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Revision as of 13:01, 7 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,045 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'DrugBank').← Previous edit		Latest revision as of 15:09, 19 August 2024 edit undoQwerfjkl (talk | contribs)Extended confirmed users, Page movers, Rollbackers212,917 editsm Added 1 {{Bare URL inline}} tag(s) using a script. For other recently-tagged pages with bare URLs, see Category:Articles with bare URLs for citations from August 2024
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			{{Short description|Medication used for cancer}}
	{{Redirect|Iressa|the genus of moth|Iressa (moth)}}
			{{For|the genus of moth|Iressa (moth)}}
			{{Use dmy dates|date=November 2022}}
	{{Drugbox		{{Drugbox
			| Watchedfields = changed
	| verifiedrevid = 443833219
			| verifiedrevid = 459450723
	| IUPAC_name = ''N''-(3-chloro-4-fluoro-phenyl)-7-methoxy-<br />6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine
	| image = Gefitinib structure.svg		| image = Gefitinib structure.svg
			| alt =
			| image2 = Gefitinib 3D ball-and-stick 3UG2.png
			| alt2 =
	<!--Clinical data-->		<!--Clinical data-->
			| pronounce = {{IPAc-en|ɡ|ɛ|ˈ|f|ɪ|t|ᵻ|n|ɪ|b}}
	| tradename = Iressa
			| tradename = Iressa, others
	| Drugs.com = {{drugs.com|monograph|gefitinib}}		| Drugs.com = {{drugs.com|monograph|gefitinib}}
	| MedlinePlus = a607002		| MedlinePlus = a607002
			| DailyMedID = Gefitinib
	| pregnancy_category = C <small>(])</small>, D <small>(])</small>
			| pregnancy_AU = C
	| legal_status = S4 <small>(Au)</small>, POM <small>(])</small>, ℞-only <small>(U.S.)</small>
			| pregnancy_category =
	| routes_of_administration = Oral
			| routes_of_administration = ]
			| ATC_prefix = L01
			| ATC_suffix = EB01
			| legal_AU = S4
			| legal_AU_comment = <ref>https://www.tga.gov.au/resources/auspar/auspar-gefitinib {{Bare URL inline|date=August 2024}}</ref>
			| legal_CA = Rx-only
			| legal_CA_comment = <ref>{{cite web | title=Iressa Product information | website=] | date=17 December 2003 | url=https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=73040 | access-date=31 March 2024}}</ref>
			| legal_UK = POM
			| legal_US = Rx-only
			| legal_US_comment = <ref name="Iressa FDA label">{{cite web | title=Iressa- gefitinib tablet, coated | website=DailyMed | date=28 February 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=827d60e8-7e07-41b7-c28b-49ef1c4a5a41 | access-date=31 March 2024}}</ref>
			| legal_EU = Rx-only
			| legal_EU_comment = <ref>{{cite web | title=Iressa EPAR | website=] (EMA) | date=24 June 2009 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/iressa | access-date=31 March 2024}}</ref>
			| legal_status =
	<!--Pharmacokinetic data-->		<!--Pharmacokinetic data-->
	| bioavailability = 59% (oral)		| bioavailability = 59% (oral)
	| protein_bound = 90%		| protein_bound = 90%
	| metabolism = Hepatic (mainly ])		| metabolism = ] (mainly ])
	| elimination_half-life = 6–49 hours		| elimination_half-life = 6–49 hours
	| excretion = Faecal		| excretion = Feces
	<!--Identifiers-->		<!--Identifiers-->
			| IUPHAR_ligand = 4941
	| CASNo_Ref = {{cascite|correct|CAS}}
	| CAS_number_Ref = {{cascite|correct|??}}		| CAS_number_Ref = {{cascite|correct|??}}
	| CAS_number = 184475-35-2		| CAS_number = 184475-35-2
	| ATC_prefix = L01
	| ATC_suffix = XE02
	| PubChem = 123631		| PubChem = 123631
