Afatinib* is an irreversible ErbB Family blocker that selectively, potently and irreversibly binds to and blocks EGFR (ErbB1), HER2 (ErbB2) and ErbB4.1,2 This page provides details about afatinib’s licensing and MoA.
Afatinib (GIOTRIF®) is an irreversible tyrosine kinase inhibitor (TKI) that is approved as monotherapy for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations. In most countries, it is restricted to EGFR TKI-naïve patients.
Afatinib is also approved in some countries, including the US and the EU, for the treatment of patients with locally advanced or metastatic NSCLC of squamous histology progressing after (US), or on or after (EU), platinum-based chemotherapy.3,4
Afatinib’s mechanism of action
The ErbB Family of receptors
The ErbB Family of receptors has four members. HER2 (ErbB2) lacks a ligand-binding domain, and is the preferred dimerisation partner for the other receptors. Ligand binding and dimerisation of these receptors activate cell proliferation and survival pathways; this occurs via a number of different homo- and heterodimers. 5,6
Genetic alterations to members of the ErbB Family, such as mutations or overexpression, have been reported in NSCLC, including in squamous cell carcinoma.7-19 Mutations in ErbB receptor tyrosine kinases can lead to overexpression or overactivation, which results in uncontrolled cell proliferation, inhibition of apoptosis, and promotion of tumor growth and spread.1,6,20,21
Afatinib: an irreversible ErbB Family blocker
Afatinib selectively, potently and irreversibly binds to and blocks EGFR (ErbB1), HER2 (ErbB2) and ErbB4. In doing so, afatinib blocks downstream signaling from all homo- and heterodimers formed by ErbB Family members.1,2
Afatinib's ability to block all ErbB Family members differentiates it from first- and third-generation TKIs, and the irreversible nature of its binding differentiates it from first-generation, reversible EGFR TKIs. Afatinib contains an electrophilic group that is able to covalently bind to conserved cysteine residues within the catalytic domains of EGFR (Cys797), HER2 (Cys805), and ErbB4 (Cys803).21 Accordingly, in preclinical studies, afatinib has shown greater inhibitory activity against activating EGFR mutations than reversible EGFR TKIs.2,22
Afatinib's mechanism of action: an irreversible ErbB Family blocker1,2
EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; HER, human epidermal growth factor receptor
Watch afatinib's mechanism of action
Reid A, et al. Eur J Cancer 2007;43(3):481-9.
Li D, et al. Oncogene 2008;27(34):4702-11.
Boehringer Ingelheim. Afatinib (GIOTRIF®): summary of product characteristics (EU). May 2018. https://www.ema.europa.eu/en/documents/product-information/giotrif-epar-product-information_en.pdf (Accessed: September 2020).
Boehringer Ingelheim. Afatinib (GIOTRIF®): summary of product characteristics (US). January 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/201292s014lbl.pdf (Accessed: September 2020).
Yarden Y, et al. Nat Rev Cancer 2012;12(8):553-63.
Hynes NE, et al. Nat Rev Cancer 2005;5(5):341-54.
Cappuzzo F, et al. J Natl Cancer Inst 2005;97(9):643-55.
Hirsch FR, et al. J Clin Oncol 2003;21(20):3798-807.
Dacic S, et al. Am J Clin Pathol 2006;125(6):860-5.
Lopez-Malpartida AV, et al. Lung Cancer 2009;65(1):25-33.
Lee HJ, et al. Lung Cancer 2010;68(3):375-82.
Gately K, et al. Clin Lung Cancer 2014;15(1):58-66.
Hirsch FR. Oncogene 2009;28 (Suppl. 1):S1-3.
Hirsch FR, et al. Oncogene 2009;28 (Suppl. 1):S32-7.
D'Arcangelo M, et al. Future Oncol 2013;9(5):699-711.
Ji H, et al. Proc Natl Acad Sci USA 2006;103(20):7817-22.
Stephens P, et al. Nature 2004;431(7008):525-6.
Yi ES, et al. Mod Pathol 1997;10(2):142-8.
Kan Z, et al. Nature 2010;466(7308):869-73.
Gazdar AF. Cancer Metastasis Rev 2010;29(1):37-48.
Solca F, et al. J Pharmacol Exp Ther 2012;343(2):342-50.
Cross DA, et al. Cancer Discov 2014;4(9):1046-61.
*Afatinib is approved in more than 80 markets, including the EU, Japan, Taiwan and Canada under the brand name GIOTRIF®, in the US under the brand name GILOTRIF® and in India under the brand name Xovoltib®; for the full list, please click here. Registration conditions differ internationally; please refer to locally approved prescribing information.
© 2020 Boehringer Ingelheim International GmbH. All rights reserved.
Page last updated: December 2020
Some links in this area will let you leave Boehringer Ingelheim's site and visit external websites. If not indicated otherwise in the imprint of the external website, the linked sites are not under the control of the Boehringer Ingelheim corporation and no entity of the Boehringer Ingelheim group of companies is responsible for the contents of such linked site or any link contained in such linked site, or any changes or updates to such sites. Neither is any entity of the Boehringer Ingelheim group of companies responsible for webcasting or any other form of transmission received from any linked site. These links are provided to you only as a convenience, and the inclusion of any link does not imply endorsement by the Boehringer Ingelheim group of companies of the site. In particular, Boehringer Ingelheim is not in a position to monitor the linked third party websites completely and permanently for violations of the law. Boehringer Ingelheim therefore accepts no responsibility for the accuracy or any other aspect of the information on this website. Boehringer Ingelheim is liable, if at all, only to the extent that it was aware of illegal content and it was technically possible and reasonable to prevent its use. The data protection declaration for this website does not apply to such linked websites.
Do you want to continue ?Continue