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Gefitinib

Gefitinib

Gefitinib

Introduction

Gefitinib is a targeted anticancer therapy that has significantly changed the landscape of treatment for non-small cell lung cancer (NSCLC). As an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), gefitinib selectively targets cancer cells with specific mutations, resulting in improved efficacy and reduced systemic toxicity compared to traditional chemotherapies. Since its approval, gefitinib has played a pivotal role in precision oncology.

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Drug Overview

Generic Name: Gefitinib

Brand Name: Iressa

Drug Class: Tyrosine kinase inhibitor (TKI)

Chemical Formula: C22H24ClFN4O3

Molecular Weight: 446.9 g/mol

Gefitinib was one of the first targeted therapies approved for cancer and is particularly beneficial in patients with EGFR mutation-positive NSCLC.

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Mechanism of Action

Gefitinib inhibits the intracellular tyrosine kinase domain of the epidermal growth factor receptor (EGFR). EGFR is a transmembrane receptor involved in the regulation of cellular proliferation, survival, and differentiation.

By binding to the ATP-binding site of EGFR, gefitinib prevents autophosphorylation and downstream signaling through pathways such as:

Ras/Raf/MEK/ERK (cell proliferation)

PI3K/AKT/mTOR (cell survival)

This inhibition induces cell cycle arrest and apoptosis in tumor cells that rely on EGFR signaling.

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Indications and Clinical Uses

Gefitinib is primarily indicated for:

1. Non-Small Cell Lung Cancer (NSCLC)

First-line therapy for patients with EGFR mutation-positive advanced or metastatic NSCLC.

Effective in exon 19 deletions and exon 21 L858R point mutations.

2. Off-label Uses (under investigation or in limited cases):

Head and neck squamous cell carcinoma

Advanced breast cancer

Esophageal cancer

Colorectal cancer

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Dosage and Administration

Standard Dose: 250 mg orally once daily

Route: Oral tablet

Food: Can be taken with or without food

Special Considerations:

Tablets can be dispersed in water for patients with swallowing difficulties.

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Pharmacokinetics

Absorption: Rapid oral absorption with peak plasma levels in 3–7 hours

Bioavailability: Moderate (~60%)

Protein Binding: >90%

Metabolism: Hepatic (CYP3A4 is the main enzyme)

Half-Life: 41 hours

Excretion: Primarily fecal

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EGFR Mutation Testing

Before initiating gefitinib therapy, patients should undergo EGFR mutation testing. This involves genetic testing of tumor tissue (biopsy) or liquid biopsy (circulating tumor DNA) to identify activating mutations.

Only patients with confirmed EGFR mutations are likely to benefit from gefitinib.

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Clinical Efficacy

Gefitinib has demonstrated impressive efficacy in several large-scale clinical trials:

IPASS Trial: In EGFR-mutated NSCLC patients, gefitinib significantly improved progression-free survival (PFS) compared to chemotherapy.

NEJ002 and WJTOG3405 Trials: Showed superior response rates and quality of life in patients on gefitinib versus standard platinum-based chemotherapy.

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Resistance to Gefitinib

Despite initial responsiveness, most patients develop resistance to gefitinib within 9–14 months. Common mechanisms include:

T790M Mutation: A secondary mutation in the EGFR gene that reduces gefitinib binding.

MET Amplification: Activates downstream pathways independent of EGFR.

Histologic Transformation: NSCLC transforming into small cell lung cancer.

Overcoming Resistance:

Second- and third-generation TKIs (e.g., osimertinib) can target resistance mutations like T790M.

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Adverse Effects

Gefitinib is generally well-tolerated compared to cytotoxic chemotherapy. Common side effects include:

Common:

Diarrhea

Acneiform rash

Dry skin

Nausea

Fatigue

Less Common but Serious:

Interstitial lung disease (rare but potentially fatal)

Hepatotoxicity (elevated liver enzymes)

Gastrointestinal perforation (rare)

Patients should be monitored closely for pulmonary symptoms and liver function.

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Contraindications and Precautions

Contraindications:

Known hypersensitivity to gefitinib or any component of the formulation

Cautions:

Pre-existing lung disease (higher risk of ILD)

Hepatic impairment

Concomitant use of CYP3A4 inducers or inhibitors

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Drug Interactions

CYP3A4 Inhibitors (e.g., ketoconazole): May increase gefitinib levels

CYP3A4 Inducers (e.g., rifampicin): May reduce gefitinib efficacy

Proton Pump Inhibitors (PPIs): May lower gefitinib absorption

Warfarin: Potential for increased anticoagulant effect

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Monitoring Parameters

Liver function tests

Pulmonary symptoms (cough, dyspnea)

Skin reactions

Periodic imaging to assess tumor response

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Use in Special Populations

Pregnancy:

Gefitinib is classified as Pregnancy Category D

Not recommended unless benefits outweigh risks

Breastfeeding:

Excretion in breast milk unknown; avoid breastfeeding

Elderly:

No dose adjustment required; monitor closely for side effects

Renal Impairment:

Use with caution; renal clearance is not the primary route

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Comparison with Other EGFR TKIs

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Patient Counseling Points

Take the tablet once daily at the same time

Report any new or worsening respiratory symptoms immediately

Avoid grapefruit and grapefruit juice

Practice good skin care to manage rash

Do not take antacids or PPIs without consulting a doctor

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Research and Future Directions

Combination Therapies:

Gefitinib combined with anti-angiogenic agents (e.g., bevacizumab) is under clinical investigation

Biomarker Research:

Exploring additional predictive biomarkers beyond EGFR

Resistance Mechanism Studies:

Identifying new resistance mutations and developing tailored TKIs

Immunotherapy Combinations:

Studying synergy between gefitinib and immune checkpoint inhibitors

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Conclusion

Gefitinib revolutionized the treatment of EGFR mutation-positive NSCLC by offering a personalized, targeted approach that delivers better outcomes and quality of life compared to conventional chemotherapy. Despite the challenge of resistance, gefitinib continues to be a cornerstone in the first-line treatment of selected NSCLC patients. Ongoing research into combination therapies and resistance mechanisms promises to further enhance its utility and prolong patient survival.

With its targeted mechanism, manageable side effect profile, and role in precision oncology, gefitinib exemplifies the progress of modern cancer therapy and continues to offer hope to thousands of lung cancer patients worldwide.

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