	| DrugBank_Ref = {{drugbankcite|correct|drugbank}}		| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
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	| ChEMBL_Ref = {{ebicite|correct|EBI}}		| ChEMBL_Ref = {{ebicite|correct|EBI}}
	| ChEMBL = 939		| ChEMBL = 939
			| synonyms = ZD1839
	<!--Chemical data-->		<!--Chemical data-->
			| IUPAC_name = ''N''-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine
	| C=22 | H=24 | Cl=1 | F=1 | N=4 | O=3
			| C=22 | H=24 | Cl=1 | F=1 | N=4 | O=3
	| molecular_weight = 446.902 g/mol
	| smiles = COc1cc2c(cc1OCCCN3CCOCC3)c(ncn2)Nc4ccc(c(c4)Cl)F		| smiles = C1COCCN1CCCOc2c(OC)cc3ncnc(c3c2)Nc4cc(Cl)c(F)cc4
	| InChI = 1/C22H24ClFN4O3/c1-29-20-13-19-16(12-21(20)31-8-2-5-28-6-9-30-10-7-28)22(26-14-25-19)27-15-3-4-18(24)17(23)11-15/h3-4,11-14H,2,5-10H2,1H3,(H,25,26,27)
	| InChIKey = XGALLCVXEZPNRQ-UHFFFAOYAI
	| StdInChI_Ref = {{stdinchicite|correct|chemspider}}		| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChI = 1S/C22H24ClFN4O3/c1-29-20-13-19-16(12-21(20)31-8-2-5-28-6-9-30-10-7-28)22(26-14-25-19)27-15-3-4-18(24)17(23)11-15/h3-4,11-14H,2,5-10H2,1H3,(H,25,26,27)		| StdInChI = 1S/C22H24ClFN4O3/c1-29-20-13-19-16(12-21(20)31-8-2-5-28-6-9-30-10-7-28)22(26-14-25-19)27-15-3-4-18(24)17(23)11-15/h3-4,11-14H,2,5-10H2,1H3,(H,25,26,27)
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	| StdInChIKey = XGALLCVXEZPNRQ-UHFFFAOYSA-N		| StdInChIKey = XGALLCVXEZPNRQ-UHFFFAOYSA-N
	}}		}}
	'''Gefitinib''' ] ({{IPAc-en|icon|ɡ|ɛ|ˈ|f|ɪ|t|ɨ|n|ɪ|b}}), trade name '''Iressa''', is a ] used in the treatment of certain types of ], particularly those with mutated and overactive ]. Gefitinib is an ], like ], which interrupts signaling through the epidermal growth factor receptor (EGFR) in target cells. It is marketed by ] and ].		'''Gefitinib''', sold under the brand name '''Iressa''', is a ] used for certain breast, lung and other ]. Gefitinib is an ], like ], which interrupts signaling through the ] (EGFR) in target cells. Therefore, it is only effective in cancers with mutated and overactive EGFR, but resistances to gefitinib can arise through other mutations. It is marketed by ] and ].
			It is on the ].<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref> It is available as a ].<ref>{{cite web | title=First Generic Drug Approvals | website=U.S. ] (FDA) | date=17 October 2022 | url=https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/first-generic-drug-approvals | access-date=28 November 2022}}</ref>
	==Mechanism of action==
	Gefitinib is the first selective inhibitor of ]'s (EGFR) ] domain. Thus gefitinib is an ]. The target protein (EGFR) is also sometimes referred to as Her1 or ErbB-1 depending on the literature source.
			== Mechanism of action ==
	EGFR is overexpressed in the cells of certain types of human ]s - for example in lung and breast cancers. This leads to inappropriate activation of the ], eventually leading to uncontrolled cell proliferation. Research on gefitinib-sensitive ]s has shown that a mutation in the EGFR tyrosine kinase domain is responsible for activating anti-apoptotic pathways.<ref name="Pao2004">{{cite journal
			Gefitinib is the first selective inhibitor of ]'s (EGFR) ] domain. Thus gefitinib is an ]. The target protein (EGFR) is a member of a family of receptors (]) which includes Her1(EGFR), Her2(erb-B2), Her3(erb-B3) and Her4 (Erb-B4).
	| author = Pao W, Miller V, Zakowski M, ''et al.''
