-life42 hours
ExcretionFaeces (63%), urine (22%)
Chemical and physical data
FormulaC21H22Cl2FN5O
Molar mass450.34 g·mol−1
3D model (JSmol)
  • C1(=C(C=CC(=C1[C@H](OC2=C(N=CC(=C2)C3=C[N](N=C3)C4CCNCC4)N)C)Cl)F)Cl
  • 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 checkY
  • Key:KTEIFNKAUNYNJU-GFCCVEGCSA-N checkY

Crizotinib, sold under the brand name Xalkori among others, is a medication used to treat non-small cell lung carcinoma (NSCLC).[1] Specifically it is used for advanced disease that is ALK-positive or ROS1-positive.[1] It is taken by mouth.[1]

Common side effects include vision problems, nausea, diarrhea, swelling, liver problems, dizziness, nerve pain, and tiredness.[1] Other side effects may include pneumonitis, low white blood cells, and QT prolongation.[1] Use in pregnancy may harm the baby.[2] It is a receptor tyrosine kinase (RTK) inhibitor.[1]

Crizotinib was approved for medical use in the United States in 2011 and Europe in 2012.[2][1] In the United Kingdom a month of medication costs the NHS about £4,700 as of 2021.[3] This amount in the United States is about 19,400 USD.[4]

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][1]

Dosage

It is typically taken at a dose of 250 mg twice per day.[1] A dose of 200 mg twice per day or 250 mg once per day may be used if certain side effects occur.[1]

Side effects

Severe ulcerations of the esophagus.

In terms of the adverse effects of the medication Crizotinib we find the following: swelling of the face, arms, body aches or pain, chest pain, chills, constipation, cough, diarrhea, double vision, headache, irregular heartbeat, loss of appetite, night blindness, pain in the back of throat when swallowing, pale skin, recurrent fainting, sneezing, sores or ulcers inside the mouth, tunnel vision (this list is by no means complete.[5]
Side effects that are not as common include [5]

  • Confusion
  • Dry mouth
  • Increased appetite
  • Repeated urination
  • Itching

Mechanism of action

Crizotinib metabolism and drug targets with links to candidate genes[6]
Human anaplastic lymphoma kinase in complex with crizotinib. PDB 2xp2[7]

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.[8] The kinase activity of the fusion protein is inhibited by crizotinib.[8] 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.[8][9] The number of new cases of ALK-fusion NSLC is about 9,000 per year in the U.S. and about 45,000 worldwide.[10][11]

It is an anti-cancer medication acting as an ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor.[12][13][14]

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.[15]

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.[16]

Crizotinib is currently thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells.[16][17] Other studies suggest that crizotinib might also act via inhibition of angiogenesis in malignant tumors.[18]

History

On August 24, 2011, the U.S. Food and Drug Administration 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.[19] 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.[20]

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.[1][21]

Research

Lung cancer

Crizotinib caused tumors to shrink or stabilize in 90% of 82 patients carrying the ALK fusion gene.[9][10] Tumors shrank at least 30% in 57% of people treated.[10] [22] Most had adenocarcinoma, and had never smoked or were former smokers.[9] 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.[9][23] They were given 250 mg crizotinib twice daily for a median duration of six months.[9] Approximately 50% of these patients suffered at least one side effect, such as nausea, vomiting, or diarrhea.[23] Some responses to crizotinib have lasted up to 15 months.[23]

A Phase III trial, PROFILE 1007,[24] compares crizotinib to standard second line chemotherapy (pemetrexed or taxotere) in the treatment of ALK-positive NSCLC.[25][11][26] Additionally, a phase 2 trial, PROFILE 1005, studies patients meeting similar criteria who have received more than one line of prior chemotherapy.[11]

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.[27] These results were confirmed in a 2017 analysis.[28]

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.[29][30][31]

Other cancers

Crizotinib is also being tested in clinical trials of advanced disseminated neuroblastoma.[32]

