Crizotinib: Difference between revisions

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{{Short description|ALK inhibitor for treatment of non-small-cell lung cancer}}

{{Drugbox

| Verifiedfields = changed

| verifiedrevid = 451459840

| Watchedfields = changed

| IUPAC_name = 3-[(1''R'')-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine

| verifiedrevid = 460108174

| image = Crizotinib structure.svg

| 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 = [[Oral administration|By mouth]]

| ATC_prefix = L01

| ATC_suffix = ED01

| legal_AU = S4

| legal_AU_comment = <ref>{{cite web | title=Prescription medicines and biologicals: TGA annual summary 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-and-biologicals-tga-annual-summary-2017 | access-date=31 March 2024}}</ref>

| tradename =

| ~~licence_EU~~ =

| legal_CA = Rx-only

| legal_UK = POM

| licence_US = Crizotinib

| pregnancy_AU =

| pregnancy_US = D

| pregnancy_category =

| legal_AU =

| legal_UK =

| legal_US = Rx-only

| legal_US_comment = <ref name="Xalkori FDA label">{{cite web | title=Xalkori- crizotinib capsule | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2a51b0de-47d6-455e-a94c-d2c737b04ff7 | access-date=18 April 2021 | archive-date=9 October 2021 | archive-url=https://web.archive.org/web/20211009140830/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2a51b0de-47d6-455e-a94c-d2c737b04ff7 | url-status=live }}</ref>

| legal_status =

| legal_EU = Rx-only

| routes_of_administration = Oral

| legal_EU_comment = <ref name="Xalkori EPAR">{{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 }}</ref>

| legal_status =

| bioavailability =

| bioavailability = 43%

| protein_bound =

| protein_bound = 91%

| metabolism =

| metabolism = [[Liver]] ([[CYP3A4]]/[[CYP3A5]]-mediated)

| elimination_half-life = 46 hours

| elimination_half-life = 42 hours

| excretion =

| excretion = Faeces (63%), urine (22%)

| IUPHAR_ligand = 4903

| CAS_number =

| CAS_number_Ref = {{cascite|changed|??}}

| ATC_prefix = none

| CAS_number = 877399-52-5

| ATC_suffix =

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 64310

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 601719

| PubChem = 11626560

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| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 53AH36668S

| KEGG = D09731

| synonyms = PF-02341066<br>1066

| KEGG_Ref = {{keggcite|changed|kegg}}

| synonyms = PF-02341066<br />1066

| PDB_ligand = VGH

| IUPAC_name = 3-[(1''R'')-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

| molecular_weight = 450.337 g/mol

| smiles = C1(=C(C=CC(=C1[C@H](OC2=C(N=CC(=C2)C3=C[N](N=C3)C4CCNCC4)N)C)Cl)F)Cl

| InChI = 1/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

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| 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

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| StdInChIKey = KTEIFNKAUNYNJU-GFCCVEGCSA-N

}}

'''Crizotinib''' (Xalkori,<ref name="Xalkori20110826">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</ref> [[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.<ref name=ClinicalTrial1/>

'''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).<ref name="Xalkori FDA label" /><ref name="Xalkori EPAR" /><ref name="FDA approval package">{{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=live }}</ref><ref>{{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= live}}</ref> Crizotinib inhibits the [[c-Met]]/[[Hepatocyte growth factor receptor]] (HGFR) [[tyrosine kinase]], which is involved in the oncogenesis of a number of other [[histology|histological]] forms of [[malignant]] [[neoplasms]].<ref name='TrialNCT00585195'>{{ClinicalTrialsGov|NCT00585195|A Study Of Oral PF-02341066, A c-Met/Hepatocyte Growth Factor Tyrosine Kinase Inhibitor, In Patients With Advanced Cancer}}</ref> It also acts as an ALK ([[anaplastic lymphoma kinase]]) and ROS1 ([[c-ros oncogene 1]]) inhibitor.<ref name="pmid22594847">{{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 }}</ref><ref name="pmid23671386">{{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 }}</ref><ref name="pmid24455567">{{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 July 2024 | doi-access = free }}</ref>

== 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. <ref name=CME/> The kinase activity of the fusion protein is also inhibited by crizotinib. <ref name=CME/>. 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.<ref name=CME/><ref name=HemOncToday/> The number of new cases of ALK-fusion NSLC is about 9,000 per year in the US and about 45,000 worldwide.<ref name=WSJ/><ref name=PfizerPress/>