			EGFR is overexpressed in the cells of certain types of human ]s - for example in lung and breast cancers. This leads to inappropriate activation of the ], eventually leading to uncontrolled cell proliferation. Research on gefitinib-sensitive ]s has shown that a mutation in the EGFR tyrosine kinase domain is responsible for activating anti-apoptotic pathways.<ref name="Pao2004">{{cite journal | vauthors = Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H | display-authors = 6 | title = EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 36 | pages = 13306–11 | date = September 2004 | pmid = 15329413 | pmc = 516528 | doi = 10.1073/pnas.0405220101 | bibcode = 2004PNAS..10113306P | doi-access = free }}</ref><!--nogap
	| title = EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib
			--><ref name="Sordella2004">{{cite journal | vauthors = Sordella R, Bell DW, Haber DA, Settleman J | title = Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways | journal = Science | volume = 305 | issue = 5687 | pages = 1163–7 | date = August 2004 | pmid = 15284455 | doi = 10.1126/science.1101637 | s2cid = 34389318 | bibcode = 2004Sci...305.1163S }}<!--| access-date = 2009-07-02--></ref> These mutations tend to confer increased sensitivity to tyrosine kinase inhibitors such as gefitinib and erlotinib. Of the types of non-small cell lung cancer histologies, ] is the type that most often harbors these mutations. These mutations are more commonly seen in Asians, women, and non-smokers (who also tend to more often have adenocarcinoma).
	| journal = Proceedings of the National Academy of Sciences of the United States of America
	| volume = 101
	| issue = 36
	| pages = 13306–11
	| year = 2004
	| month = September
	| pmid = 15329413
	| pmc = 516528
	| doi = 10.1073/pnas.0405220101
	| accessdate = 2009-07-02
	}}</ref><!--nogap
	--><ref name="Sordella2004">{{cite journal
	| author = Sordella R, Bell DW, Haber DA, Settleman J
	| title = Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways
	| journal = Science
	| volume = 305
	| issue = 5687
	| pages = 1163–7
	| year = 2004
	| month = August
	| pmid = 15284455
	| doi = 10.1126/science.1101637
	| accessdate = 2009-07-02
	}}</ref> These mutations tend to confer increased sensitivity to tyrosine kinase inhibitors such as gefitinib and erlotinib. Of the types of non-small cell lung cancer histologies, ] is the type that most often harbors these mutations. These mutations are more commonly seen in Asians, women, and non-smokers (who also tend to more often have adenocarcinoma).
	Gefitinib inhibits EGFR tyrosine kinase by binding to the ] (ATP)-binding site of the enzyme. Thus the function of the EGFR tyrosine kinase in activating the ] is inhibited, and malignant cells are inhibited.<ref>Takimoto CH, Calvo E. in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) . 11 ed. 2008.</ref>		Gefitinib inhibits EGFR tyrosine kinase by binding to the ] (ATP)-binding site of the enzyme.<ref>{{cite journal | vauthors = Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA | display-authors = 6 | title = Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib | journal = The New England Journal of Medicine | volume = 350 | issue = 21 | pages = 2129–39 | date = May 2004 | pmid = 15118073 | doi = 10.1056/nejmoa040938 | url = http://repository.cshl.edu/22429/1/EGFR%20Mutations.pdf }}</ref> Thus the function of the EGFR tyrosine kinase in activating the ] is inhibited, and malignant cells are inhibited.<ref>Takimoto CH, Calvo E. {{Webarchive|url=https://web.archive.org/web/20090515221337/http://www.cancernetwork.com/cancer-management-11/chapter03/article/10165/1402628 |date=15 May 2009 }} in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) {{Webarchive|url=https://web.archive.org/web/20131004224102/http://www.cancernetwork.com/cancer-management-11/ |date=4 October 2013 }}. 11 ed. 2008.</ref>
	==Clinical uses==		==Clinical uses==
			Gefitinib is marketed in many countries.{{cn|date=March 2024}}
	FDA approved in May 2003 for ]<ref name=Label2003>http://www.accessdata.fda.gov/drugsatfda_docs/label/2003/021399lbl.pdf</ref>, Gefitinib is currently marketed in over 64 countries.
