Afatinib

Afatinib is a potent, selective and irreversible blocker of the ErbB family of receptor tyrosine kinases. Certain mutations in the kinase domain of the epidermal growth factor receptor (EGFR) keep the receptor switched on, sometimes without any bound ligand, and support the growth of non-small cell lung cancer cells. Afatinib binds covalently to these receptors and shuts down their signalling.

Mechanism of Action

• Irreversible ErbB blockade: afatinib binds covalently to the kinase domains and irreversibly blocks signalling from all homo- and heterodimers formed by EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4, inhibiting tyrosine kinase autophosphorylation.
• Sensitive mutations: lung tumours with the common activating EGFR mutations (exon 19 deletions and the exon 21 L858R substitution) and with several less common ones (exon 18 G719X, exon 21 L861Q) are particularly sensitive. Activity against exon 20 insertion mutations is limited.
• Non-clinical activity: in disease models with a deregulated ErbB pathway, afatinib alone blocked ErbB signalling and caused tumour growth inhibition or regression. It also inhibited proliferation of cell lines overexpressing HER2.
• Acquired resistance: a secondary T790M mutation is a major mechanism, found in about 50% of tumours that progress on afatinib; EGFR inhibitors that target T790M may then be considered as the next treatment. MET gene amplification has also been observed clinically.

Pharmacokinetics

• Absorption: peak plasma levels about 2 to 5 hours after a dose; exposure rises slightly more than in proportion to dose between 20 and 50 mg. A high-fat meal lowers Cmax by 50% and AUC by 39% compared with fasting, and in a population analysis steady-state exposure was on average 26% lower when food was eaten within 3 hours before or 1 hour after a dose. The tablets are therefore taken without food.
• Distribution: about 95% bound to human plasma proteins in vitro, both by ordinary non-covalent binding and by covalent binding.
• Metabolism: enzyme-catalysed metabolism plays a negligible role in vivo. The main circulating metabolites are covalent adducts of afatinib with proteins.
• Elimination: mainly in the faeces. After a 15 mg oral solution, 85.4% of the dose was recovered in faeces and 4.3% in urine, unchanged afatinib making up 88% of the recovered dose. The effective half-life is about 37 hours; steady state is reached within 8 days, with accumulation of 2.77-fold (AUC) and 2.11-fold (Cmax). In patients treated for more than 6 months a terminal half-life of 344 hours was estimated.
• Special populations: less than 5% of a dose is excreted by the kidneys. After a single 40 mg dose, exposure relative to healthy volunteers was 101% (Cmax) and 122% (AUC) in moderate renal impairment, and 122% and 150% in severe renal impairment. Exposure is also higher in women and in patients with lower body weight. Mild or moderate hepatic impairment does not change exposure significantly.

Afatinib is indicated as monotherapy in adults for:

• EGFR-mutation-positive NSCLC: locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutation(s), in patients who have not previously been treated with an EGFR tyrosine kinase inhibitor.
• Squamous NSCLC: locally advanced or metastatic NSCLC of squamous histology that is progressing on or after platinum-based chemotherapy.

• Hypersensitivity to afatinib or to any of the excipients.

The side effects are generally those expected from inhibiting EGFR. The most frequent are diarrhoea and skin reactions, together with stomatitis and paronychia (nail infection). At 40 mg once daily, dose reductions because of side effects were needed in 57% of patients in the LUX-Lung 3 trial and 25% in LUX-Lung 8, and dose reduction lowered the frequency of the common reactions.

Very common (≥1/10): paronychia, decreased appetite, epistaxis, diarrhoea, stomatitis, nausea, vomiting, rash, acneiform dermatitis (acne), pruritus, dry skin.

Common (≥1/100 to <1/10): cystitis, dehydration, hypokalaemia, dysgeusia, conjunctivitis, dry eye, rhinorrhoea, dyspepsia, cheilitis, increased alanine and aspartate aminotransferases, palmar-plantar erythrodysaesthesia syndrome, nail disorders, muscle spasms, renal impairment or renal failure, pyrexia, weight loss.

Uncommon (≥1/1,000 to <1/100): keratitis, aberrant eyelash growth, interstitial lung disease, pancreatitis, gastrointestinal perforation.

Rare (≥1/10,000 to <1/1,000): Stevens-Johnson syndrome and toxic epidermal necrolysis (post-marketing experience, in cases with potential alternative causes).

Important serious reactions are interstitial lung disease (ILD)-like reactions (0.7% of patients, some fatal), hepatic failure, gastrointestinal perforation, severe bullous, blistering or exfoliative skin conditions, keratitis, and diarrhoea leading to dehydration, which rarely proved fatal. Raised liver enzymes were mainly transient and did not lead to discontinuation.

