What is an Epidermal Growth Factor Receptor (EGFR) inhibitor?

Epidermal Growth Factor Receptor (EGFR) Inhibitors

EGFR inhibitors are targeted cancer therapies that block the activity of the epidermal growth factor receptor, a transmembrane glycoprotein that regulates cell growth and proliferation, with primary applications in treating EGFR-mutant non-small cell lung cancer, colorectal cancer, and head and neck cancers. 1

Types of EGFR Inhibitors

EGFR inhibitors fall into two main categories:

1. Tyrosine Kinase Inhibitors (TKIs)

   • Small molecules that work intracellularly by blocking ATP binding to the tyrosine kinase domain
   • Examples include:
     • Gefitinib: First-generation EGFR-TKI 2
     • Erlotinib: First-generation EGFR-TKI 3
     • Afatinib: Second-generation EGFR-TKI 1
     • Osimertinib: Third-generation EGFR-TKI 1

2. Monoclonal Antibodies

   • Target the extracellular domain of EGFR
   • Examples include:
     • Cetuximab: Used in colorectal and head/neck cancers 1
     • Panitumumab: Used primarily in colorectal cancer 1

Mechanism of Action

EGFR inhibitors work by:

• Reversibly or irreversibly binding to the EGFR tyrosine kinase domain
• Preventing autophosphorylation of tyrosine residues
• Blocking downstream signaling pathways that promote cell proliferation and survival
• Inhibiting tumor growth and inducing apoptosis 3, 2

Third-generation EGFR-TKIs like osimertinib have higher binding affinity for EGFR mutations (particularly exon 19 deletions or L858R mutations) than for wild-type EGFR, allowing for more selective targeting of cancer cells. 1

Clinical Applications

Non-Small Cell Lung Cancer (NSCLC)

• First-line treatment for patients with EGFR-mutant advanced NSCLC
• Osimertinib is the preferred first-line agent due to superior efficacy and CNS penetration
• Significantly improves progression-free survival compared to platinum-based chemotherapy 1

Head and Neck Cancers

• Cetuximab is used alone or in combination with chemotherapy
• Particularly effective in squamous cell carcinomas 1

Colorectal Cancer

• Anti-EGFR antibodies (cetuximab, panitumumab) are used in RAS wild-type metastatic colorectal cancer
• Limited efficacy in BRAF-mutated colorectal cancer 1

Common Adverse Events

1. Cutaneous Toxicities (most common)

   • Acneiform rash (occurs in 30-90% of patients)
   • Dry skin
   • Paronychia
   • Hair changes 1, 4

2. Gastrointestinal Effects

   • Diarrhea (occurs in 24-41% of patients)
   • Stomatitis/mucositis 1

3. Other Adverse Effects

   • Interstitial lung disease (rare but serious)
   • Hepatotoxicity
   • Ocular toxicity
   • Hypomagnesemia 1, 5

Management of Adverse Events

Cutaneous Toxicities

• Prevention: Regular use of emollients
• Treatment:
  • Grade 1-2: Topical antibiotics/corticosteroids
  • Grade 2 (prolonged/intolerable): Consider dose reduction
  • Grade 3-4: Interrupt treatment, systemic antibiotics, resume at lower dose when improved 1

Diarrhea

• Dietary modifications: Low-fat, low-fiber diet; minimize fruit, red meat, alcohol, spicy food, caffeine
• Treatment:
  • Persistent diarrhea (>48h): Loperamide plus oral isotonic solution
  • If no improvement: Discontinue drug, restart at reduced dose when symptoms improve 1

Resistance Mechanisms

Patients eventually develop resistance to EGFR inhibitors through:

1. On-target resistance: Secondary EGFR mutations (e.g., T790M, C797S)
2. Off-target resistance: Activation of bypass pathways (MET amplification, HER2 amplification)
3. Histological transformation: Transformation to small cell lung cancer 1

Clinical Pearls

• Smoking reduces erlotinib plasma concentrations by approximately 50-60% due to CYP1A2 induction; dose adjustments may be needed in current smokers 3
• EGFR mutation testing is essential before initiating EGFR-TKI therapy in NSCLC
• Third-generation EGFR-TKIs should be prioritized for patients with CNS metastases due to better blood-brain barrier penetration 1
• Skin toxicity management is crucial for maintaining quality of life and treatment adherence 1, 4

EGFR inhibitors have transformed the treatment landscape for several cancer types, particularly EGFR-mutant NSCLC, where they have significantly improved survival outcomes and quality of life compared to traditional chemotherapy.