Afatinib (GIOTRIF®) 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 tyrosine kinase inhibitor (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 on or after platinum-based chemotherapy.1
Afatinib’s mechanism of action
Afatinib selectively, potently and irreversibly binds to and blocks EGFR (ErbB1), HER2 (ErbB2) and ErbB4. In doing so, afatinib blocks downstream signalling from all homo- and heterodimers formed by ErbB Family members.2,3 Its irreversible binding differentiates afatinib 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).4 Accordingly, in preclinical studies, afatinib has shown greater inhibitory activity against activating EGFR mutations than reversible EGFR TKIs.3,5
Afatinib, an irreversible ErbB Family blocker
EGFR, epithelial growth factor receptor
Watch 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.6,7
Genetic alterations to members of the ErbB Family, such as mutations or overexpression, have been reported in NSCLC, including in squamous cell carcinoma.8-20 Mutations in ErbB receptor tyrosine kinases can lead to overexpression or overactivation, which results in uncontrolled cell proliferation, inhibition of apoptosis, and promotion of tumour growth and spread.2,4,7,21
- Afatinib (GIOTRIF®) summary of product characteristics - May 2016. Accessed: April 2017.
- Reid A, et al. Eur J Cancer 2007;43(3):481–9.
- Li D, et al. Oncogene 2008;27(34):4702-11.
- Solca F, et al. J Pharmacol Exp Ther 2012;343(2):342–50.
- Cross DA, et al. Cancer Discov 2014;4(9):1046-61.
- 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.