Afatinib (Gilotrif) is a TKI (tyrosine kinase inhibitor) that irreversibly inhibits EGFR (epidermal growth factor receptor).

It is used for the treatment of patients with metastatic NSCLC (non-small cell lung cancer).

It is indicated for the treatment of EGFR mutation-positive tumors.

It is also indicated for the treatment of patients with metastatic squamous cell carcinoma (NSCLC) who have not responded to platinum-based chemotherapy.

Afatinib vs Cisplatin and pemetrexed chemotherapy:

Cisplatin-based chemotherapy regimen is considered as the optimal therapy for patients with NSCLC.

A study by  V. Sequist et al compared afatinib with cisplatin and pemetrexed in patients with EGFR mutation-positive stage IIIB/IV lung adenocarcinoma.

The study showed a significant progression-free survival benefit and improvement in the symptoms of lung cancer treated with afatinib compared to cisplatin plus pemetrexed chemotherapy.

The treatment was well tolerated with few manageable adverse effects.

Afatinib versus cisplatin plus gemcitabine:

Another study compared afatinib with cisplatin + gemcitabine in Asian patients with advanced non-small-cell lung cancer harboring EGFR mutations.

The study showed significant improvements in progression-free survival in Asian patients with EGFR mutation-positive advanced lung NSCLC with manageable adverse effects. (Ref). 

Afatinib dosage in adults:

The usual dose is 40 mg once daily.

If the patient tolerat this dose, it is then increased to 50 mg once daily after three weeks.

Dosage forms and strengths:

• Available as 40 mg, 30 mg, and 20 mg tablets.

Withhold GILOTRIF if any of the following side effects are observed:

• NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) side effects of Grade 3 or higher
• Diarrhea of grade 2 or higher severity does not get better even with antidiarrheal treatment for two or more days.
• Skin reactions of Grade 2 or higher which do not improve and persist for 7 days or more, are severe, and not tolerated by the patient.

Dose in Children:

Not studied in children.

Pregnancy Category C

• According to the labeling of the manufacturer, it should be avoided during pregnancy.
• Women in reproductive age groups must be advised to use contraception during treatment, and for at least two weeks following the last dose. 

Afatinib use in kidney disease:

• Afatinib should be avoided in severe renal impairment.
• In severe renal impairment  (eGFR of 15 to 29 ml/min), the recommended dose of afatinib is 30 mg orally once daily.   

Afatinib use in liver disease:

• Gilotrif should be avoided in severe liver disease.
• In mild to moderate liver disease, it should be used with caution and symptoms and signs suggestive of hepatotoxicity should be monitored.

Afatinib side effects:

• Acne,
• conjunctivitis,
• cystitis,
• loss of appetite,
• volume depletion,
• diarrhea,
• dry eyes and skin
• dyspepsia and heartburn
• nose bleeds,
• hand-foot syndrome,
• electrolyte imbalance especially hypokalemia
• muscle spasms,
• paronychia,
• itching,
• fever,
• rash,
• renal failure,
• flu and rhinorrhoea,
• weight loss,
• Interstitial lung disease,
• keratitis,
• alopecia,
• bone marrow suppression,
• hyperuricemia,
• nausea and vomiting,
• oral mucositis,
• thromboembolism
• tumor lysis syndrome.

Important safety information

Limit sun exposure while taking GILOTRIF

• Limit your time in the sun.
• Patients should be advised sunscreen, to wear a hat, and cover the skin while taking Gilotrif to avoid sunburns and a rash.

Severe side effects associated with GILOTRIF:

• Diarrhea.

Diarrhea is a common side effect. It may result in volume depletion and dehydration and rarely, when severe, can result in renal failure.

• Skin reactions.

Redness, rashes, blisters, acne, and steven-johnsons syndrome have all been reported in patients using this drug.

• Lung or breathing problems.

GILOTRIF may cause inflammation of the lung manifested by shortness of breath, cough, fever and chest pain that may lead to death. These symptoms may mimic primary lung disease.

• Liver problems.

GILOTRIF is hepatotoxic and can cause serious liver disease leading to death.

Liver disease may be manifested by any of the following symptoms:

• Jaundice manifesting as yellowing of eyes (conjunctiva) and skin
• a dark or brown urine
• right upper quadrant pain.
• bleeding tendency or bruising after minor trauma.
• feeling tired and exhauseted.

• Eye problems. 

Gilotrif is toxic to the eyes as well. Symptoms of eye-related side effects may include:

• Pain, swelling, redness, or tearing of the eyes
• impaired or blurred vision
• Photophobia and hypersensitivity to light
• irritation and dryness.

• Heart problems may occur with its use.

Patients may notice any of the following symptoms:

• new or worsening shortness of breath on exertion or even at rest
• leg swelling or swelling around the eyes
• a cough, which may be more evident on lying down.
• tiredness and fatigue manifesting as reduced exercise tolerance.
• Palpitations or a feeling that your heart is pounding or racing
• Weight gain because of fluid accumulation in the cavities such as the lungs and peritoneal cavity.

Contraindications and Cautions:

Patients suffering from heart disease and conditions that affect ejection fraction

• At baseline and throughout treatment, cardiac monitoring should be considered, including assessment left ventricular ejection percentage.

Diarrhea:

• It is recommended to take proactive measures. Avoid sun exposure History of keratitis.

New symptoms of a weakened lung (e.g., shortness or cough, fever, etc.):

• Do not start treatment until interstitial pulmonary disease is eliminated.

Keratitis and dry eyes:

• For a thorough assessment, consult immediately with an ophthalmologist.

Signs and symptoms of a skin reaction.

• Skin reactions can sometimes be very severe. Patients may develop Stevens-Johnson Syndrome which can involve the mucosa and eyes. The treatment must be stopped in such cases or when eye symptoms are severe such as in patients with ulcerative keratitis.

Warnings and Precautions

• Patients with Grade 2 or greater renal impairment should be advised to stop taking the drug until their renal function returns to normal or improves to Grade 1.
• Reintroduce at a lower dose, at least 10 mg less than the dose at which side effects occurred.

Afatinib (Gilotrif) should be Permanently discontinued if:

• Exfoliative, bullous, or blistering skin lesions can cause serious and life-threatening problems
• A diagnosis of ILD (interstitial pulmonary disease) is made.
• Severe drug-induced liver disease
• Persistent symptoms of ulcerative Keratitis
• Left ventricular dysfunction manifests as persistent shortness of breath.
• Severe or intolerable side effects even in lower doses.

Monitor:

• Monitor for a response to therapy.
• For adverse reactions (see contraindications and side effects), monitor Renal function tests, liver function tests, eye examination, and pulmonary function tests.

How to administer afatinib (Gilotrif)?

• Afatinib should be taken on an empty stomach preferably one hour before or two hours after a meal.
• When it is taken immediately following a fatty meal, its absorption decreases by 39%. 

Afatinib Mechanism of action (MOA):

• Afatinib is an irreversible inhibitor tyrosine kinase inhibitor. It binds to EDFR, HER2, and HER4 and permanently downregulate the ErbB signaling. Hence it is used to treat EGFR mutant-positive metastatic cancer cells.

Pharmacokinetics:

• It takes between 2 and 5 hours for plasma to reach peak concentration.
• After 8 days, the steady-state plasma concentration is attained.
• The half-life of the elimination is approximately 37 hours.
• The majority of excretion occurs via the stomach (85% via the feces).

International Brands of Afatinib:

Gilotrif

Brands in Pakistan:

Afatinib (Gilotrif).