crizotinib
{{Short description|ALK inhibitor for treatment of non-small-cell lung cancer}}
{{Use dmy dates|date=March 2024}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 460108174
| image = Crizotinib_fix.svg
| width = 275
| alt =
| caption =
| pronounce =
| tradename = Xalkori, others
| Drugs.com = {{drugs.com|monograph|crizotinib}}
| MedlinePlus = a612018
| DailyMedID = Crizotinib
| pregnancy_AU = D
| pregnancy_category =
| routes_of_administration = By mouth
| ATC_prefix = L01
| ATC_suffix = ED01
| legal_AU = S4
| legal_CA = Rx-only
| legal_UK = POM
| legal_US = Rx-only
| legal_EU = Rx-only
| legal_EU_comment = {{cite web | title=Xalkori EPAR | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/xalkori | access-date=18 April 2021 | archive-date=19 April 2021 | archive-url=https://web.archive.org/web/20210419003103/https://www.ema.europa.eu/en/medicines/human/EPAR/xalkori | url-status=live }}
| legal_status =
| bioavailability = 43%
| protein_bound = 91%
| metabolism = Liver (CYP3A4/CYP3A5-mediated)
| elimination_half-life = 42 hours
| excretion = Faeces (63%), urine (22%)
| IUPHAR_ligand = 4903
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 877399-52-5
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 64310
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 601719
| PubChem = 11626560
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB08700
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 9801307
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 53AH36668S
| KEGG = D09731
| KEGG_Ref = {{keggcite|changed|kegg}}
| synonyms = PF-02341066
1066
| PDB_ligand = VGH
| IUPAC_name = 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine
| C=21 | H=22 | Cl=2 | F=1 | N=5 | O=1
| smiles = C1(=C(C=CC(=C1[C@H](OC2=C(N=CC(=C2)C3=C[N](N=C3)C4CCNCC4)N)C)Cl)F)Cl
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = KTEIFNKAUNYNJU-GFCCVEGCSA-N
}}
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).{{cite web | title=Drug Approval Package: Xalkori Capsules (crizotinib) NDA #202570 | website=U.S. Food and Drug Administration (FDA) | date=27 September 2011 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202570Orig1s000TOC.cfm | access-date=18 April 2021 | archive-date=7 April 2021 | archive-url=https://web.archive.org/web/20210407110925/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202570Orig1s000TOC.cfm | url-status=dead }}{{cite web|url= https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202570Orig1s000SumR.pdf|title= Summary Review for Regulatory Action|date= 26 August 2011|website= U.S. Food and Drug Administration (FDA)|access-date= 19 April 2021|archive-date= 6 April 2021|archive-url= https://web.archive.org/web/20210406185359/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202570Orig1s000SumR.pdf|url-status= dead}} 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.{{ClinicalTrialsGov|NCT00585195|A Study Of Oral PF-02341066, A c-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer}} It also acts as an ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor.{{cite journal | vauthors = Forde PM, Rudin CM | title = Crizotinib in the treatment of non-small-cell lung cancer | journal = Expert Opinion on Pharmacotherapy | volume = 13 | issue = 8 | pages = 1195–201 | date = June 2012 | pmid = 22594847 | doi = 10.1517/14656566.2012.688029 | s2cid = 23715951 }}{{cite journal | vauthors = Roberts PJ | title = Clinical use of crizotinib for the treatment of non-small cell lung cancer | journal = Biologics: Targets and Therapy | volume = 7 | pages = 91–101 | year = 2013 | pmid = 23671386 | pmc = 3643289 | doi = 10.2147/BTT.S29026 | doi-access = free }}{{cite journal | vauthors = Sahu A, Prabhash K, Noronha V, Joshi A, Desai S | title = Crizotinib: A comprehensive review | journal = South Asian Journal of Cancer | volume = 2 | issue = 2 | pages = 91–7 | date = April 2013 | pmid = 24455567 | pmc = 3876666 | doi = 10.4103/2278-330X.110506 | doi-broken-date = 1 November 2024 | doi-access = free }}
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.
