United States Food and Drug Administration Drug Approval Summary

Abstract

Gefitinib is often referred to as a "specific" or "selective" inhibitor of epidermal growth factor receptor. Studies demonstrate, however, that gefitinib inhibits the activity of other intracellular transmembrane tyrosine-specific protein kinases at concentrations similar to those at which it inhibits the epidermal growth factor signal. Maximum plasma concentrations resulting from clinically relevant doses are 0.5-1 M or more, well within the IC 50 values of several tyrosine kinases. No clinical studies have been performed that demonstrate a correlation between epidermal growth factor receptor expression and response to gefitinib. Gefitinib is 60% available after oral administration and is widely distributed throughout the body. Gefitinib is extensively metabolized in the liver by cytochrome P450 3A4 enzyme. Over a 10-day period, approximately 86% of an orally administered radioactive dose is recovered in the feces, with <4% of the dose in the urine. After daily oral administration, steady-state plasma levels are reached in 10 days and are 2-fold higher than those achieved after single doses. Gefitinib effectiveness was demonstrated in a randomized, double-blind, Phase II, multicenter trial comparing two oral doses of gefitinib (250 versus 500 mg/day). A total of 216 patients were enrolled. The 142 patients who were refractory to or intolerant of a platinum and docetaxel comprised the evaluable population for the efficacy analysis. A partial tumor response occurred in 14% (9 of 66) of patients receiving 250 mg/day gefitinib and in 8% (6 of 76) of patients receiving 500 mg/day gefitinib. The overall objective response rate (RR) for both doses combined was 10.6% (15 of 142 patients; 95% confidence interval, 6.0 -16.8%). Responses were more frequent in females and in nonsmokers. The median duration of response was 7.0 months (range, 4.6 -18.6؉ months). Other submitted data included the results of two large trials conducted in chemotherapy-naive, stage III and IV non-small cell lung cancer patients. Patients were randomized to receive gefitinib (250 or 500 mg daily) or placebo, in combination with either gemcitabine plus cisplatin (n ‫؍‬ 1093) or carboplatin plus paclitaxel (n ‫؍‬ 1037). Results from this study showed no benefit (RR, time to progression, or survival) from adding gefitinib to chemotherapy. Consequently, gefinitib is only recommended for use as monotherapy. Common adverse events associated with gefitinib treatment included diarrhea, rash, acne, dry skin, nausea, and vomiting. Interstitial lung disease has been observed in patients receiving gefitinib. Worldwide, the incidence of interstitial lung disease was about 1% (2% in the Japanese postmarketing experience and about 0.3% in a United States expanded access program). Approximately one-third of the cases have been fatal. Gefitinib was approved under accelerated approval regulations on the basis of a surrogate end point, RR. No controlled gefitinib trials, to date, demonstrate a clinical benefit, such as improvement in diseaserelated symptoms or incr...

An Apoferritin‐based Drug Delivery System for the Tyrosine Kinase Inhibitor Gefitinib

“…[ 18 ] Gefi tinib ("Iressa," ZD1839) is an orally active, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. [ 19 ] This receptor family comprises four homologous receptors: EGFR (ErbB1/HER1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4), which have an extracellular ligand binding domain, a single hydrophobic trans-membrane domain and a cytoplasmic tyrosine kinase domain. These receptors are activated by either homo-or heterodimerization upon ligand binding resulting in phosphorylation of specifi c tyrosine residues.…”

“…[ 24,25 ] However, the therapeutic window of this drug is drastically narrowed by poor bioavailability, acquired resistance due to insuffi cient or ineffective cellular uptake and systemic toxicity resulting from interactions between drug and healthy tissue. [ 19,26 ] Also, orally administered Gefi tinib is taken up extensively by human serum albumin and hence other delivery systems such as liposomes have been investigated. [ 27 ] Development of a selective targeted delivery system would improve effi ciency of Gefi tinib treatment.…”

A combination of gefitinib and FOLFOX-4 as first-line treatment in advanced colorectal cancer patients. A GISCAD multicentre phase II study including a biological analysis of EGFR overexpression, amplification and NF-kB activation

“…Gefitinib is a potent small-molecule inhibitor of tyrosine kinase domain of EGFR. It has demonstrated activity in non-small-cell lung cancer (Cohen et al, 2004). It is orally available and is an attractive therapeutic option in colorectal cancer patients.…”

Analysis of FDA Approved Anticancer Drugs Reveals the Future of Cancer Therapy

“…No clinical studies have been performed that demonstrate a correlation between epidermal growth factor receptor expression and response to gefitinib. 28 In drug combinations, gefitinib showed no added benefit in survival or time to progression compared with standard chemotherapy alone. 29 So far, gefitinib is not effective in drug combinations, [29][30][31] but it causes 10% responses alone.…”