			Iressa was approved and marketed in July 2002, in Japan, making it the first country to import the drug.{{cn|date=March 2024}}
	In June 2005 the FDA withdrew approval for use in new patients due to lack of evidence that it extended life.<ref>http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm110473.htm </ref>
			The FDA approved gefitinib in May 2003, for ] (NSCLC).<ref name="Iressa FDA label" /> It was approved as monotherapy for the treatment of people with locally advanced or metastatic NSCLC after failure of both platinum-based and docetaxel chemotherapies.<ref name="Iressa FDA label" />
	In Europe gefitinib is indicated since 2009 in advanced NSCLC in all lines of treatment for patients harbouring EGFR mutations.
	This label was granted after gefitinib demonstrated as a first line treatment to significantly improve progression-free survival vs. a platinum doublet regime in patients harbouring such mutations. IPASS has been the first of four phase III trials to have confirmed gefitinib superiority in this patient population.{{fact|date=November 2011}}
			In June 2005, the FDA withdrew approval for use in new patients due to lack of evidence that it extended life.<ref name=FDA-110473>{{cite web |url= https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/gefitinib-marketed-iressa-information |title=Gefitinib (marketed as Iressa) Information | work =U.S. ] (FDA) |date=3 November 2018 }}</ref>
	In most of the other countries where gefitinib is currently marketed it is approved for patients with advanced NSCLC who had received at least one previous chemotherapy regime. However, applications to expand its label as a first line treatment in patients harbouring EGFR mutations is currently in process based on the latest scientific evidence.{{fact|date=November 2011}}
			In the European Union, gefitinib is indicated since 2009 in advanced NSCLC in all ] for patients harbouring EGFR mutations. This label was granted after gefitinib demonstrated as a ] to significantly improve ] vs. a platinum doublet regime in patients harbouring such mutations. IPASS has been the first of four phase III trials to have confirmed gefitinib superiority in this patient population.<ref name=Mok2014>{{cite journal | vauthors = Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M | display-authors = 6 | title = Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma | journal = The New England Journal of Medicine | volume = 361 | issue = 10 | pages = 947–57 | date = September 2009 | pmid = 19692680 | doi = 10.1056/nejmoa0810699 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Sebastian M, Schmittel A, Reck M | title = First-line treatment of EGFR-mutated nonsmall cell lung cancer: critical review on study methodology | journal = European Respiratory Review | volume = 23 | issue = 131 | pages = 92–105 | date = March 2014 | pmid = 24591666 | doi = 10.1183/09059180.00008413 | pmc = 9487257 | doi-access = free }}</ref>
	While gefitinib has yet to be proven to be effective in other cancers, there is potential for its use in the treatment of other cancers where EGFR overexpression is involved.{{fact|date=November 2011}}
			In most of the other countries where gefitinib is marketed it is approved for people with advanced NSCLC who had received at least one previous chemotherapy regime. However, applications to expand its label as a first-line treatment in patients harbouring EGFR mutations is currently in process based on the latest scientific evidence.<ref>{{cite journal | vauthors = Gijtenbeek RG, Damhuis RA, Groen HJ, van der Wekken AJ, van Geffen WH | title = Nationwide Real-world Cohort Study of First-line Tyrosine Kinase Inhibitor Treatment in Epidermal Growth Factor Receptor-mutated Non-small-cell Lung Cancer | language = English | journal = Clinical Lung Cancer | volume = 21 | issue = 6 | pages = e647–e653 | date = November 2020 | pmid = 32636159 | doi = 10.1016/j.cllc.2020.05.019 | s2cid = 219505386 | url = https://research.rug.nl/en/publications/ef0a1944-ddd9-45f4-9e6c-fe91d07935d0 }}</ref><ref>{{cite journal | vauthors = Gijtenbeek RG, Damhuis RA, van der Wekken AJ, Hendriks LE, Groen HJ, van Geffen WH | title = Overall survival in advanced epidermal growth factor receptor mutated non-small cell lung cancer using different tyrosine kinase inhibitors in The Netherlands: a retrospective, nationwide registry study | journal = The Lancet Regional Health. Europe | volume = 27 | pages = 100592 | date = April 2023 | pmid = 36817181 | pmc = 9932646 | doi = 10.1016/j.lanepe.2023.100592 }}</ref> As at August 2012 New Zealand has approved gefitinib as first-line treatment for patients with EGFR mutation for naive locally advanced or metastatic, unresectable NSCLC. This is publicly funded for an initial four-month term and renewal if no progression.