== Medical uses ==

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.<ref name='Janoueix'>Janoueix-Lerosey I, Schleiermacher G, Delattre O. Molecular pathogenesis of peripheral neuroblastic tumors. Oncogene 2010;29:1566-79.</ref>

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.<ref name="Xalkori FDA label" /><ref name="Xalkori EPAR" />

It is also indicated for the treatment of unresectable, recurrent, or refractory inflammatory anaplastic lymphoma kinase (ALK)-positive myofibroblastic tumors (IMT).<ref name="Xalkori FDA label" /><ref>{{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=live }} {{PD-notice}}</ref>

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.<ref name='TrialNCT00585195'>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</ref>

== Mechanism of action ==

Crizotinib is currently thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells.<ref name="TrialNCT00585195"/><ref name='ChristensenZou'>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.</ref> Other studies suggest that Crizotinib may also act via inhibition of [[angiogenesis]] in malignant tumors.<ref name='ZouLi'>{{cite journal |url=http://cancerres.aacrjournals.org/content/67/9/4408.abstract |author=Zou HY, Li Q, Lee JH, Arango ME, ''et al''. |title=An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. |journal=Cancer Res |year=2007 |volume=67 |pages=4408–17 |issue=9}}</ref>

[[File:2xp2.png|thumb|Human anaplastic lymphoma kinase in complex with crizotinib. PDB {{PDBe|2xp2}}<ref name="pmid21812414">{{cite journal | vauthors = 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 | display-authors = 6 | title = 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 = Journal of Medicinal Chemistry | volume = 54 | issue = 18 | pages = 6342–63 | date = September 2011 | pmid = 21812414 | doi = 10.1021/jm2007613 }}</ref>]]

Crizotinib has an [[aminopyridine]] structure, and functions as a [[protein kinase]] inhibitor by competitive binding within the [[Adenosine triphosphate|ATP]]-binding pocket of target kinases. About 4% of patients with [[non-small cell lung carcinoma]] have a [[chromosome|chromosomal]] rearrangement that generates a [[fusion gene]] between ''[[EML4]]'' ('echinoderm microtubule-associated protein-like 4') and [[Anaplastic lymphoma kinase|''ALK'']] ('anaplastic lymphoma kinase'), which results in constitutive [[kinase]] activity that contributes to [[carcinogenesis]] and seems to drive the [[malignant]] [[phenotype]].<ref name=CME/> The kinase activity of the fusion protein is inhibited by crizotinib.<ref name=CME/> 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.<ref name=CME/><ref name=HemOncToday/> The number of new cases of [[ALK-fusion NSLC|''ALK''-fusion NSLC]] is about 9,000 per year in the U.S. and about 45,000 worldwide.<ref name=WSJ/><ref name=PfizerPress/>

''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.<ref name='Janoueix'>{{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 }}</ref>

== Clinical trials ==

Crizotinib is thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells.<ref name="TrialNCT00585195"/><ref name='Christensen_2007'>{{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 }}</ref> Other studies suggest that crizotinib might also act via inhibition of [[angiogenesis]] in malignant tumors.<ref name = "Zou_2007">{{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 }}</ref>

== 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 cancer]]s that express the abnormal [[anaplastic lymphoma kinase]] (ALK) gene.<ref name="FDA approval package" /> Approval required a [[companion diagnostic|companion molecular test]] for the [[EML4-ALK fusion]]. In March 2016, the FDA approved crizotinib in [[ROS1]]-positive non-small cell lung cancer.<ref>{{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}}</ref>

In October 2012, the [[European Medicines Agency]] (EMA) approved the use of crizotinib to treat non-small cell [[lung cancer]]s that express the abnormal [[anaplastic lymphoma kinase]] (ALK) gene.<ref name="Xalkori EPAR" /><ref>{{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}}</ref>

== Research ==

=== Lung cancer ===

Crizotinib caused tumors to shrink or stabilize in 90% of 82 patients carrying the ''ALK'' fusion gene.<ref name=HemOncToday/><ref name=WSJ/> Tumors shrank at least 30% in 57% of people treated.<ref name=WSJ/>

<ref>{{cite web |url=http://www.ascopost.com/articles/july-2010/novel-agent-demonstrates-striking-activity-in-alk-positive-nsclc |title=Novel Agent Demonstrates Striking Activity in ALK-positive NSCLC |author=Helwick |year=2010 }} NB Fig 1.</ref>