It is also indicated for the treatment of unresectable, recurrent, or refractory inflammatory anaplastic lymphoma kinase (ALK)-positive myofibroblastic tumors (IMT).{{cite press release | title=FDA approves crizotinib for ALK-positive inflammatory myofibroblastic tumor | website=U.S. Food and Drug Administration (FDA) | date=14 July 2022 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-crizotinib-alk-positive-inflammatory-myofibroblastic-tumor | access-date=14 July 2022 | archive-date=14 July 2022 | archive-url=https://web.archive.org/web/20220714194811/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-crizotinib-alk-positive-inflammatory-myofibroblastic-tumor | url-status=dead }} {{PD-notice}}
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.{{cite journal | vauthors = Janoueix-Lerosey I, Schleiermacher G, Delattre O | title = Molecular pathogenesis of peripheral neuroblastic tumors | journal = Oncogene | volume = 29 | issue = 11 | pages = 1566–79 | date = March 2010 | pmid = 20101209 | doi = 10.1038/onc.2009.518 | doi-access = free }}
Crizotinib is thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells.{{cite journal | vauthors = Christensen JG, Zou HY, Arango ME, Li Q, Lee JH, McDonnell SR, Yamazaki S, Alton GR, Mroczkowski B, Los G | display-authors = 6 | title = Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma | journal = Molecular Cancer Therapeutics | volume = 6 | issue = 12 Pt 1 | pages = 3314–22 | date = December 2007 | pmid = 18089725 | doi = 10.1158/1535-7163.MCT-07-0365 | doi-access = free }} Other studies suggest that crizotinib might also act via inhibition of angiogenesis in malignant tumors.{{cite journal | vauthors = 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 | display-authors = 6 | title = An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms | journal = Cancer Research | volume = 67 | issue = 9 | pages = 4408–17 | date = May 2007 | pmid = 17483355 | doi = 10.1158/0008-5472.CAN-06-4443 | doi-access = free }}
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. 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.{{cite web|url=http://www.fiercepharma.com/pharma/nice-backs-pfizer-s-xalkori-after-squeezing-out-a-new-discount|title=NICE backs Pfizer's Xalkori after squeezing out a new discount – FiercePharma|date=18 August 2016|access-date=18 August 2016|archive-date=8 August 2020|archive-url=https://web.archive.org/web/20200808151550/https://www.fiercepharma.com/pharma/nice-backs-pfizer-s-xalkori-after-squeezing-out-a-new-discount|url-status=live}}
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.{{cite web|publisher=European Medicines Agency|title=Xalkori - EMEA/H/C/002489 - T/0059|year=2012|url=https://www.ema.europa.eu/documents/product-information/xalkori-epar-product-information_en.pdf|access-date=22 October 2018|archive-date=4 October 2018|archive-url=https://web.archive.org/web/20181004223130/https://www.ema.europa.eu/documents/product-information/xalkori-epar-product-information_en.pdf|url-status=live}}
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.
