EGFR inhibitors

Epidermal Growth Factor Receptor (EGFR) inhibitors are a class of anticancer drugs that target the EGFR protein, a transmembrane receptor tyrosine kinase involved in regulating cell growth, survival, proliferation, and differentiation. Abnormal activation of EGFR through mutations, overexpression, or amplification is implicated in various human cancers, particularly non-small cell lung cancer (NSCLC), colorectal cancer, and head and neck squamous cell carcinoma.

EGFR inhibitors are broadly categorized into two types:

1. Monoclonal antibodies – which bind to the extracellular domain of the EGFR to prevent ligand binding and receptor activation.

2. Tyrosine kinase inhibitors (TKIs) – which block the intracellular tyrosine kinase domain, inhibiting signal transduction.

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1. Pharmacological Classification

A. Small Molecule Tyrosine Kinase Inhibitors (TKIs) – Oral Agents

These inhibit the EGFR tyrosine kinase domain and are often used in cancers with activating EGFR mutations.

• First-generation EGFR TKIs:

  • Gefitinib

  • Erlotinib

  • Icotinib (used mainly in China)

  • These bind reversibly to EGFR and are effective in tumors with specific EGFR mutations (e.g., exon 19 deletions, L858R).

• Second-generation EGFR TKIs:

  • Afatinib

  • Dacomitinib

  • Irreversibly inhibit EGFR and other members of the ErbB family.

• Third-generation EGFR TKIs:

  • Osimertinib

  • Selectively inhibit both sensitizing EGFR mutations and the T790M resistance mutation.

B. Monoclonal Antibodies – Intravenous Agents

Target the extracellular domain of EGFR to prevent ligand binding.

• Cetuximab – Chimeric monoclonal antibody (IgG1)

• Panitumumab – Fully human monoclonal antibody (IgG2)

• Necitumumab – Human monoclonal antibody

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2. Mechanism of Action

Small-Molecule TKIs:

• Bind to the ATP-binding site in the intracellular tyrosine kinase domain of EGFR.

• Prevent phosphorylation and subsequent activation of downstream signaling pathways:

  • RAS-RAF-MEK-ERK pathway – proliferation

  • PI3K-AKT-mTOR pathway – survival

  • JAK-STAT pathway – immune regulation and growth

• Inhibition leads to apoptosis, cell cycle arrest, and decreased angiogenesis.

Monoclonal Antibodies:

• Bind to the extracellular ligand-binding domain of EGFR.

• Prevent ligand (e.g., EGF or TGF-α) binding and dimerization of the receptor.

• Induce receptor internalization and degradation.

• Trigger antibody-dependent cellular cytotoxicity (ADCC), especially with cetuximab.

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3. Clinical Indications

A. Non-Small Cell Lung Cancer (NSCLC):

• EGFR mutations are present in 10–15% of Caucasian and up to 50% of Asian patients with NSCLC.

• First-line therapy for EGFR-mutant NSCLC includes:

  • Osimertinib (preferred due to CNS penetration and activity against T790M).

  • Afatinib, Dacomitinib, Gefitinib, or Erlotinib in selected settings.

B. Colorectal Cancer:

• Cetuximab and Panitumumab are approved for metastatic colorectal cancer (mCRC) that is RAS wild-type.

• Not effective in patients with KRAS or NRAS mutations.

C. Head and Neck Squamous Cell Carcinoma:

• Cetuximab is used in combination with radiation therapy or chemotherapy.

D. Other:

• Glioblastoma (experimental and limited efficacy)

• Pancreatic cancer (e.g., Erlotinib with gemcitabine)

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4. Resistance Mechanisms

Resistance to EGFR inhibitors can be either primary (intrinsic) or acquired (develops after initial response):

A. Primary Resistance:

• Presence of other driver mutations (e.g., KRAS, ALK, ROS1).

• Tumors lacking EGFR dependency.

B. Acquired Resistance:

• T790M mutation (common cause after 1st- or 2nd-gen TKI therapy).

