Continuing Education Activity

Afatinib, a tyrosine kinase inhibitor, is a widely used medication for non-small cell lung carcinoma. Afatinib is a targeted therapy that irreversibly inhibits the ErbB family of tyrosine kinases. It is the first-line FDA-approved indication to treat locally advanced or metastatic non-small cell lung cancer (NSCLC) that harbors nonresistant epidermal growth factor receptor (EGFR) mutations, and the second-line treatment of advanced squamous non-small cell lung cancer (NSCLC). Afatinib is also under investigation as monotherapy in patients with HER2-positive breast cancer who had progressed despite trastuzumab treatment. 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 improving the interprofessional approach to managing the drug.

Objectives:

• Identify the mechanism of action of afatinib.
• Describe the possible adverse effects of afatinib.
• Summarize the appropriate monitoring for patients using 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 harbors 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]

Aredo J. et al. found that afatinib had limited activity in non-small cell lung cancer patients previously treated with osimertinib who developed resistance to it because of an acquired EGFR mutation.[4]

Li. T. examined afatinib activity on uncommon EGFR mutations, e.g., Gly719Xaa, Ser768Ile, and Leu861Gln. Forty-two patients with uncommon EGFR mutation received treatment with afatinib for advanced lung adenocarcinoma. The investigators found that afatinib was effective in treatment.[5]

Xu H. et al. found that afatinib and anlotinib effectively treat lung adenocarcinoma in patients with the rare mutation p.Asp769Tyr.[6]

Saran F. et al. conducted a clinical trial in patients with glioblastoma multiforme to determine the maximum tolerated dose of afatinib in combination with radiotherapy and with or without temozolomide. The maximum tolerated dose of afatinib was 30 mg daily with radiotherapy and temozolomide and 40 mg of afatinib daily with radiotherapy.[7]

Afatinib is being examined for treating HER2-positive gastric cancer.[8]

Mechanism of Action

Like other protein kinase inhibitors, the mechanism of action of afatinib is to irreversibly inhibit the 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 and 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.[9]

Afatinib exerts antineoplastic effects in head and neck squamous cell carcinoma (HNSCC) by suppressing mTORC1, which initiates apoptosis of the cancer cells.[10] Combining autophagy inhibitors with afatinib could improve the treatment of HNSCC.

Zhu X. et al. conducted a study on afatinib-resistant lung adenocarcinoma cell line (HCC827 AR). The baculovirus IAP repeat protein 5 (BIRC5) was overexpressed in this cell line and was detected on Western blot analysis. BIRC5 overexpression may confer resistance to afatinib by dysregulation of apoptosis. The BIRC5 inhibitor, YM155, restored afatinib activity against the lung adenocarcinoma cell line.[11]

Administration

Afatinib is an orally administered drug that 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 (68 F to 77 F). 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.[12]

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 is 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.[13]

• 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%)

Liu X. et al. reported on two cases of interstitial pneumonia during afatinib therapy.[14] The first case is a 58-year-old man with advanced lung adenocarcinoma. The patient had the following EGFR mutations: exon 18 G719X and exon 20 S781I. The patient presented with shortness of breath and fever 68 days after starting afatinib therapy. The patient received treatment with an empirical antimicrobial and a low-dose glucocorticoid. The afatinib-induced interstitial pneumonia was not diagnosed. The patient died 15 days after the onset of symptoms because of pulmonary inflammation.

The second case is a 57-year-old man with advanced lung adenocarcinoma. The patient had the following EGFR mutation: exon 21 L861Q. The patient presented with shortness of breath and fever 22 days after starting afatinib therapy. The patient received empirical antimicrobial therapy, and five days later, the patient received a CT scan which showed pulmonary inflammation. The patient was diagnosed with afatinib-induced interstitial pneumonia and was promptly treated with glucocorticoid therapy which quickly resolved the pneumonia. The investigators conclude that clinicians need to be vigilant for the uncommon afatinib-induced interstitial pneumonia and to promptly treat it with glucocorticoid therapy.

Contraindications

No known contraindications are listed in the manufacturer's labeling thus far. However, like many medications, prescribers should withhold dosing for any adverse drug reactions.[15]

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 examining the drug's use during pregnancy. Instead, A strong recommendation is that women of reproductive age use an effective contraception method during therapy. 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. Breastfeeding can resume two weeks after the last dose.[16]

Monitoring

Afatinib has several monitoring requirements.[17][18] These include:

• Given 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.[19]
• Monitor for signs and symptoms of volume depletion in patients with diarrhea
• Hepatic impairment was commonly observed in clinical trials; it is advised to monitor liver function periodically during treatment.
• The patient's 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 that raise concern 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.

Takahashi T. et al. studied using afatinib trough plasma concentrations in patients with non-small-cell lung cancer to improve the safety and efficacy of afatinib therapy.[20]

Toxicity

There is not much research and data regarding 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.[12]

Enhancing Healthcare Team Outcomes

Afatinib is a relatively new drug for the treatment of metastatic non-small cell lung cancer. Although this drug can easily be administered by patients orally as once-daily dosing, close follow-up with the oncologist and/or primary care clinician (MD, DO, NP, or PA), specialty-trained nurses, and pharmacists are 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 nurse. Nurses will encounter patients at follow-up visits and document medication adherence and signs of adverse events, which they should communicate with the rest of the interprofessional healthcare team. All interprofessional team members are responsible for meticulously documenting all interactions, observations, test results, and interventions in the patient's medical record; this allows all team members to operate from the same up-to-date information.

Better communications between health care providers, patients, and pharmacists are recommended to improve patient care and build a better side effect profile for such a new drug, eventually leading to better patient care. This collaboration demonstrates the clinical benefit of an interprofessional healthcare team. [Level 5]