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 details 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 tumour 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 signalling 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
EGFR, epidermal growth factor receptor; HER, human epidermal growth factor receptor
Watch afatinib's mechanism of action
Watch afatinib’s mechanism of action
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Boehringer Ingelheim. Afatinib (GIOTRIF®): summary of product characteristics (EU). July 2018. https://www.ema.europa.eu/en/documents/product-information/giotrif-epar-product-information_en.pdf (Accessed: August 2019).
Boehringer Ingelheim. Afatinib (GIOTRIF®): summary of product characteristics (US). January 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/201292s014lbl.pdf (Accessed: August 2019).
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*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 see here. Registration conditions differ internationally; please refer to locally approved prescribing information.
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