<ref>{{cite web | url=http://www.pharmac.govt.nz/2012/07/09/2012.07.10%20gefitinib%20funded.pdf | title=PHARMAC funds new targeted lung cancer drug | publisher=PHARMAC | date=10 July 2012 | access-date=22 January 2017 | type=Media release | archive-date=27 April 2017 | archive-url=https://web.archive.org/web/20170427015928/http://www.pharmac.govt.nz/2012/07/09/2012.07.10%20gefitinib%20funded.pdf | url-status=dead }}</ref>
	(( ] is another EGFR tyrosine kinase inhibitor that has a similar mechanism of action than gefitinib. However, since there is so far little evidence of erlotinib as a first line treatment in NSCLC, its label is currently restricted to patients who have at least received one previous chemotherapy regime. ))
			In July 2015, the FDA approved gefitinib as a first-line treatment for NSCLC.<ref name=FDA-454678>{{cite web|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm454678.htm|title=FDA approves targeted therapy for first-line treatment of patients with a type of metastatic lung cancer|website=U.S. ] (FDA)|access-date=16 December 2019|archive-date=26 January 2018|archive-url=https://web.archive.org/web/20180126103140/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm454678.htm|url-status=dead}}</ref>
			==Experimental uses==
			In August 2013, the ] reported that researchers in ] and ] found, in a small-scale ] of 12 patients, that the effectiveness of ] for treating ] was improved when Gefitinib was also administered.<ref>{{cite news|url=https://www.bbc.co.uk/news/uk-scotland-edinburgh-east-fife-24021956|title=Lung cancer drug 'could help treat ectopic pregnancy'|work=BBC News Online |date=9 September 2013}}</ref>
	==Studies==		==Studies==
	IPASS (IRESSA Pan-Asia Study) was a randomized, large-scale, double-blinded study which compared gefitinib vs. carboplatin/ paclitaxel as a first line treatment in NSCLC.<ref>Mok TS et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Eng J Med 2009; 361. 10.1056/NEJMoa0810699.</ref>		IPASS (IRESSA Pan-Asia Study) was a randomized, large-scale, double-blinded study which compared gefitinib vs. carboplatin/ paclitaxel as a first-line treatment in advanced NSCLC.<ref>{{cite journal | vauthors = Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, Nishiwaki Y, Ohe Y, Yang JJ, Chewaskulyong B, Jiang H, Duffield EL, Watkins CL, Armour AA, Fukuoka M | display-authors = 6 | title = Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma | journal = The New England Journal of Medicine | volume = 361 | issue = 10 | pages = 947–57 | date = September 2009 | pmid = 19692680 | doi = 10.1056/NEJMoa0810699 | doi-access = free }}</ref>
	IPASS studied 1,217 patients with confirmed adenocarnicoma histology which were former or never smokers. A pre-planned sub-group analyses showed that progression-free survival (PFS) was significantly longer for IRESSA than chemotherapy in patients with EGFR mutation positive tumours (HR 0.48, 95 per cent CI 0.36 to 0.64, p less than 0.0001), and significantly longer for chemotherapy than IRESSA in patients with EGFR mutation negative tumours (HR 2.85, 95 per cent CI 2.05 to 3.98, p less than 0.0001).		IPASS studied 1,217 patients with confirmed adenocarcinoma histology who were former or never smokers. A pre-planned sub-group analyses showed that progression-free survival (PFS) was significantly longer for gefitinib than chemotherapy in patients with ''EGFR'' mutation positive tumours (HR 0.48, 95 per cent CI 0.36 to 0.64, p less than 0.0001), and significantly longer for chemotherapy than gefitinib in patients with ''EGFR'' mutation negative tumours (HR 2.85, 95 per cent CI 2.05 to 3.98, p less than 0.0001).