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,{{cite web | url = http://www.pfizer.com/files/news/asco/crizotinib_fact_sheet.pdf | title = Crizotinib Clinical Trials – Currently Ongoing and/or Enrolling | publisher = Pfizer | work = Fact Sheet | access-date = 16 August 2014 | archive-date = 3 March 2016 | archive-url = https://web.archive.org/web/20160303231640/http://www.pfizer.com/files/news/asco/crizotinib_fact_sheet.pdf | url-status = live }} 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.{{cite news|url=http://www.roche.com/inv-update-2016-02-10b-annex.pdf|title=Chugai's ALK Inhibitor "Alecensa" Trial Stopped Early for Benefit|publisher=Roche|date=February 2016|access-date=8 December 2017|archive-date=18 April 2016|archive-url=https://web.archive.org/web/20160418085455/http://www.roche.com/inv-update-2016-02-10b-annex.pdf|url-status=live}} These results were confirmed in a 2017 analysis.{{cite news|url=https://www.healio.com/hematology-oncology/lung-cancer/news/online/%7Ba97a3d66-e12d-42a5-9b72-4d330b151aaf%7D/fda-approves-alecensa-for-alk--positive-metastatic-non-small-cell-lung-cancer|title=FDA approves Alecensa for ALK-positive metastatic non-small cell lung cancer|publisher=Healio|date=November 2017|access-date=8 December 2017|archive-date=9 December 2017|archive-url=https://web.archive.org/web/20171209044234/https://www.healio.com/hematology-oncology/lung-cancer/news/online/%7Ba97a3d66-e12d-42a5-9b72-4d330b151aaf%7D/fda-approves-alecensa-for-alk--positive-metastatic-non-small-cell-lung-cancer|url-status=live}}
= 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.{{cite journal|vauthors=Gambacorti-Passerini C et al|title=Clinical Activity of Crizotinib In Advanced, Chemoresistant ALK+ Lymphoma Patients|year=2010| journal=Annual Meeting of the American Society of Hematology|location=Orlando, Florida}}{{cite journal | vauthors = Gambacorti-Passerini C, Messa C, Pogliani EM | title = Crizotinib in anaplastic large-cell lymphoma | journal = The New England Journal of Medicine | volume = 364 | issue = 8 | pages = 775–6 | date = February 2011 | pmid = 21345110 | doi = 10.1056/NEJMc1013224 | doi-access = free }}{{cite journal | vauthors = Gambacorti Passerini C, Farina F, Stasia A, Redaelli S, Ceccon M, Mologni L, Messa C, Guerra L, Giudici G, Sala E, Mussolin L, Deeren D, King MH, Steurer M, Ordemann R, Cohen AM, Grube M, Bernard L, Chiriano G, Antolini L, Piazza R | display-authors = 6 | title = Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase-positive lymphoma patients | journal = Journal of the National Cancer Institute | volume = 106 | issue = 2 | pages = djt378 | date = February 2014 | pmid = 24491302 | doi = 10.1093/jnci/djt378 | doi-access = free }}
= Other cancers =
Crizotinib is also being tested in clinical trials of advanced disseminated neuroblastoma.{{cite journal | vauthors = Wood AC, Laudenslager M, Haglund EA, Attiyeh EF, Pawel B, Courtright J, Plegaria J, Christensen JG, Maris JM, Mosse YP | title = Inhibition of ALK mutated neuroblastomas by the selective inhibitor PF-02341066 | journal = J Clin Oncol | year = 2009 | volume = 27 | issue = 15s. suppl; abstr 10008b | pages = 10008b | doi = 10.1200/jco.2009.27.15_suppl.10008b | url = http://meeting.ascopubs.org/cgi/content/short/27/15S/10008b | archive-url = https://archive.today/20140816140343/http://meeting.ascopubs.org/cgi/content/short/27/15S/10008b | url-status = dead | archive-date = 16 August 2014 | url-access = subscription }}
References
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External links
- {{cite web | title=Crizotinib | work=NCI Drug Dictionary | publisher=National Cancer Institute | url=https://www.cancer.gov/publications/dictionaries/cancer-drug/def/crizotinib }}
- {{cite web | title=Crizotinib | website=National Cancer Institute | date=11 October 2011 | url=https://www.cancer.gov/about-cancer/treatment/drugs/crizotinib }}
- {{ClinicalTrialsGov|NCT00585195|A Study Of Oral PF-02341066, A C-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer (PROFILE 1001)}}
- {{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}}
- {{ClinicalTrialsGov|NCT00939770|Crizotinib in Treating Younger Patients With Relapsed or Refractory Solid Tumors or Anaplastic Large Cell Lymphoma}}
- {{ClinicalTrialsGov|NCT01154140|A Clinical Trial Testing The Efficacy Of Crizotinib Versus Standard Chemotherapy Pemetrexed Plus Cisplatin Or Carboplatin In Patients With ALK Positive Non Squamous Cancer Of The Lung (PROFILE 1014)}}
- {{ClinicalTrialsGov|NCT01979536|Brentuximab Vedotin or Crizotinib and Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage II-IV Anaplastic Large Cell Lymphoma}}
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