<ref>{{cite web |url=http://www.ascopost.com/articles/july-2010/novel-agent-demonstrates-striking-activity-in-alk-positive-nsclc |title=Novel Agent Demonstrates Striking Activity in ALK-positive NSCLC |author=Helwick |year=2010 |url-status=dead |archive-url=https://web.archive.org/web/20110128120505/http://www.ascopost.com/articles/july-2010/novel-agent-demonstrates-striking-activity-in-alk-positive-nsclc |archive-date=28 January 2011 }} NB Fig 1.</ref>

Most had adenocarcinoma, and had never smoked or were former smokers.<ref name=HemOncToday/> 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.<ref name=HemOncToday/><ref name=MSNBC/> They were given 250 mg crizotinib twice daily for a median duration of six months.<ref name=HemOncToday/> Approximately 50% of these patients ~~suffered~~ at least one side effect, such as nausea, vomiting, or diarrhea.<ref name=MSNBC/> Some responses to crizotinib have lasted up to 15 months.<ref name=MSNBC/>

Most had adenocarcinoma, and had never smoked or were former smokers.<ref name=HemOncToday/> 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.<ref name=HemOncToday/><ref name=MSNBC/> They were given 250 mg crizotinib twice daily for a median duration of six months.<ref name=HemOncToday/> Approximately 50% of these patients had at least one side effect, such as nausea, vomiting, or diarrhea.<ref name=MSNBC/> Some responses to crizotinib have lasted up to 15 months.<ref name=MSNBC/>

A ~~phase~~ 3 trial, PROFILE 1007<ref>http://www.pfizer.com/files/news/asco/~~crizotinib_pf_02341066_1007_trial_bkgder_2010~~.pdf</ref>, compares crizotinib to standard second line chemotherapy ([[pemetrexed]] or [[taxotere]]) in the treatment of ''ALK''-positive NSCLC.<ref name=ClinicalTrial1/><ref name=PfizerPress/><ref name=ClinicalTrial2/> Additionally, a phase 2 trial, PROFILE 1005, studies patients meeting similar criteria who have received more than one line of prior chemotherapy.<ref name=PfizerPress/>

A Phase III trial, PROFILE 1007,<ref name="urlwww.pfizer.com">{{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 }}</ref> compares crizotinib to standard second line chemotherapy ([[pemetrexed]] or [[taxotere]]) in the treatment of ''ALK''-positive NSCLC.<ref name=ClinicalTrial1/><ref name=PfizerPress/><ref name=ClinicalTrial2/> Additionally, a phase 2 trial, PROFILE 1005, studies patients meeting similar criteria who have received more than one line of prior chemotherapy.<ref name=PfizerPress/>

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.<ref>{{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}}</ref> These results were confirmed in a 2017 analysis.<ref name=FDA2017-11>{{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}}</ref>

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 cancer]]s that express the abnormal [[anaplastic lymphoma kinase]] (ALK) gene.<ref name="Xalkori20110826"/> Approval required a companion molecular test for the EML4-ALK fusion.

=== Lymphomas ===

Crizotinib is also being tested in clinical trials of advanced disseminated [[anaplastic large-cell lymphoma]],<ref name="TrialNCT00585195"/> and [[neuroblastoma]].<ref name='NeuroblastomaTrial'>{{cite web |url=http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=65&abstractID=35242 |title=Inhibition of ALK mutated neuroblastomas by the selective inhibitor PF-02341066. |year=2009 }}</ref>

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.<ref>{{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}}</ref><ref>{{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 }}</ref><ref>{{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 }}</ref>

=== Other cancers ===

==References==

Crizotinib is also being tested in clinical trials of advanced disseminated [[neuroblastoma]].<ref name='NeuroblastomaTrial'>{{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 }}</ref>

{{reflist|2|refs=

<ref name=ClinicalTrial1>{{ClinicalTrialsGov|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</ref>

== References ==

<ref name=CME>{{cite web | url = http://cme.medscape.com/viewarticle/720896_transcript | title = Maintenance Therapy for Non-Small Cell Lung Cancer | date = 2010-05-12 | publisher = MedscapeCME | accessdate = 2010-06-07}}</ref>

{{reflist|refs=

<ref name=HemOncToday>{{cite web | url = http://www.hemonctoday.com/article.aspx?rid=65251 | title = ALK inhibitor crizotinib has high response rate in patients with ALK-positive NSCLC | date = 2010-06-05 | publisher = HemOncToday | accessdate = 2010-06-07}}</ref>

<ref name=ClinicalTrial1>{{ClinicalTrialsGov|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}}</ref>