	This, in 2009, was the first time a targeted monotherapy has demonstrated significantly longer PFS than doublet chemotherapy.		This, in 2009, was the first time a targeted monotherapy has demonstrated significantly longer PFS than doublet chemotherapy.
	===EGFR Diagnostic tests===		===EGFR diagnostic tests===
	Genzyme, QIAGEN & other companies make tests to detect EGFR mutations, designed to help predict which lung cancer patients may respond best to some therapies, including gefitinib and erlotinib.		Roche Diagnostics, Genzyme, QIAGEN, Argenomics S.A. & other companies make tests to detect ''EGFR'' mutations, designed to help predict which lung cancer patients may respond best to some therapies, including gefitinib and ].
	The tests examine the genetics of tumors removed for biopsy for mutations that make them susceptible to treatment.		The tests examine the genetics of tumors removed for biopsy for mutations that make them susceptible to treatment.
	The EGFR mutation test may also help AstraZeneca win regulatory approval for use of their drugs as initial therapies. Currently the TK inhibitors are approved for use only after other drugs fail.{{fact|date=November 2011}} In the case of gefitinib, the drug works only in about 10% of patients with advanced non-small cell lung cancer, the most common type of lung cancer.		The ''EGFR'' mutation test may also help AstraZeneca win regulatory approval for use of their drugs as initial therapies. Currently the TK inhibitors are approved for use only after other drugs fail.{{citation needed|date=November 2011}} In the case of gefitinib, the drug works only in about 10% of patients with advanced non-small cell lung cancer, the most common type of lung cancer.
	==Adverse effects==		==Adverse effects==
	As gefitinib is a selective chemotherapeutic agent, its tolerability profile is far superior to previous ] agents. ]s (ADRs) do still occur however, but may be preferable to the fatal consequences of not taking the therapy.		As gefitinib is a selective chemotherapeutic agent, its tolerability profile is better than previous ] agents. ]s (ADRs) are acceptable for a potentially fatal disease.
	] is reported very commonly. Other common adverse effects (≥1% of patients) include: ], nausea, ], ], ], ], skin reactions, ], asymptomatic elevations of ]s, ], ], ].<ref name="AMH2004">Rossi S, editor. ] 2004. Adelaide: Australian Medicines Handbook; 2004. ISBN 0-9578521-4-2.</ref>		]-like rash is reported very commonly. Other common adverse effects (≥1% of patients) include: ], nausea, ], ], ], ], skin reactions, ], asymptomatic elevations of ]s, ], ], ].<ref name="AMH2004">{{cite book | veditors = Rossi S | title = ] | date = 2004 | location = Adelaide | publisher = Australian Medicines Handbook | isbn = 0-9578521-4-2 }}</ref>
	Infrequent adverse effects (0.1–1% of patients) include: ], ]l erosion, aberrant eyelash and hair growth.<ref name="AMH2004" />		Infrequent adverse effects (0.1–1% of patients) include: ], ]l erosion, aberrant eyelash and hair growth.<ref name="AMH2004" />
			== Resistance ==
	Iressa was approved and marketed from July 2002 in Japan, making it the first country to import the drug. Over 800 people have died due to Iressa’s side effects, according to the Health, Labor and Welfare Ministry.