Afatinib is a substrate of the transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and is barely metabolised by enzymes, so its interactions arise at the transporter level.

• Strong P-gp inhibitors (ritonavir, ciclosporin, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, amiodarone): ritonavir given 1 hour before a 20 mg dose raised afatinib exposure by 48% (AUC) and 39% (Cmax); given at the same time as, or 6 hours after, a 40 mg dose the effect was smaller (relative AUC 119% and 111%). Use staggered dosing, taking the inhibitor as far apart from afatinib as possible, preferably 6 hours (inhibitors taken twice daily) or 12 hours (taken once daily).
• Strong P-gp inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St John’s wort): may lower afatinib exposure. Pre-treatment with rifampicin reduced AUC by 34% and Cmax by 22%.
• Afatinib as an inhibitor: it is a moderate P-gp inhibitor in vitro, but changes in plasma levels of other P-gp substrates are considered unlikely. It is also a BCRP substrate and inhibitor in vitro and may increase the bioavailability of orally administered BCRP substrates such as rosuvastatin and sulfasalazine.
• Food: a high-fat meal cuts afatinib exposure by about 50% (Cmax) and 39% (AUC). Take it without food: nothing to eat for at least 3 hours before and at least 1 hour after the dose.

Treatment should be started and supervised by a physician experienced in the use of anticancer therapies. EGFR mutation status should be established before treatment begins. The tablets are swallowed whole with water, without food: nothing to eat for at least 3 hours before and at least 1 hour after the dose. If swallowing whole tablets is not possible, the tablet can be dropped, uncrushed, into about 100 mL of non-carbonated drinking water (no other liquid) and stirred occasionally for up to 15 minutes until it breaks into very small particles. The dispersion is drunk immediately, the glass is rinsed with about 100 mL of water, and that is drunk too. The dispersion can also be given through a gastric tube.

Recommended Dose

• 40 mg once daily, continued until disease progression or until the patient can no longer tolerate it.
• Dose escalation: a maximum of 50 mg a day may be considered in patients who tolerate 40 mg during the first cycle (21 days for EGFR-mutation-positive NSCLC, 28 days for squamous NSCLC), meaning no diarrhoea, rash, stomatitis or other reactions above CTCAE grade 1. It is not done in patients who have had a dose reduction. The maximum daily dose is 50 mg.

Dose Adjustments for Side Effects

• Grade 1 or 2 reactions: no interruption and no dose change. For diarrhoea, an anti-diarrhoeal medicine such as loperamide is taken at once and continued for persistent diarrhoea until loose stools stop.
• Prolonged or intolerable grade 2 reactions, and more severe ones: interrupt until the reaction is grade 0 or 1, then resume with the dose reduced in 10 mg steps. The SmPC defines prolonged by duration for diarrhoea and rash (see Table 1 of the SmPC). If 20 mg a day cannot be tolerated, permanent discontinuation should be considered.
• Suspected interstitial lung disease: interrupt treatment pending evaluation and stop permanently if ILD is diagnosed.
• P-gp inhibitors: use staggered dosing (see Drug Interactions).

Special Populations

• Renal impairment: no change to the starting dose in mild (eGFR 60–89), moderate (eGFR 30–59) or severe (eGFR 15–29 mL/min/1.73 m²) impairment; patients with severe impairment are monitored and the dose adjusted if it is not tolerated. Treatment is not recommended when eGFR is below 15 mL/min/1.73 m² or in patients on dialysis.
• Hepatic impairment: no change in mild (Child-Pugh A) or moderate (Child-Pugh B) impairment. Afatinib has not been studied in severe (Child-Pugh C) impairment, and treatment there is not recommended.
• Children and adolescents: there is no relevant use in NSCLC, and safety and efficacy have not been established; treatment is not recommended.

Missed Dose

A missed dose is taken the same day as soon as it is remembered. If the next dose is due within 8 hours, the missed dose is skipped.

EGFR Mutation Testing

A well-validated, robust method should be used to establish EGFR mutation status, to avoid false negative or false positive results.

Diarrhoea

Diarrhoea, including severe diarrhoea, is common. It may lead to dehydration, with or without renal impairment, and in rare cases has been fatal. It usually appears within the first 2 weeks, and grade 3 diarrhoea most often within the first 6 weeks. Management should be proactive, particularly in those first 6 weeks: adequate hydration plus an anti-diarrhoeal medicine (for example loperamide, escalated if needed to the highest recommended approved dose), started at the first sign and continued until loose stools have stopped for 12 hours. Patients should have the anti-diarrhoeal medicine to hand. Severe diarrhoea may require interruption and dose reduction or discontinuation, and dehydrated patients may need intravenous fluids and electrolytes.

