Iressa (Gefitinib, ZD1839)

BackgroundLung cancer is the leading cause of cancer death among men and women in the United States, with approximately 157,000 deaths per year.¹ The Ameri-can Society of Clinical Oncology estimates that 172,000 new cases of lung cancer are diagnosed each year, 80% of which are deemed non?small cell lung cancer (NSCLC). Survival rates at 1 year for people with lung cancer are 42%.² Among the major risk factors for lung cancer are tobacco smoking (including cigarettes, cigars, pipes, and environmental smoke), asbestos, and radon. Currently, treatment for lung cancer includes surgery, radiation, and chemotherapy. The mainstays of chemotherapy have included platinum-based regimens and docetaxel. With low rates of 1-year survival, researchers have investigated new avenues for the treatment of lung cancer. Iressa, manufactured by AstraZeneca and recently approved by the FDA, is indicated as monotherapy for the treatment of locally advanced or metastatic NSCLC after failure of both platinum-based and docetaxel chemotherapies.Pharmacology

Iressa is thought to inhibit the intra-cellular phosphorylation of tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the epidermal growth factor receptor (EGFR-TK). Expression of EGFR has been widely reported in human tumors and has been associated with metastasis, late-stage disease, resistance to chemotherapy, and poor prognosis.³ Iressa is absorbed slowly, with peak plasma levels occurring 3 to 7 hours after dosing. The mean oral bioavail-ability of Iressa is 60%, which is not significantly altered by food. Iressa undergoes extensive hepatic metabolism in humans, predominantly by CYP3A4. Excretion occurs mostly via the feces (86%), with renal elimination of drug and metabolites accounting for less than 4% of the administered dose. The elimination half-life of Iressa is approximately 48 hours.³Clinical Trials

The Iressa Dose Evaluation in Advanced Lung cancer study (IDEAL-2) evaluated the efficacy of Iressa (250 mg vs 500 mg) as third-line therapy in 142 patients who had failed platinum and docetaxel therapies due to toxicity or lack of efficacy on these agents. In the group receiving the recommended dose of 250 mg/day, response rates (defined as at least 50% tumor shrinkage lasting at least 1 month) were reported to be 13.6% (n = 66). Patients receiving 500 mg/day were reported to have a 7.9% (n = 76) response rate and to have experienced a greater incidence of adverse effects. The overall combined response rate for the 250-and 500-mg doses was 10.6%.⁴ The Iressa NSCLC Trial Assessing Combination Treatment (INTACT I & II) trials were large, placebo-controlled, randomized studies examining the use of Iressa as first-line therapy for chemotherapy-naive patients with stage III or IV NSCLC. Patients (n = 2130) were randomized to receive Ires-sa 250 mg, 500 mg, or placebo, all in combination with platinum therapy. The results showed no statistically significant differences in overall survival. Thus, there was no benefit from adding Iressa to standard platinum-based chemotherapy.^5,6Safety Cases of interstitial lung disease have been observed in patients receiving Ires-sa at an overall incidence of about 1% (2% in Japan and 0.3% in the United States), one third of these cases being fatal. The most frequent adverse effects reported with Iressa include diarrhea (48%), rash (43%), acne (25%), dry skin (13%), nausea (13%), and vomiting (12%).³ In clinical trials, 2% of patients stopped taking Iressa because of an adverse drug reaction. Iressa is metabolized by CYP3A4; therefore, inducers and inhibitors of this enzyme should be used with caution if taken concomitantly.

Outlook

The recommended dose of Iressa is a single 250-mg tablet daily. Iressa appears to be useful as a last-line agent for the treatment of NSCLC after all traditional treatment options have failed. Continued long-term safety analysis and phase 4 studies are warranted with regard to the drug?s clinical application.

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