			Gefitinib and other first-generation EGFR inhibitors reversibly bind to the receptor protein, effectively competing for the ATP binding pocket. Secondary mutations can arise that alter the binding site, the most common mutation being ], where a threonine is replaced by a methionine at amino acid position 790, which is in the ligand-binding domain that typically binds ATP.<ref>{{cite journal | vauthors = Tan CS, Gilligan D, Pacey S | title = Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer | journal = The Lancet. Oncology | volume = 16 | issue = 9 | pages = e447–e459 | date = September 2015 | pmid = 26370354 | doi = 10.1016/S1470-2045(15)00246-6 | url = https://www.repository.cam.ac.uk/handle/1810/252502 }}</ref> Threonine 790 is the gatekeeper residue, meaning it is key in determining specificity in the binding pocket. When it is mutated into a methionine, researchers originally hypothesized that it caused drug inhibition due to the steric hindrance of the bulkier methionine that selected for the binding of ATP instead of gefitinib.<ref>{{cite journal | vauthors = Ko B, Paucar D, Halmos B | title = ''EGFR'' T790M: revealing the secrets of a gatekeeper | journal = Lung Cancer: Targets and Therapy| year = 2017 | volume = 8 | pages = 147–159 | pmid = 29070957 | doi = 10.2147/LCTT.S117944 | pmc = 5640399 | doi-access = free }}</ref> As of 2008, the current hypothesized mechanism is that resistance to gefitinib is conveyed by increasing the ATP affinity of EGFR on an enzymatic level, meaning that the protein preferentially binds ATP over gefitinib.<ref>{{cite journal | vauthors = Yun CH, Mengwasser KE, Toms AV, Woo MS, Greulich H, Wong KK, Meyerson M, Eck MJ | display-authors = 6 | title = The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 6 | pages = 2070–5 | date = February 2008 | pmid = 18227510 | doi = 10.1073/pnas.0709662105 | pmc = 2538882 | bibcode = 2008PNAS..105.2070Y | doi-access = free }}</ref>
			In order to combat this acquired resistance to gefitinib and other first-generation inhibitors, researchers have used irreversible EGFR inhibitors like ] or ], called ] (TKIs). These new drugs ] to the ATP binding pocket, so when they are attached to EGFR, they cannot be displaced by ATP.<ref>{{cite journal | vauthors = Kwak EL, Sordella R, Bell DW, Godin-Heymann N, Okimoto RA, Brannigan BW, Harris PL, Driscoll DR, Fidias P, Lynch TJ, Rabindran SK, McGinnis JP, Wissner A, Sharma SV, Isselbacher KJ, Settleman J, Haber DA | display-authors = 6 | title = Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 21 | pages = 7665–70 | date = May 2005 | pmid = 15897464 | doi = 10.1073/pnas.0502860102 | pmc = 1129023 | bibcode = 2005PNAS..102.7665K | doi-access = free }}</ref> Even if the mutated versions of EGFR have a higher affinity for ATP, they will eventually use the irreversible inhibitors as ligands, which effectively shuts down their activity. When enough irreversible ligands have bound to EGFR, proliferation will be halted and apoptosis will be triggered through multiple pathways; for example, Bim can be activated after it is no longer inhibited by ERK, one of the kinases in the EGFR signaling pathway.<ref>{{cite journal | vauthors = O'Reilly LA, Kruse EA, Puthalakath H, Kelly PN, Kaufmann T, Huang DC, Strasser A | title = MEK/ERK-mediated phosphorylation of Bim is required to ensure survival of T and B lymphocytes during mitogenic stimulation | journal = Journal of Immunology | volume = 183 | issue = 1 | pages = 261–9 | date = July 2009 | pmid = 19542438 | pmc = 2950174 | doi = 10.4049/jimmunol.0803853 }}</ref> Even with gefitinib halting progression of NSCLC, the development of the cancer progresses after 9 to 13 months due to acquired resistances like the T790M mutation. These TKIs like dacomitinib extended overall survival by close to a year.<ref>{{cite journal | vauthors = Lavacchi D, Mazzoni F, Giaccone G | title = Clinical evaluation of dacomitinib for the treatment of metastatic non-small cell lung cancer (NSCLC): current perspectives | journal = Drug Design, Development and Therapy| volume = 13 | pages = 3187–3198 | date = 2019 | pmid = 31564835 | pmc = 6735534 | doi = 10.2147/DDDT.S194231 | doi-access = free }}</ref>
	==See also==
	*], another EGFR tyrosine kinase inhibitor that has a similar mechanism of action to gefitinib
	*]
	==References==		== References ==
	{{reflist}}		{{Reflist}}
			== External links ==
			* {{cite web | title=Gefitinib | website=National Cancer Institute | url=https://www.cancer.gov/publications/dictionaries/cancer-drug/def/gefitinib }}
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