See also

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 "Xalkori EPAR". European Medicines Agency (EMA). Archived from the original on 19 April 2021. Retrieved 18 April 2021.
  2. ↑ 2.0 2.1 2.2 2.3 "Xalkori- crizotinib capsule". DailyMed. Archived from the original on 9 October 2021. Retrieved 18 April 2021.
  3. ↑ BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 1019. ISBN 978-0857114105.
  4. ↑ "Xalkori Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 17 December 2019. Retrieved 7 January 2022.
  5. ↑ 5.0 5.1 "Crizotinib Side Effects: Common, Severe, Long Term". Drugs.com. Archived from the original on 6 November 2020. Retrieved 8 October 2021.
  6. ↑ "Crizotinib Pathway, Pharmacokinetics/Pharmacodynamics". PharmGKB. Retrieved 1 March 2024.
  7. ↑ Cui JJ, Tran-Dubé M, Shen H, Nambu M, Kung PP, Pairish M, et al. (September 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)". Journal of Medicinal Chemistry. 54 (18): 6342–63. doi:10.1021/jm2007613. PMID 21812414.
  8. ↑ 8.0 8.1 8.2 "Maintenance Therapy for Non-Small Cell Lung Cancer". MedscapeCME. 2010-05-12. Archived from the original on 2012-12-06. Retrieved 2010-06-07.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 "ALK inhibitor crizotinib has high response rate in patients with ALK-positive NSCLC". HemOncToday. 2010-06-05. Archived from the original on 2020-04-06. Retrieved 2010-06-07.
  10. ↑ 10.0 10.1 10.2 Winslow R (2010-06-07). "Advances Come in War on Cancer". The Wall Street Journal. Archived from the original on 2021-10-09. Retrieved 2010-06-07.
  11. ↑ 11.0 11.1 11.2 "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.
  12. ↑ Forde PM, Rudin CM (June 2012). "Crizotinib in the treatment of non-small-cell lung cancer". Expert Opinion on Pharmacotherapy. 13 (8): 1195–201. doi:10.1517/14656566.2012.688029. PMID 22594847. S2CID 23715951.
  13. ↑ 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.
  14. ↑ Sahu A, Prabhash K, Noronha V, Joshi A, Desai S (April 2013). "Crizotinib: A comprehensive review". South Asian Journal of Cancer. 2 (2): 91–7. doi:10.4103/2278-330X.110506. PMC 3876666. PMID 24455567.
  15. ↑ Janoueix-Lerosey I, Schleiermacher G, Delattre O (March 2010). "Molecular pathogenesis of peripheral neuroblastic tumors". Oncogene. 29 (11): 1566–79. doi:10.1038/onc.2009.518. PMID 20101209.
  16. ↑ 16.0 16.1 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
  17. ↑ Christensen JG, Zou HY, Arango ME, Li Q, Lee JH, McDonnell SR, et al. (December 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". Molecular Cancer Therapeutics. 6 (12 Pt 1): 3314–22. doi:10.1158/1535-7163.MCT-07-0365. PMID 18089725.
  18. ↑ Zou HY, Li Q, Lee JH, Arango ME, McDonnell SR, Yamazaki S, et al. (May 2007). "An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms". Cancer Research. 67 (9): 4408–17. doi:10.1158/0008-5472.CAN-06-4443. PMID 17483355.
  19. ↑ "Drug Approval Package: Xalkori Capsules (crizotinib) NDA #202570". U.S. Food and Drug Administration (FDA). 27 September 2011. Archived from the original on 7 April 2021. Retrieved 18 April 2021.
  20. ↑ "NICE backs Pfizer's Xalkori after squeezing out a new discount - FiercePharma". Archived from the original on 2020-08-08. Retrieved 2021-09-28.
  21. ↑ "Xalkori - EMEA/H/C/002489 - T/0059" (PDF). European Medicines Agency. 2012. Archived (PDF) from the original on 2018-10-04. Retrieved 2021-09-28.
  22. ↑ Helwick (2010). "Novel Agent Demonstrates Striking Activity in ALK-positive NSCLC". Archived from the original on 2011-01-28. NB Fig 1.
  23. ↑ 23.0 23.1 23.2 "Gene-based lung cancer drug shows promise". NBC News. 2010-05-07. Retrieved 2010-06-07.
  24. ↑ "Crizotinib Clinical Trials – Currently Ongoing and/or Enrolling" (PDF). Fact Sheet. Pfizer. Archived (PDF) from the original on 2016-03-03. Retrieved 2021-09-28.
  25. ↑ 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
  26. ↑ 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
  27. ↑ "Chugai's ALK Inhibitor "Alecensa" Trial Stopped Early for Benefit" (PDF). Roche. February 2016. Archived from the original (PDF) on 2016-04-18. Retrieved 2021-09-28.
  28. ↑ "FDA approves Alecensa for ALK-positive metastatic non-small cell lung cancer". Healio. November 2017. Archived from the original on 2017-12-09. Retrieved 2021-09-28.
  29. ↑ Gambacorti-Passerini C, et al. (2010). "Clinical Activity of Crizotinib In Advanced, Chemoresistant ALK+ Lymphoma Patients". Annual Meeting of the American Society of Hematology. Orlando, Florida.
  30. ↑ Gambacorti-Passerini C, Messa C, Pogliani EM (February 2011). "Crizotinib in anaplastic large-cell lymphoma". The New England Journal of Medicine. 364 (8): 775–6. doi:10.1056/NEJMc1013224. PMID 21345110.
  31. ↑ Gambacorti Passerini C, Farina F, Stasia A, Redaelli S, Ceccon M, Mologni L, et al. (February 2014). "Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase-positive lymphoma patients". Journal of the National Cancer Institute. 106 (2): djt378. doi:10.1093/jnci/djt378. PMID 24491302.
  32. ↑ 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.

External links

External sites:
Identifiers:
  • "Crizotinib". NCI Drug Dictionary. National Cancer Institute. Archived from the original on 2020-11-11. Retrieved 2021-09-28.
  • "Crizotinib". National Cancer Institute. Archived from the original on 2021-07-09. Retrieved 2021-09-28.
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