Afatinib

Afatinib is a targeted therapy that irreversibly inhibits the ErbB family of tyrosine kinases.[1] The first line FDA-approved indication is to treat locally advanced or metastatic non-small cell lung cancer (NSCLC) that harbor nonresistant epidermal growth factor receptor (EGFR) mutations. It is reported to be the second-line treatment of advanced squamous non-small cell lung cancer (NSCLC).[1] Afatinib is also under investigation as monotherapy in patients with HER2-positive breast cancer who had progressed despite trastuzumab treatment. However, it does not yet have FDA approval.[2]

There are three known tyrosine kinase inhibitors (EGFR TKIs) widely used as a treatment for advanced non-small cell lung cancer (NSCLC) with proven efficacy: gefitinib, erlotinib, and afatinib.[3] Based on the reported data, afatinib is not superior to erlotinib in treating EGFR-mutant NSCLC.[3] However, afatinib was found to be more effective than erlotinib in treating advanced squamous cell carcinoma (as second-line treatment).[3]

The mechanism of action of afatinib like other protein kinase inhibitors is to irreversibly inhibit epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and HER4.[1] EGFR and HER2 are part of the receptor tyrosine kinase family and play significant roles in tumor cell proliferation as well as tumor vascularization. These receptors are known to exhibit overexpression in many types of cancer cell types. Afatinib also has activity against T790 mutations that are not sensitive to their standard therapies.[4]

Afatinib is an orally administered drug, which is only available in tablet form. It should be taken on an empty stomach at least 1 hour before or 2 hours after a meal, as absorption decreases with high-fat meals. The tablet should be swallowed whole, with at least 8 ounces of water. The tablet should never be crushed or dissolved. The storage of this tablet should be at room temperature (68F to 77F). The recommended dosage is 40 mg tablets daily in a patient with normal creatinine and without any major liver dysfunction until disease progression, or the patient no longer tolerates it. Following oral administration, the time to peak plasma concentration (Tmax) is reported to be between 2 to 5 hours.[5]

This medication is available in the following form/doses:

• Tablet: 20 mg, 30 mg and 40 mg

For both non-small cell and squamous non-small cell metastatic cancers, dosing is 40 mg orally once daily, preferably more than an hour before or 2 hours after food.

The treatment dosing adjustments for creatinine clearance: 

• CrCl 30 to 89 ml/min/1.73 m2: no dosage adjustment necessary 
• CrCl 15 to 29 ml/min/1.73 m2: 30 mg PO daily 
• CrCl less than 15 ml/min/1.73 m2: Not studied

The treatment dosage for hepatic impairment: 

• Mild-Moderate (Child-Pugh A or B): No dosage adjustment necessary 
• Severe (Child-Pugh C): Closely monitor and adjust the dose if not tolerated

Afatinib has a predictable and manageable side effect profile based on a study by Keating et al.[1] However, like other medications, it has a particular adverse event profile. The most common reported adverse events are diarrhea and rash/acne in 88% and 82% of patients, respectively.[6]

• Dermatologic:
  • Acneiform eruption (less than or equal to 70% to 90%)
  • Skin rash (less than or equal to 70% to 90%)
  • Paronychia (11% to 58%)
  • Xeroderma (31%), pruritus (10% to 21%),
  • Cheilitis (12%)
• Endocrine & metabolic:
  • Decreased serum potassium (11% to 30%)
  • Weight loss (17%)
  • Hypokalemia (11%)
• Gastrointestinal:
  • Diarrhea (75% to 96%)
  • Stomatitis (30% to 71%)
  • Decreased appetite (25% to 29%)
  • Nausea (21% to 25%)
  • Vomiting (13% to 23%)
• Genitourinary:
  • Cystitis (13%)
• Hematologic & oncologic:
  • Abnormal lymphocytes (decreased: 38%; grades 3/4: 9%)
  • Decreased white blood cell count (12%; grades 3/4: 1%)
• Hepatic:
  • Increased serum ALT (10% to 54%)
  • Increased serum alkaline phosphatase (34% to 51%)
  • Increased serum AST (7% to 46%)
  • Abnormal hepatic function tests (6% to 18%)
  • Increased serum bilirubin (3% to 16%)
• Ophthalmic:
  • Conjunctivitis (11%)
• Renal:
  • Decreased creatinine clearance (49%)
• Respiratory:
  • Epistaxis (17%)
  • Rhinorrhea (11%)
• Miscellaneous:
  • Fever (12%)

The following side effects occurred in 1 to 10% of patients.

• Central nervous system:
  • Fatigue (under 2%)
• Dermatologic:
  • Nail disease (3% to 9%)
  • Palmar-plantar erythrodysesthesia (2% to 7%)
• Ophthalmic:
  • Keratitis (less than or equal to 2%)
• Renal:
  • Renal insufficiency (6%)
• Respiratory:
  • Interstitial pulmonary disease (2%) [6]
  • Dyspnea (less than 2%)

No known contraindications are listed in the manufacturer's labeling thus far. However, similar to many medications, prescribers should withhold dosing for any drug-related adverse reactions. 

This drug requires permanent discontinuation in the event of: 

• Any life-threatening bullous, blistering, or exfoliative skin lesions.
• Confirmed interstitial lung disease (ILD)
• Severe drug-induced hepatic impairment 
• Persistent ulcerative keratitis 
• Symptomatic left ventricle dysfunction
• Severe or intolerable adverse reaction occurring at a dose of 20 mg per day 

This drug is not recommended during pregnancy, as no adequate clinical trials exist during pregnancy. Instead, A strong recommendation is that women of reproductive age should use an effective contraception method during therapy, and it should be continued at least for two weeks after the last dose of afatinib. The manufacturer warns against using this medication during breastfeeding, given potential serious adverse reactions in a breastfed infant.