Continuing Education Activity

Afatinib, a tyrosine kinase inhibitor, is a widely used medication for non-small cell lung carcinoma. This activity educates health care providers on the indications, mechanism of action, adverse reactions, and toxicity. It also reviews the necessity of enhancing health care outcomes by necessitating an interprofessional approach to the management of the drug.

Objectives:

• Identify the mechanism of action of afatinib.
• Describe the adverse effects and contraindications of afatinib.
• Summarize the appropriate monitoring of the potential toxicity of afatinib.
• Review interprofessional team strategies for enhancing care coordination and communication to advance afatinib use and improve outcomes.

Indications

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]

Mechanism of Action

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]

Administration

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

Adverse Effects

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%)

Contraindications

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.

Monitoring

Afatinib has the following monitoring requirements[7]:

• Given the fact that dermatology adverse reactions are the most common reported adverse reactions during treatment, patients should be advised to avoid sun exposure if possible or utilize adequate sun protection
• Monitor for signs and symptoms of volume depletion in patients with diarrhea
• Hepatic impairment was observed commonly in clinical trials; it is advised to monitor liver function periodically during the treatment course
• Renal function requires periodic monitoring
• Keratitis is one of the rare adverse effects but reported in clinical trials - therapy should be interrupted with any suspected keratitis 
• Recommended to reduce the dose in case of paronychia
• Monitor patients for any signs and symptoms concerning for pulmonary toxicity - interstitial lung disease occurred in a small percentage of patients
• Assess left ventricle function before and during treatment in high-risk cardiac patients - this drug should be used with caution in patients with cardiac risk factors and/or decreased left ventricle heart failure as patients with significant cardiac history met exclusion criteria for clinical trials

Toxicity

There is not much research and data in regards to toxic and therapeutic levels of afatinib. However, it has been reported to have a predictable and manageable profile in terms of side effects.

Some serious adverse reactions have been identified, including hepatic impairment, dermatology complications, and rarely lung and cardiac complications. Afatinib should be dose adjusted in case of concomitant treatment with P-glycoprotein inducers or inhibitors.[5]

Enhancing Healthcare Team Outcomes

Afatinib is a relatively new drug for the treatment of metastatic non-small cell lung cancer. Although, this drug easily can be administered by patients orally as once-daily dosing, close follow up with the oncologist and/or primary care physician, specialty-trained nurses, and pharmacist is necessary during the treatment. Pharmacists could be the best primary source for any questions or concerns by patients. They can also perform medication reconciliation, verify dosing, and should report any issues to the prescribing physician or nursing staff. Nurses will encounter patients at followup visits and should document medication compliance as well as signs of adverse events, which they should communicate with the rest of the interprofessional healthcare team.

Better communications between health care providers, patients, and pharmacists are recommended to improve patient care and also to build a better side effect profile for such a new drug, which eventually will lead to better patient care. This collaboration demonstrates the clinical benefit of an interprofessional healthcare team. [Level V]