<ref name=WSJ>{{cite news | url = http://online.wsj.com/article/SB10001424052748704002104575291103764336126.html?mod=WSJ_WSJ_US_News_3 | title = Advances Come in War on Cancer | date = 2010-06-07 | publisher = The Wall Street Journal | accessdate = 2010-06-07 | first=Ron | last=Winslow}}</ref>

<ref name=CME>{{cite web | url = http://cme.medscape.com/viewarticle/720896_transcript | title = Maintenance Therapy for Non-Small Cell Lung Cancer | date = 12 May 2010 | publisher = MedscapeCME | access-date = 7 June 2010 | archive-date = 6 December 2012 | archive-url = https://archive.today/20121206015439/http://cme.medscape.com/viewarticle/720896_transcript | url-status = live }}</ref>

<ref name=PfizerPress>{{cite press release | title = Pfizer Oncology To Present New Clinical Data From Ten Molecules Across Multiple Tumor Types | url = http://media.pfizer.com/files/news/press_releases/2010/asco_curtain_raiser_052010.pdf | publisher = Pfizer Oncology | date = 2010-05-20 | accessdate = 2010-06-07}}</ref>

<ref name=~~MSNBC~~>{{cite web | url = http://www.~~msnbc.msn~~.com/~~id/37527542/ns/health-cancer/~~ | title = ~~Gene-based~~ ~~lung~~ ~~cancer~~ ~~drug~~ ~~shows~~ ~~promise~~ | date = 2010~~-05-07~~ | publisher = ~~MSNBC.com~~ | ~~accessdate~~ = 2010-06-07}}</ref>

<ref name=HemOncToday>{{cite web | url = http://www.hemonctoday.com/article.aspx?rid=65251 | title = ALK inhibitor crizotinib has high response rate in patients with ALK-positive NSCLC | date = 5 June 2010 | publisher = HemOncToday | access-date = 7 June 2010 | archive-date = 6 April 2020 | archive-url = https://web.archive.org/web/20200406034739/http://www.hemonctoday.com/article.aspx?rid=65251 | url-status = live }}</ref>

<ref name=WSJ>{{cite news | url = https://www.wsj.com/articles/SB10001424052748704002104575291103764336126?mod=WSJ_WSJ_US_News_3 | title = Advances Come in War on Cancer | date = 7 June 2010 | publisher = The Wall Street Journal | access-date = 7 June 2010 | vauthors = Winslow R | archive-date = 9 October 2021 | archive-url = https://web.archive.org/web/20211009140831/https://www.wsj.com/articles/SB10001424052748704002104575291103764336126?mod=WSJ_WSJ_US_News_3 | url-status = live }}</ref>

<ref name=ClinicalTrial2>{{ClinicalTrialsGov|NCT00932893}}</ref>

<ref name=PfizerPress>{{cite press release | title = Pfizer Oncology To Present New Clinical Data From Ten Molecules Across Multiple Tumor Types | url = http://media.pfizer.com/files/news/press_releases/2010/asco_curtain_raiser_052010.pdf | publisher = Pfizer Oncology | date = 20 May 2010 | access-date = 7 June 2010 | url-status = dead | archive-url = https://web.archive.org/web/20100612203421/http://media.pfizer.com/files/news/press_releases/2010/asco_curtain_raiser_052010.pdf | archive-date = 12 June 2010 }}</ref>

<ref name=MSNBC>{{cite web | url = http://www.nbcnews.com/id/37527542 | title = Gene-based lung cancer drug shows promise | date = 7 May 2010 | work = NBC News | access-date = 7 June 2010}}{{dead link|date=August 2024|bot=medic}}{{cbignore|bot=medic}}</ref>

<ref name=ClinicalTrial2>{{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}}</ref>

}}

== 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}}

[[Category:Non-receptor tyrosine kinase inhibitors]]

[[Category:Organochlorides]]

[[Category:Organofluorides]]

[[Category:Pyridines]]

[[Category:Pfizer]]

[[Category:Pyrazoles]]

[[Category:Piperidines]]

[[Category:Chloroarenes]]

[[pt:Crizotinib]]

[[Category:CYP3A4 inhibitors]]

[[Category:Fluoroarenes]]

[[Category:Aminopyridines]]

[[Category:Drugs developed by Pfizer]]

[[Category:Drugs developed by Merck]]

[[Category:Pyrazoles]]

[[Category:4-Piperidinyl compounds]]

[[Category:Receptor tyrosine kinase inhibitors]]

[[Category:Ethers]]