Pharmacology Update

Gefitinib Tablets (Iressa—AstraZeneca)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

The FDA recently approved gefitinib, an inhibitor of tyrosine kinase activity of the epidermal growth factor receptor (EGFR), for the treatment of non-small-cell lung cancer (NSCLC). The drug received an accelerated approval, reserved for new drugs for life-threatening conditions. Gefitinib, which is administered orally once a day, is similar to imatinib (Gleevec). Gefitinib is marketed by AstraZeneca as "Iressa."


Gefitinib is approved as monotherapy for the treatment of patients with locally advanced or metastatic NSCLC after failure of both platinum-based and docetaxel chemotherapies.1


The recommended dose is 250 mg daily. It may be taken without regard to meals.

Gefitinib is available as 250 mg tablets. A 500-mg dose should be considered in patients with concomitant therapy with a potent inducer of CYP 3A4 (eg, rifampin, phenytoin).

A brief hiatus of up to 14 days, followed by reinstatement, may be considered in patients with poorly tolerated diarrhea or skin reaction.

Potential Advantages

In patients who have failed one or more chemotherapy regimens, gefitinib has been reported to produce objective radiographic response, improvement in disease-related symptoms, and quality of life in patients with NSCLC.1-3,8

Potential Disadvantages

Response rates were highly variable—5.1% in males, 17.5% in females, 4.6% in current or previous smokers, 29.4% in nonsmokers, 12.4% in adenocarcinomas, and 5.7% in other NSCLC.1 The addition of gefitinib to carboplatin and paclitaxel or cisplatin with gemcitabine failed to show any improvement in response rate, survival, or quality of life.1 Interstitial lung disease has been reported with use of the drug with a reported incidence of 2% in the Japanese postmarketing experience.4 The incidence ranged from 0.3% to 1% in US studies.1 Approximately one-third of the cases were fatal. Patients should be monitored for acute onset or worsening of pulmonary symptoms such as dyspnea, cough, or fever. Liver enzymes should be monitored for increases in liver transaminases. Gefitinib is metabolized by CYP 3A4 and can interact with inhibitors or inducers of this isoenzyme. Patients on warfarin should be monitored for possible elevation of the International Normalization Ratio (INR). Antisecretory drugs (histamine-2 receptor antagonists or proton pump inhibitors) may reduce the plasma levels of gefitinib. Other side effects associated with the 250 mg dose include diarrhea (48%), rash (43%), nausea (18%), and vomiting (12%). The onset of adverse events occurred within the first month.1


Gefitinib is an inhibitor of tyrosine kinase of the epidermal growth factor receptor. Activation of these receptors has been shown to increase angiogenesis, cell proliferation and metastasis and to decrease apoptosis.2 EGFR with tyrosine kinase activity is generally present in NSCLC specimens and in 25% of tumor specimens have been found to overexpress this activity.5 Despite this apparent targeted therapy, the mean response rate is somewhat modest. In patients who have received 2 or more chemotherapy regimens (n = 216), the mean radiographic tumor response rate for gefitinib monotherapy (250 mg or 500 mg) was 10.6% (95% CI, 6-16.8%).1,2,8 Median duration of response was 7 months (range, 4.4-18.6 months). About 40% of patients had symptomatic response, and 29% of patients showed improvement in quality of life. In patients who have failed 1 or 2 regimens (n = 210) the mean response rate was about 19%.2,3 One hundred and forty patients were assessed for symptom response and quality of life and about 38% and 23% showed improvement, respectively. Overall survival ranged from 6.0 to 7.9 months.8 The efficacy of 250 mg and 500 mg were similar, but the lower dose is better tolerated. The use of gefitinib as first-line treatment in combination with chemotherapy did not provide any benefit in terms of tumor response, time to progression, or overall survival.1,6,7 The FDA’s Oncology Drugs Advisory committee agreed that tumor response was sufficient for an accelerated approval, but improvement in symptoms or quality of life were not sufficient to support such claims.9 Gefitinib is generally well tolerated, with infrequent incidences of fatal interstitial lung disease reported. The wholesale cost of gefitinib is $1560 for a month’s supply.

Clinical Implications

Gefitinib may provide palliative treatment for patients with advanced disease who have failed both platinium-based and docetaxel chemotherapies. The overall benefit is modest, but variable, as some may gain greater benefit than others. AstraZeneca has agreed to complete 2 ongoing placebo-controlled survival trials in Phase IV.9  


1. Iressa Product Information. AstraZeneca Pharmaceuticals. May 2003.

2. Culy CR, Faulds D. Drugs. 2002;62(15):2237-2248.

3. Fukuoka M, et al. J Clin Oncol. 2003;May 13;Epub.

4. FDC Report. "The Pink Sheet." 2003;65(19):5-6.

5. Rusch V, et al. Clin Cancer Res. 1997;3:515-522.

6. Johnson DH, et al. Ann Oncol. 2002;12:127-128.

7. Giaconne G, et al. Ann Oncol. 2002;12:2-3.

8. Schiller J, et al. Chest. 2002;122(4 suppl):168S.

9. FDC Report. "The Pink Sheet." 2003;65(19):3-4.

Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Asst. Clinical Professor of Medicine, University of California-San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Both are associate editors of Internal Medicine Alert.