Afatinib — Drug Monograph
Brand names: Gilotrif
Drug class: Tyrosine Kinase Inhibitor
Mechanism of Action
Afatinib is an irreversible, covalent pan-ErbB family kinase inhibitor that binds covalently to the ATP-binding site of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4), permanently blocking their kinase activity and downstream RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling. Unlike reversible first-generation EGFR TKIs (erlotinib, gefitinib), afatinib forms an irreversible Michael adduct with cysteine residues (Cys773 of EGFR, Cys805 of HER2), providing sustained target suppression. This broad ErbB blockade is particularly effective against EGFR exon 19 deletions and exon 21 L858R point mutations…
FDA Indications
- First-line treatment of metastatic non-small cell lung cancer (NSCLC) with non-resistant EGFR mutations as detected by an FDA-approved test — specifically exon 19 deletions or exon 21 (L858R) substitution mutations
- Second-line treatment of metastatic, squamous cell carcinoma of the lung progressing after platinum-based chemotherapy
Common Side Effects
- Diarrhea (≥96%; Grade 3 in ~14% — the most common and dose-limiting toxicity)
- Acneiform rash / dermatitis (≥90%; Grade 3 in ~16%)
- Stomatitis / oral mucositis (≥71%)
- Paronychia / nail effects (≥58%)
- Dry skin / xerosis (≥31%)
- Decreased appetite (≥29%)
- Nausea (≥25%)
- Vomiting (≥23%)
- Pruritus (≥21%)
- Epistaxis (≥17%)
- Weight loss (≥17%)
- Conjunctivitis (≥11%)
- Cystitis (≥13%)
- Elevated ALT/AST (≥10%)
Clinical Pearl
The LUX-Lung 3 and LUX-Lung 6 trials established afatinib as a first-line option for common EGFR-mutant NSCLC (exon 19 del and L858R), demonstrating superior PFS vs platinum-based chemotherapy. However, a critical paradigm shift occurred following the FLAURA trial — osimertinib (3rd-generation EGFR TKI) demonstrated superior OS, superior PFS, and improved CNS penetration compared to afatinib/gefitinib, and osimertinib is now the preferred first-line agent for common EGFR mutations at most…
Related Therapies & Mechanisms
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