Afatinib: Difference between revisions

{{Short description|Chemical compound}}

{{distinguish|apatinib}}

| verifiedrevid =

| image = Afatinib2DACS.svg

| image2 = Afatinib 3D ball-and-stick 4G5P.png

| tradename = Gilotrif, Giotrif

| Drugs.com = {{Drugs.com||afatinib}}

| =

| =

| DailyMedID = Afatinib

| routes_of_administration = [[Oral administration|By mouth]]

| ATC_prefix = L01

| ATC_suffix = EB03

| ATC_supplemental =

| legal_US_comment = <ref name = "Gilotrif FDA label" />

| legal_EU = Rx-only

| bioavailability =

| index2_label = as salt

| IUPHAR_ligand = 5667

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

| KEGG = D09724

| KEGG2_Ref = {{keggcite|changed|kegg}}

| KEGG2 = D09733

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

| ChEMBL = 1173655

| IUPAC_name = ''N''-[4-[(3-Chloro-4-fluorophenyl)amino]-7-<nowiki>[[</nowiki>(3''S'')-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide

'''Afatinib''' name '''Gilotrif''' , is a [[non-small cell lung carcinoma]] (NSCLC).<ref name="Spreitzer" /><ref name="Minkovsky" /><ref name="FDA" /> It the [[tyrosine kinase]] [[ |]] /

It is mainly used to treating cases of NSCLC that harbour mutations in the [[epidermal growth factor receptor]] (EGFR) gene.<ref>{{cite journal | vauthors = Vavalà T | title = Role of afatinib in the treatment of advanced lung squamous cell carcinoma | journal = Clinical Pharmacology | volume = 9 | pages = 147–157 | date = 2017 | pmid = 29225480 | pmc = 5709991 | doi = 10.2147/CPAA.S112715 | doi-access = free }}</ref>

It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref>

==Medical uses==

It has received regulatory approval for use as a treatment for non-small cell lung cancer,<ref name = "Gilotrif FDA label" /><ref name = TGA/><ref name =EMC/><ref name = EMA/> although there is emerging evidence to support its use in other cancers such as breast cancer.<ref name = Lin/>

Adverse effects by frequency include:<ref name = "Gilotrif FDA label">{{cite web|title=Gilotrif (afatinib) tablet, film coated | work=DailyMed|publisher=Boehringer Ingelheim Pharmaceuticals, Inc.|date=18 October 2019 |access-date=4 November 2020|url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=fd638e5e-8032-e7ca-0179-95e96ab5d387}}</ref><ref name = TGA>{{cite web|title=Giotrif Afatinib (as afatinib dimaleate)|work=TGA eBusiness Services|publisher=Boehringer Ingelheim Pty Limited|date=7 November 2013|access-date=28 January 2014|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2013-PI-02417-1|format=PDF}}</ref><ref name = EMC>{{cite web|title=Giotrif 20 mg film-coated tablets – Summary of Product Characteristics (SPC)|work=electronic Medicines Compendium|publisher=Boehringer Ingelheim Limited|date=20 January 2014|access-date=28 January 2014|url=http://www.medicines.org.uk/emc/medicine/28353/SPC/Giotrif+20+mg+film-coated+tablets/}}</ref><ref name = EMA>{{cite web|title=Giotrif : EPAR -Product Information|work=European Medicines Agency|publisher=Boehringer Ingelheim International GmbH|date=16 October 2013|access-date=28 January 2014|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002280/WC500152392.pdf}}</ref><ref name = MSR>{{cite web|title=Gilotrif (afatinib) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=28 January 2014|url=http://reference.medscape.com/drug/gilotrif-afatinib-999864#showall}}</ref>

Very common (>10% frequency):

{{div col|colwidth=18em}}

* (>90%)

{{}}

Common (1–10% frequency):

{{div col|colwidth=18em}}

{{}}

Uncommon (0.1-1% frequency):

Like [[lapatinib]] and [[neratinib]], afatinib is a [[ kinase inhibitor]] that also irreversibly inhibits human epidermal growth factor receptor 2 (Her2) and [[epidermal growth factor receptor]] (EGFR) kinases. Afatinib is not only active against EGFR mutations targeted by first generation TKIs like [[erlotinib]] or [[gefitinib]], but also against to these .{{ |date= }} Because of its additional activity against Her2, it is being investigated for breast cancer as well as other EGFR and Her2 driven cancers.<ref name="Minkovsky" />

[[File:Afatinib mechanism.svg|thumb|left|upright=2|Afatinib [[covalent]]ly binds to [[cysteine]] number 797 of the [[epidermal growth factor receptor]] (EGFR) via a [[Michael addition]] ([[IC50|IC₅₀]] = 0.5&nbsp;[[nanomolar|nM]]).<ref>Schubert-Zsilavecz, M, Wurglics, M, ''Neue Arzneimittel Frühjahr 2013''. {{ }}</ref>]]

==Clinical trials==

In March 2010, a Phase III trial in NSCLC patients called ''Lux-Lung 5'' began with this drug.<ref name="LUX-Lung 5" />

Fall 2010 interim results suggested the drug extended [[progression-free survival]] threefold compared to placebo, but did not extend overall survival.<ref name="businesswire" /> In May 2012, the Phase IIb/III trial ''Lux-Lung 1'' came to the same conclusion.<ref name="Miller" />

