GIOTRIF 30 mg

Indications

• Non-small cell lung cancer (NSCLC) with EGFR mutations
• Locally advanced or metastatic NSCLC after progression on prior chemotherapy
• First-line treatment for metastatic NSCLC with common EGFR mutations

Dosage

Children: Safety and efficacy in paediatric patients have not been established; refer to the BNF for Children for specific dosing recommendations.

Adults: The recommended starting dose of Afatinib for adults is 40 mg once daily, which may be increased to 50 mg once daily based on tolerability and clinical response.

Mechanism of action

Afatinib irreversibly binds to the tyrosine kinase domain of the EGFR family, inhibiting phosphorylation and subsequent activation of the receptor. This leads to a downstream blockade of signaling pathways involved in cell growth, proliferation, and survival, particularly the MAPK and PI3K-AKT pathways, resulting in reduced tumor growth.

Pharmacodynamics

The pharmacodynamic effects of Afatinib manifest as reduced tumor cell proliferation and enhanced apoptosis in cancer cells that express activating mutations of EGFR. The drug has been shown to improve progression-free survival in patients with EGFR mutation-positive NSCLC compared to standard chemotherapy. Common side effects include diarrhea, rash, and stomatitis, which are indicative of its mechanism of action on epithelial tissues.

Pharmacokinetics

Afatinib is well absorbed following oral administration, with peak plasma concentrations occurring approximately 2 to 5 hours post-dose. Its bioavailability is approximately 100%, and it has a mean elimination half-life of about 37 hours. Afatinib is extensively metabolized in the liver, predominantly by CYP3A4 and UGT1A1 pathways, with excretion occurring primarily through feces. Due to its long half-life, it is typically administered once daily.

Adverse effects

• diarrhoea
• dizziness
• haemorrhage
• headache
• increased liver enzymes
• skin reactions

Interactions

• calcium channel blockers (increases exposure)
• ciclosporin (increases exposure)
• ivacaftor (increases exposure)
• lapatinib (increases exposure)
• macrolides (increases exposure)
• neratinib (increases exposure)
• ranolazine (increases exposure)
• rucaparib (increases exposure)
• St. John's wort (decreases exposure)
• tacrolimus (increases exposure)

Precautions

• Caution in patients with cardiac risk factors
• Monitor cardiac ejection fraction at baseline and during treatment
• Consider alternative treatment options in patients at high risk for thromboembolic disease
• Protect skin from sun exposure due to risk of skin cancer
• Monitor for signs and symptoms of infection, especially in patients at increased risk

Pregnancy

Avoid use during pregnancy due to potential risk to the fetus; seek advice regarding reproductive health.

Breast-feeding

Avoid breastfeeding during treatment and for 2 days after the last dose, as it may be present in breast milk.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Afatinib 40 mg oral tablet
• Afatinib 30 mg oral tablet
• Afatinib 20 mg oral tablet
• Afatinib 50 mg oral tablet

Mechanism of action

Afatinib is a potent and selective, irreversible ErbB family blocker. Afatinib covalently binds to and irreversibly blocks signaling from all homo and heterodimers formed by the ErbB family members EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4. In particular, afatinib covalently binds to the kinase domains of EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in downregulation of ErbB signaling. Certain mutations in EGFR, including non-resistant mutations in its kinase domain, can result in increased autophosphorylation of the receptor, leading to receptor activation, sometimes in the absence of ligand binding, and can support cell proliferation in NSCLC. Non-resistant mutations are defined as those occurring in exons constituting the kinase domain of EGFR that lead to increased receptor activation and where efficacy is predicted by 1) clinically meaningful tumor shrinkage with the recommended dose of afatinib and/or 2) inhibition of cellular proliferation or EGFR tyrosine kinase phosphorylation at concentrations of afatinib sustainable at the recommended dosage according to validated methods. The most commonly found of these mutations are exon 21 L858R substitutions and exon 19 deletions. Moreover, afatinib demonstrated inhibition of autophosphorylation and/or in vitro proliferation of cell lines expressing wild-type EGFR and in those expressing selected EGFR exon 19 deletion mutations, exon 21 L858R mutations, or other less common non-resistant mutations, at afatinib concentrations achieved in patients. In addition, afatinib inhibited in vitro proliferation of cell lines overexpressing HER2.

Pharmacodynamics

Aberrant ErbB signaling triggered by receptor mutations, and/or amplification, and/or receptor ligand overexpression contributes to the malignant phenotype. Mutation in EGFR defines a distinct molecular subtype of lung cancer. In non-clinical disease models with ErbB pathway deregulation, afatinib as a single agent effectively blocks ErbB receptor signaling resulting in tumor growth inhibition or tumor regression. NSCLC tumors with common activating EGFR mutations (Del 19, L858R) and several less common EGFR mutations in exon 18 (G719X) and exon 21 (L861Q) are particularly sensitive to afatinib treatment in non-clinical and clinical settings. Limited non-clinical and/or clinical activity was observed in NSCLC tumors with insertion mutations in exon 20. The acquisition of a secondary T790M mutation is a major mechanism of acquired resistance to afatinib and gene dosage of the T790M-containing allele correlates with the degree of resistance in vitro. The T790M mutation is found in approximately 50% of patients' tumors upon disease progression on afatinib, for which T790M targeted EGFR TKIs may be considered as a next line treatment option. Other potential mechanisms of resistance to afatinib have been suggested preclinically and MET gene amplification has been observed clinically. At the same time, the effect of multiple doses of afatinib (50 mg once daily) on cardiac electrophysiology and the QTc interval was evaluated in an open-label, single-arm study in patients with relapsed or refractory solid tumors. Ultimately, no large changes in the mean QTc interval (i.e., >20 ms) were detected in the study.