Continuing Education Activity

Afatinib is a tyrosine kinase inhibitor for managing non–small cell lung carcinoma (NSCLC). Afatinib is designed to cause irreversible inhibition of the ErbB family of tyrosine kinases. The FDA has approved afatinib for treating locally advanced or metastatic NSCLC characterized by nonresistant epidermal growth factor receptor (EGFR) mutations. Additionally, it is a second-line option for advanced squamous NSCLC. Beyond these applications, afatinib is being investigated as a monotherapy for individuals with HER2-positive breast cancer who have experienced progression despite management with trastuzumab. This activity aims to familiarize healthcare providers with afatinib's approved indications and mechanism of action while addressing potential adverse reactions and highlighting considerations regarding toxicity.

Objectives:

• Identify the mechanism of action of afatinib.

• Determine the possible adverse effects of afatinib.

• Implement appropriate monitoring for patients undergoing afatinib therapy.

• Develop interprofessional team strategies for enhancing care coordination and communication to advance afatinib use and improve outcomes.

Indications

Afatinib is a medication that targets and irreversibly inhibits the ErbB family of tyrosine kinases.[1] This drug is FDA-approved for managing locally advanced or metastatic non-small cell lung cancer (NSCLC) associated with nonresistant epidermal growth factor receptor (EGFR) mutations. Additionally, afatinib is a second-line treatment of advanced squamous non-small cell lung cancer (NSCLC).[1] Afatinib is also being investigated as monotherapy in patients with HER2-positive breast cancer who had progressed despite trastuzumab treatment. However, it does not yet have FDA approval for this indication.[2]

There are 3 known tyrosine kinase inhibitors (TKIs) that are proven effective in treating advanced non-small-cell lung cancer (NSCLC): 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 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 patients with non-small cell lung cancer 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 (eg, Gly719Xaa, Ser768Ile, and Leu861Gln). Forty-two patients with unusual EGFR mutation received treatment with afatinib for advanced lung adenocarcinoma. The investigators found that afatinib was effective in treating this condition.[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 with radiotherapy.[7]

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

Mechanism of Action

Similarly to other protein kinase inhibitors, afatinib's mechanism of action involves irreversibly inhibiting 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 vascularization. These receptors are known to exhibit overexpression in many cancer cell types.

Afatinib loses its activity against T790M EGFR mutations, and osimertinib has a high clinical response rate to this mutation.[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 lines (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]

Afatinib helps manage rare epidermal growth factor receptor (EGFR) mutations. It effectively treats osimertinib resistance mutations, such as G724S and L718Q/V. Afatinib also effectively treats E709X, E709_T710delinsX, some rare exon 19, and some 20 exon insertional mutations. However, some rare exon 19 and some 20 exon insertional mutations do not respond to afatinib treatment.[12]

Administration

Available Dosage Forms

Afatinib is an orally administered drug that is only available in tablet form. These tablets can be in 20, 30, or 40 mg doses. An afatinib tablet 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. This medication should be stored at room temperature (68 °F to 77 °F or 20 °C to 25 °C).

Adult Dosing

The recommended dosage is 40 mg tablets daily in a patient with normal creatinine clearance without any significant liver dysfunction until the disease progresses or the patient no longer tolerates it. Following oral administration, the time to peak plasma concentration (Tmax) is reported to be between 2 and 5 hours.[13]

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 intake.

Specific Patient Populations

Hepatic impairment: No dosage adjustment is necessary for mild-moderate (Child-Pugh A or B) hepatic impairment. For severe (Child-Pugh C) hepatic impairment, the patient should be closely monitored, and the dose should be adjusted if not tolerated.

Renal impairment: The dosage changes for patients with kidney disease are based on creatinine clearance (CrCl): 

• 30 to 89 mL/min/1.73 m²: no dosage adjustment necessary 
• 15 to 29 mL/min/1.73 m²: 30 mg PO daily 
• <15 mL/min/1.73 m²: Not studied

Adverse Effects

Based on a study by Keating et al, afatinib has a predictable and manageable side effect profile.[1] However, like other medications, it has a particular adverse event profile. The most commonly reported adverse events are diarrhea and rash/acne in 88% and 82% of patients, respectively.[14]

• Dermatologic:
  • Acneiform eruption (≤90%)
  • Skin rash (≤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 up to 10% of patients.

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

Liu X et al reported 2 cases of interstitial pneumonia during afatinib therapy.[15] The first case is a 58-year-old man with advanced lung adenocarcinoma. The patient had EGFR mutations, including exon 18 G719X and exon 20 S781I. This patient presented with shortness of breath and fever 68 days after starting afatinib therapy and 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 EGFR mutations, including exon 21 L861Q. This patient presented with shortness of breath and fever 22 days after starting afatinib therapy. The patient received empirical antimicrobial treatment, and 5 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 concluded that clinicians must be vigilant for the uncommon event of afatinib-induced interstitial pneumonia and treat it promptly with glucocorticoid therapy.

Contraindications

Warnings and Precautions

No contraindications are listed in the manufacturer's labeling thus far. However, prescribers should withhold dosing for any adverse drug reactions.[16]

Permanent discontinuation of this drug is required if any of the following are recorded. 

• Life-threatening bullous, blistering, or exfoliative skin lesions.
• Interstitial lung disease (ILD)
• Severe drug-induced hepatic impairment 
• Persistent ulcerative keratitis 
• Symptomatic left ventricle dysfunction
• Severe or intolerable adverse reactions occurring at a dose of 20 mg/d 

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 2 weeks after the last dose of afatinib. The manufacturer warns against using this medication during breastfeeding, given the potentially severe adverse reactions in a breastfed infant. Breastfeeding can resume 2 weeks after the last dose.[17]

Monitoring

Afatinib has several monitoring requirements.[18][19] These include:

• Since dermatology adverse reactions are the most commonly reported during treatment, patients should be advised to avoid sun exposure if possible or utilize adequate sun protection.[20]
• 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.
• Renal function requires periodic monitoring.
• Keratitis is one of the rare adverse effects reported in clinical trials; therapy should be interrupted with any suspected keratitis. 
• It is recommended to reduce the dose in patients with 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 patients with high-risk cardiac conditions. This drug should be used with caution in patients with cardiac risk factors 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.[21]

Toxicity

Limited research and data regarding toxic and therapeutic levels of afatinib are available. However, it has been reported to have a predictable and manageable profile in terms of side effects.

Some severe 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.[13]

Enhancing Healthcare Team Outcomes

Afatinib is an orally administered drug for the treatment of metastatic non-small cell lung cancer, which was FDA-approved in 2013. Although this drug can easily be administered by patients orally as once-daily dosing, close follow-up with the oncologist or primary care clinician, specialty-trained nurses, and pharmacists are necessary during the treatment. Pharmacists are the best primary source for patients' questions or concerns. 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 reporting 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 communication between health care providers, patients, and pharmacists is recommended to improve patient care and build a better adverse effect profile, eventually leading to better patient care. This collaboration demonstrates the clinical benefit of an interprofessional healthcare team.