In January 2015, a Phase III trial in people with NSCLC suggested the drug extended life expectancy in stage IV NSCLC adenocarcinoma with EGFR Mutation type del 19-positive tumors, compared to cisplatin-based chemotherapy by a year (33 months vs. 21 months).<ref>{{cite journal | vauthors = Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O'Byrne K, Feng J, Lu S, Huang Y, Geater SL, Lee KY, Tsai CM, Gorbunova V, Hirsh V, Bennouna J, Orlov S, Mok T, Boyer M, Su WC, Lee KH, Kato T, Massey D, Shahidi M, Zazulina V, Sequist LV | display-authors = 6 | title = Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials | journal = The Lancet. Oncology | volume = 16 | issue = 2 | pages = 141–51 | date = February 2015 | pmid = 25589191 | doi = 10.1016/s1470-2045(14)71173-8 | url = https://eprints.qut.edu.au/95333/1/95333.pdf }}</ref> It also shows strong activity against [[exon]] 18 mutations (particularly G719) and is currently the preferred EGFR-TKI therapy for exon 18 mutations (particularly G719x).<ref>{{cite journal | vauthors = Kobayashi Y, Togashi Y, Yatabe Y, Mizuuchi H, Jangchul P, Kondo C, Shimoji M, Sato K, Suda K, Tomizawa K, Takemoto T, Hida T, Nishio K, Mitsudomi T | display-authors = 6 | title = EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs | journal = Clinical Cancer Research | volume = 21 | issue = 23 | pages = 5305–13 | date = December 2015 | pmid = 26206867 | doi = 10.1158/1078-0432.CCR-15-1046 | doi-access = free }}</ref>{{Verify source|date=September 2016}}

Phase II results for breast cancer that over-expresses the protein [[human epidermal growth factor receptor 2]] (Her2-positive breast cancer) were described as promising by the authors, with 19 of 41 patients achieving benefit from afatinib.<ref name="Lin" /> [[Double-blind]] Phase III trials are under way to confirm or refute this finding. Her2-negative breast cancers showed limited or no response to the drug.<ref name="Schuler" />

== Society and culture ==

=== Brand names ===

{{unreferenced section|date=November 2020}}

In [[Bangladesh]] under the trade name Afanix.

{{reflist|refs=

<ref name="Spreitzer">{{cite journal | vauthors = Spreitzer H | date = 13 May 2008 | title = Neue Wirkstoffe – Tovok | journal = Österreichische Apothekerzeitung | issue = 10/2008 | pages = 498 | language = German }}

<ref name="Minkovsky">{{cite journal | vauthors = Minkovsky N, Berezov A | title = BIBW-2992, a dual receptor tyrosine kinase inhibitor for the treatment of solid tumors | journal = Current Opinion in Investigational Drugs | volume = 9 | issue = 12 | pages = 1336–46 | date = December 2008 | pmid = 19037840 }}</ref>

<ref name="">{{cite |url=://www..////|title= () |date=11 }}</ref>

<ref name="LUX-Lung 5">{{cite web | title=LUX-Lung 5: Afatinib Plus Weekly Paclitaxel Versus Investigator's Choice of Single Agent Chemotherapy Following Afatinib Monotherapy in Non-small Cell Lung Cancer Patients Failing Erlotinib or Gefitinib | website=ClinicalTrials.gov | url=https://www.clinicaltrials.gov/study/NCT01085136 | access-date=2024-08-04}}</ref>

<ref name="businesswire">{{cite press release|url=http://www.businesswire.com/news/home/20101011005810/en/Afatinib-BIBW-2992*-Triples-Progression-Free-Survival|title=Afatinib (BIBW 2992*) Triples Progression Free Survival in Phase III Study in Lung Cancer Patients|publisher=BusinessWire|date=11 October 2010}}</ref>

<ref name="Schuler">{{cite journal | vauthors = Schuler M, Awada A, Harter P, Canon JL, Possinger K, Schmidt M, De Grève J, Neven P, Dirix L, Jonat W, Beckmann MW, Schütte J, Fasching PA, Gottschalk N, Besse-Hammer T, Fleischer F, Wind S, Uttenreuther-Fischer M, Piccart M, Harbeck N | display-authors = 6 | title = A phase II trial to assess efficacy and safety of afatinib in extensively pretreated patients with HER2-negative metastatic breast cancer | journal = Breast Cancer Research and Treatment | volume = 134 | issue = 3 | pages = 1149–59 | date = August 2012 | pmid = 22763464 | pmc = 3409367 | doi = 10.1007/s10549-012-2126-1 }}</ref>

<ref name="Lin">{{cite journal | vauthors = Lin NU, Winer EP, Wheatley D, Carey LA, Houston S, Mendelson D, Munster P, Frakes L, Kelly S, Garcia AA, Cleator S, Uttenreuther-Fischer M, Jones H, Wind S, Vinisko R, Hickish T | display-authors = 6 | title = A phase II study of afatinib (BIBW 2992), an irreversible ErbB family blocker, in patients with HER2-positive metastatic breast cancer progressing after trastuzumab | journal = Breast Cancer Research and Treatment | volume = 133 | issue = 3 | pages = 1057–65 | date = June 2012 | pmid = 22418700 | pmc = 3387495 | doi = 10.1007/s10549-012-2003-y }}</ref>

<ref name="Miller">{{cite journal | vauthors = Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW, Zhou C, Su WC, Wang M, Sun Y, Heo DS, Crino L, Tan EH, Chao TY, Shahidi M, Cong XJ, Lorence RM, Yang JC | display-authors = 6 | title = Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial | journal = The Lancet. Oncology | volume = 13 | issue = 5 | pages = 528–38 | date = May 2012 | pmid = 22452896 | doi = 10.1016/S1470-2045(12)70087-6 }}</ref>

==External links==

{{Commonscat-inline|Afatinib}}

*{{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/afatinib | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Afatinib }}

*{{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/afatinib%20dimaleate | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Afatinib dimaleate }}

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[[Category:Drugs developed by Boehringer Ingelheim]]

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