• MET amplification

• HER2 amplification

• Histological transformation (e.g., to small cell carcinoma)

• EMT (epithelial-mesenchymal transition)

Third-generation TKIs like osimertinib are designed to overcome T790M-mediated resistance.

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5. Pharmacokinetics

Drug	Half-life	Bioavailability	Route	Metabolism
Gefitinib	~48 hrs	~60%	Oral	CYP3A4, CYP2D6
Erlotinib	~36 hrs	~60%	Oral	CYP3A4, CYP1A2
Afatinib	~37 hrs	~92%	Oral	Minimal CYP
Osimertinib	~48 hrs	~70%	Oral	CYP3A4
Cetuximab	~114 hrs	N/A	IV	Reticuloendothelial system
Panitumumab	~180 hrs	N/A	IV	Proteolytic catabolism

Food can affect bioavailability, especially for erlotinib (increased with food intake).

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6. Adverse Effects

Common (for both TKIs and monoclonals):

• Dermatologic toxicity:

  • Acneiform rash (correlates with efficacy)

  • Dry skin, pruritus

• Gastrointestinal:

  • Diarrhea (especially with afatinib)

  • Stomatitis

• Ocular:

  • Conjunctivitis

  • Keratitis

Unique to TKIs:

• Interstitial lung disease (ILD)/pneumonitis

• Hepatotoxicity

• QT prolongation (especially osimertinib)

Unique to monoclonal antibodies:

• Infusion-related reactions (more common with cetuximab)

• Hypomagnesemia (panitumumab)

• Anaphylaxis (especially chimeric antibody cetuximab)

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7. Contraindications and Precautions

• Known hypersensitivity to the active compound or excipients.

• Caution in patients with:

  • Pre-existing interstitial lung disease (ILD)

  • Cardiac history (due to QT prolongation risk with osimertinib)

  • Severe hepatic impairment (dose adjustment may be required)

Pre-medication is required for cetuximab (antihistamines) to reduce infusion-related reactions.

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8. Drug Interactions

A. CYP450-mediated:

• TKIs (like gefitinib, erlotinib, osimertinib) are metabolized by CYP3A4:

  • Inhibitors (e.g., ketoconazole, clarithromycin) may increase plasma levels.

  • Inducers (e.g., rifampin, phenytoin, carbamazepine) may reduce efficacy.

B. Gastric pH-altering agents:

• Antacids, PPIs, H2-receptor antagonists can reduce TKI absorption (particularly gefitinib and erlotinib).

C. QT-prolonging agents:

• Combining osimertinib with other QT-prolonging drugs (e.g., antiarrhythmics, certain antibiotics) increases risk of arrhythmias.

D. Monoclonal antibodies:

• Minimal CYP interaction.

• Live vaccines should be avoided due to immunosuppression.

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9. Dosing Overview

Drug	Typical Dose
Gefitinib	250 mg orally daily
Erlotinib	150 mg orally daily (NSCLC)
Afatinib	40 mg orally daily
Osimertinib	80 mg orally daily
Cetuximab	Initial 400 mg/m² IV, then 250 mg/m² weekly
Panitumumab	6 mg/kg IV every 2 weeks

Dosing adjustments may be required based on hepatic or renal impairment and toxicity profile.

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10. Monitoring Parameters

• Baseline and periodic EGFR mutation testing in NSCLC.

• Liver function tests (LFTs) for TKIs.

• Magnesium levels for monoclonal antibodies.

• Dermatologic examination regularly.

• ECG for QT prolongation (especially with osimertinib).

• Respiratory symptoms for early detection of ILD.

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11. Emerging Therapies and Research

• Fourth-generation EGFR TKIs are in development to target C797S mutation (resistance to osimertinib).

• Combination therapies (EGFR TKIs + MET inhibitors, VEGF inhibitors, or immune checkpoint inhibitors) are under active investigation.

• Bispecific antibodies targeting EGFR and MET or HER3 are being tested in clinical trials.

• Liquid biopsy (circulating tumor DNA) is increasingly used to detect resistance mutations and guide therapy adjustments.