Skin Reactions

Rash and acne are usually a mild or moderate erythematous, acneiform rash that may appear or worsen in sun-exposed areas, so protective clothing and sunscreen are advisable. Early treatment (emollients, antibiotics) helps patients stay on therapy. Severe reactions may need interruption, dose reduction, additional treatment and referral to a specialist in skin reactions. Bullous, blistering and exfoliative conditions, including rare cases suggestive of Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported; treatment is interrupted or stopped if they are severe.

Women, Low Body Weight and Renal Impairment

Exposure to afatinib is higher in female patients, in patients with lower body weight and in those with underlying renal impairment, which may raise the risk of diarrhoea, rash or acne and stomatitis. Closer monitoring is recommended.

Interstitial Lung Disease

ILD or ILD-like reactions (lung infiltration, pneumonitis, acute respiratory distress syndrome, allergic alveolitis), some fatal, have been reported. They occurred in 0.7% of patients across all clinical trials, 0.5% being grade 3 or higher. Patients with a history of ILD have not been studied. Any acute onset or unexplained worsening of respiratory symptoms (dyspnoea, cough, fever) needs careful assessment; treatment is interrupted during the investigation and stopped permanently if ILD is diagnosed.

Liver Function

Hepatic failure, including fatal cases, occurred in fewer than 1% of patients, with confounding factors such as pre-existing liver disease and progression of the cancer. Liver function should be tested periodically in patients with pre-existing liver disease. Grade 3 ALT and AST rises occurred in 2.4% (LUX-Lung 3) and 1.6% (LUX-Lung 8) of patients with normal baseline liver tests on 40 mg a day. Treatment may need to be interrupted if liver function worsens and is stopped if severe hepatic impairment develops.

Gastrointestinal Perforation

Perforation, including fatal cases, occurred in 0.2% of patients in all randomised controlled trials, mostly in patients with other risk factors: corticosteroids, NSAIDs or anti-angiogenic agents, gastrointestinal ulceration, diverticular disease, age or bowel metastases. Treatment is stopped permanently if it occurs.

Keratitis

Acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain or red eye should be referred promptly to an eye specialist. Treatment is interrupted or stopped if ulcerative keratitis is confirmed, and the benefits and risks of continuing are weighed if keratitis is diagnosed. Use with caution in patients with a history of keratitis, ulcerative keratitis or severe dry eye. Contact lens use is also a risk factor.

Left Ventricular Function

Left ventricular dysfunction has been associated with HER2 inhibition. Trial data do not suggest an effect on cardiac contractility, but patients with an abnormal left ventricular ejection fraction (LVEF) or a significant cardiac history have not been studied. In patients with cardiac risk factors or conditions that can affect LVEF, cardiac monitoring including LVEF at baseline and during treatment should be considered. If LVEF is below the institution’s lower limit of normal, cardiology consultation and treatment interruption or discontinuation should be considered.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should avoid becoming pregnant and use adequate contraception during treatment and for at least 1 month after the last dose.
• Pregnancy: mechanistically, all EGFR-targeting medicines may cause foetal harm. Animal studies showed no direct or indirect reproductive toxicity and no teratogenicity up to maternally lethal doses, but exposures were similar to or below those in patients. There are few or no data in pregnant women, so the risk is unknown; a patient who becomes pregnant should be told of the potential hazard to the foetus.
• Breastfeeding: afatinib is excreted in animal milk and is likely to be excreted in human milk. A risk to the breastfed child cannot be excluded, and mothers are advised not to breastfeed during treatment.
• Fertility: no studies in humans. Animal data showed effects on reproductive organs at higher doses, so an effect on human fertility cannot be excluded.

Lactose

Each tablet contains lactose monohydrate (118 mg in the 20 mg tablet, 176 mg in the 30 mg, 235 mg in the 40 mg and 294 mg in the 50 mg tablet). Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take it.

Effect on Driving

Afatinib has a minor influence on the ability to drive and use machines. Ocular reactions (conjunctivitis, dry eye, keratitis) have been reported and may affect this ability.

Blister packs: store in the original package to protect from moisture and light. Bottles: keep tightly closed to protect from moisture and store in the original package to protect from light. The SmPC sets no temperature limit. Keep out of the sight and reach of children. Giotrif is supplied in blisters of 7 × 1, 14 × 1 or 28 × 1 tablets (each blister packed with a desiccant sachet in an aluminium pouch) or in a bottle of 30 tablets with a desiccant in the cap; not all pack sizes may be marketed.

3 years, in blister or bottle. Once a bottle has been opened, the tablets must be used within 2 months.

Prescription only (Rx). Treatment is started and supervised by a physician experienced in the use of anticancer therapies. Afatinib tablets are taken at home, so they are supplied to the patient or to the treating clinic on prescription.