Gefitinib
Introduction
Gefitinib is an epidermal growth factor receptor (EGFR) inhibitor used in the treatment of certain types of non-small cell lung cancer (NSCLC). It is a small molecule tyrosine kinase inhibitor (TKI) that specifically targets the EGFR tyrosine kinase domain, thereby inhibiting the downstream signaling pathways that promote tumor cell proliferation and survival. Gefitinib is marketed under the trade name Iressa and was the first EGFR TKI to be approved for clinical use.
Mechanism of Action
Gefitinib exerts its therapeutic effects by binding to the adenosine triphosphate (ATP) binding site of the EGFR tyrosine kinase domain. This binding inhibits the autophosphorylation of the receptor, which is necessary for the activation of downstream signaling pathways such as the Ras-Raf-MEK-ERK pathway and the PI3K-AKT pathway. These pathways are crucial for cell proliferation, survival, and differentiation. By inhibiting these pathways, gefitinib effectively reduces the growth and survival of cancer cells that overexpress or harbor mutations in the EGFR gene.
Pharmacokinetics
Gefitinib is administered orally and has a bioavailability of approximately 60%. It is extensively metabolized in the liver, primarily by the cytochrome P450 enzyme CYP3A4. The drug and its metabolites are excreted mainly via the feces, with a minor portion excreted in the urine. The half-life of gefitinib is approximately 48 hours, allowing for once-daily dosing. Factors such as liver function, concomitant medications, and genetic polymorphisms in metabolic enzymes can influence the pharmacokinetics of gefitinib.
Clinical Applications
Gefitinib is primarily used in the treatment of NSCLC, particularly in patients with activating mutations in the EGFR gene. These mutations, often found in exons 18-21, lead to constitutive activation of the receptor and increased sensitivity to EGFR TKIs. Gefitinib has shown significant efficacy in patients with these mutations, leading to improved progression-free survival and overall response rates compared to conventional chemotherapy.
First-Line Therapy
In patients with EGFR-mutant NSCLC, gefitinib is often used as a first-line therapy. Clinical trials have demonstrated its superiority over platinum-based chemotherapy in this patient population. The IPASS trial, for example, showed that gefitinib significantly improved progression-free survival compared to carboplatin-paclitaxel in Asian patients with advanced NSCLC harboring EGFR mutations.
Second-Line Therapy
Gefitinib can also be used as a second-line therapy in patients who have progressed on or are intolerant to first-line chemotherapy. In this setting, gefitinib has been shown to provide clinical benefit, particularly in patients with EGFR mutations or high EGFR protein expression.
Resistance Mechanisms
Despite the initial efficacy of gefitinib, most patients eventually develop resistance to the drug. Several mechanisms of resistance have been identified, including secondary mutations in the EGFR gene (e.g., T790M mutation), activation of alternative signaling pathways (e.g., MET amplification), and phenotypic changes such as epithelial-to-mesenchymal transition (EMT). Understanding these resistance mechanisms has led to the development of next-generation EGFR TKIs and combination therapies aimed at overcoming resistance.
Adverse Effects
The most common adverse effects of gefitinib include skin rash, diarrhea, and elevated liver enzymes. These side effects are generally mild to moderate in severity and can often be managed with supportive care. More serious adverse effects, such as interstitial lung disease (ILD), although rare, can occur and may require discontinuation of the drug.
Drug Interactions
Gefitinib is metabolized by CYP3A4, and its plasma levels can be affected by drugs that induce or inhibit this enzyme. For example, concomitant use of CYP3A4 inducers such as rifampicin can reduce gefitinib levels and efficacy, while CYP3A4 inhibitors such as ketoconazole can increase gefitinib levels and the risk of adverse effects. Additionally, gefitinib can interact with drugs that alter gastric pH, such as proton pump inhibitors, which can reduce its absorption.
Pharmacogenomics
The efficacy of gefitinib is closely linked to the presence of specific EGFR mutations. Patients with activating mutations in the EGFR gene, particularly those in exons 19 and 21, are more likely to respond to gefitinib. Conversely, patients with wild-type EGFR or resistance mutations such as T790M are less likely to benefit from the drug. Genetic testing for EGFR mutations is therefore recommended before initiating gefitinib therapy.
Future Directions
Research is ongoing to improve the efficacy and overcome resistance to gefitinib. Strategies include the development of next-generation EGFR TKIs, combination therapies targeting multiple pathways, and personalized treatment approaches based on the molecular profile of the tumor. Additionally, efforts are being made to identify biomarkers that can predict response to gefitinib and monitor treatment efficacy.