What type of agent is afatinib (tyrosine kinase inhibitor)?

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Afatinib: Drug Classification and Mechanism

Afatinib is a second-generation, irreversible tyrosine kinase inhibitor (TKI) that covalently binds to and inhibits the entire ErbB/HER family of receptors, including EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4). 1

Mechanism of Action

Afatinib irreversibly inhibits tyrosine kinase autophosphorylation by covalently binding to the kinase domains of EGFR, HER2, and HER4, resulting in downregulation of ErbB signaling. 1 This distinguishes it from first-generation EGFR-TKIs (erlotinib, gefitinib) which are reversible inhibitors. 2

Key Pharmacologic Features:

  • Chemical classification: 4-anilinoquinazoline derivative presented as dimaleate salt 1
  • Binding mechanism: Forms irreversible covalent bonds with target kinases, unlike reversible first-generation TKIs 1
  • Target spectrum: Pan-HER family inhibitor affecting EGFR, HER2, and HER4 2
  • Molecular action: Inhibits both autophosphorylation and cellular proliferation in cell lines expressing wild-type EGFR, EGFR exon 19 deletions, exon 21 L858R mutations, and other non-resistant mutations 1

Clinical Classification Context

Afatinib is FDA-approved as a second-generation EGFR tyrosine kinase inhibitor for first-line treatment of metastatic NSCLC with specific EGFR mutations. 2 The NCCN classifies it as a preferred first-line therapy option (Category 1) for patients with sensitizing EGFR mutations including the common exon 19 deletions and L858R mutations. 2

Distinction from Other TKI Generations:

  • First-generation TKIs (erlotinib, gefitinib): Reversible EGFR inhibitors 2
  • Second-generation TKIs (afatinib): Irreversible pan-HER family inhibitors 2
  • Third-generation TKIs (osimertinib): Target both sensitizing mutations and T790M resistance mutation 2

Specific Mutation Activity

Afatinib demonstrates particular efficacy against uncommon EGFR mutations (G719X, S768I, L861Q), where it is recommended as a preferred first-line option alongside osimertinib. 2 Post-hoc analysis of LUX-Lung trials showed response rates of 100% for S768I, 77.8% for G719X, and 56.3% for L861Q mutations. 2

References

2
Guideline

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Dr.Oracle Medical Advisory Board & Editors, 2025

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This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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