On May 5, 2003,
gefitinib (
Iressa;
ZD1839) 250-mg
tablets (AstraZeneca Inc.) received accelerated approval by the United States Food and Drug Administration as monotherapy for patients with locally advanced or metastatic
non-small cell lung cancer after failure of both
platinum-based and
docetaxel chemotherapies. Information provided in this summary includes chemistry manufacturing and controls, clinical pharmacology, and clinical trial efficacy and safety results.
Gefitinib is an
anilinoquinazoline compound with the chemical name 4-quinazolinamine,N-(3-chloro-4-flurophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]. It has the molecular formula C(22)H(24)ClFN(4)O(3).
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 microM 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 post-marketing 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 disease-related symptoms or increased survival. Accelerated approval regulations require the sponsor to conduct additional studies to verify that
gefitinib therapy produces such benefit.