Gefitinib (ZD1839,Iressa®): a selective epidermal growth factor receptor-tyrosine kinase inhibitor

Abstract

Objective: To provide a comprehensive review of the clinical pharmacology and toxicology of gefitinib, with particular attention to its use in early clinical trials.

Data source: A PubMed search was conducted using the terms ZD1839, gefitinib, and epidermal growth factor receptor (EGFR). All data from this search were reviewed and other relevant papers identified. The abstracts from the annual meetings of the American Society of Clinical Oncology were also reviewed.

Data extraction: The aim of the review was to be comprehensive and descriptive. The authors reviewed studies and case reports containing information deemed to be of interest.

Conclusions: EGFR is expressed, overex-pressed, or disregulated in a variety of human solid tumors, resulting in an enhancement of tumor growth. Gefitinib is a selective reversible inhibitor of EGFR that has shown activity in several tumor types. As an oral agent, it is extensively metabolized in the liver through the cytochrome P450 enzyme system, particularly the isoenzyme CYP3A4. In the phase II, IDEAL 1 and 2 trials, gefitinib has shown a response rate of 8.8% -18.4% in refractory lung cancer. Clinical trials in various other nonlung cancer patients include studies of gefitinib as a monotherapy or in combination with various chemotherapy, radiation, and/or hormone therapy regimens. Skin and gastrointestinal toxi-cities are the most frequent adverse events of gefitinib. Recently, interstitial pneumonia has emerged as one of the serious adverse effects among gefitinib patients. In summary, the role of gefitinib in combination or as a monotherapy for a variety of cancers is still evolving.

Keywords

epidermal growth factor receptor gefitinib Iressa®non-small cell lung cancer tyrosine kinase inhibitor ZD1839

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References

Sedlacek HH. Kinase inhibitors in cancer therapy: a look ahead. Drugs 2000; 59: 435-476.

Woodburn Jr. The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol Ther 1999; 12: 241-250.

Sung T , Miller DC , Hayes RL et al. Preferential inactivation of the p53 tumor suppresser pathway and lack of EGFR amplification distinguish de novo high grade pediatric astrocytomas from de novo adult astrocytomas. Brain Pathol 2000; 10: 249-259.

Porebska I , Harlozinska A , Bojarowski T. Expression of the tyrosine kinase activity growth factor receptors (EGFR, ERBB2, ERBB3) in colorectal adenocarcinomas and adenomas. Tumor Biol 2000; 21: 105-115.

Salmon DS , Brandt R , Ciardiello F et al. Epidermal growth factor related peptides and their receptors in human malignancies. Crit Rev Oncol-Haematol 1995; 19: 183-232.

De Bono JS , Rowinsky EK. The ErbB receptor family: a therapeutic target for cancer. Trends Mol Med 2002; 8(4 suppl): S19-S26.

Ciardiello F , Tortora G. A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor. Clin Cancer Res 2001; 7: 2958-2970.

Wakeling AE , Barker AJ , Davies DH et al. Specific inhibition of epidermal growth factor receptor tyrosine kinase by 4-anilinoquinazolines. Breast Cancer Res Treat 1996; 38: 67-73.

Raben D , Helfrich BA , Chan D et al. ZD1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor, alone and in combination with radiation and chemotherapy as a new therapeutic strategy in non-small cell lung cancer. Semin Oncol 2002; 29(suppl 4): 37-46.

10.

Ciardiello F , Caputo R , Bianco R et al. Antitumour effect and potentiation of cytotoxic drug activity in human cancer cells by ZD1839 (Iress), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res 2000; 6: 2053-2063.

11.

Woodburn JR , Barker AJ , Gibson KH et al. ZD1839, an epidermal growth factor tyrosine kinase inhibitor selected for clinical development. Proc Am Assoc Cancer Res 1997; 38: 633-634.

12.

Stea B , Falsey R , Carey S et al. Growth inhibition and radiosensitization of glioblastoma multiforme by the tyrosine kinase inhibitor ZD1839 (Iressa). Proc Am Assoc Cancer Res 2002; 43: abstract 3899.

13.

Sirotnak FM , Zakowski MF , Miller VA et al. Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by co-administration of ZD1829 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res 2000; 6: 4885-4892.

14.

Normanno N , Capiglio M , De Luca A et al. Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab on human breast cancer cell growth. Proc Am Assoc Cancer Res 2001; 42: 774-774.

15.

Moulder SL , Yakes FM , Muthuswami SK et al. Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2) overexpres-sing breast cancer cells in vitro and in vivo. Cancer Res 2001; 61: 8887-8895.

16.

Ciardiello F , Caputo R , Bianco R et al. ZD1839 (Iressa), an EGFR-selective tyrosine kinase inhibitor enhances activity of taxanes in bcl-2 overexpressing, multidrug resistant MCF-7 ADR human breast cancer cells. Proc Am Assoc Cancer Res 2001; 42: 853-853.

17.

Ciardiello F , Caputo R , Bianco R et al. Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa) a selective epidermal growth factor receptor kinase inhibitor. Clin Cancer Res 2001; 7: 1459-1465.

18.

Ranson M , Hammond L , Ferry D et al. ZD1839, a selective oral epidermal growth factor receptor-tyrsine kinase inhibitor is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. J Clin Oncol 2002; 20: 2240-2250.

19.

Swaisland H , Laight A , Stafford L et al. Pharmacokinetics and tolerability of the orally active selective epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in healthy volunteers. Clin Pharmacokinet 2001; 40: 297-306.

20.

Twelves C , White J , Harris AL et al. A phase I pharmacokinetic and tolerability trial of ZD1839 (Iressa) in hepatically impaired patients with solid tumours. Proc Am Soc Clin Oncol 2002; 21: 85a-85a (abstract 339).

21.

Swaisland H , Smith RP , Farebrother J et al. The effect of the induction and inhibition of CYP3A4 on the pharmacokinetics of single oral doses of ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), in healthy male volunteers. Proc Am Soc Clin Oncol 2002; 21: 83a-83a (abstract 328).

22.

Baselga J , Rischin D , Ranson M et al. Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 2002; 20: 4292-4302.

23.

Goss G , Hirte H , Lorimer I et al. Final results of the dose escalation phase of a phase I pharmacokinetics (PK), pharmacodynamic (PD) and biological activity study of ZD1839: NCIC-CTG IND.122. Proc Am Soc Clin Oncol 2001; 20: abstract 335.

24.

Baselga J , Herbst R , LoRusso P et al. Continuous administration of ZD1839 (Iressa), a novel oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFRTKI), in patients with five selected tumour types: evidence of activity and good tolerability. Proc Am Soc Clin Oncol 2000; 19: 177a-177a (abstract 686).

25.

Miller VA , Johnson DH , Krug LM et al. Pilot trial of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib plus carboplatin and paclitaxel in patients with stage IIIB or IV non-small cell lung cancer. J Clin Oncol 2003; 21: 2094-2100.

26.

Gonzalez-Larriba JL , Giaccone G , Van Oosterom AT et al. ZD1839 (Iressa) in combination with gemcitabine and cisplatin in chemonaive patients with advanced solid tumours: final results of phase I tiral. Proc Am Soc Clin Oncol 2002; 21: 95a-95a (abstract 376).

27.

Fukuoka M , Yano S , Giaccone G et al . Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 2003; 21: 2237-2246.

28.

Kris MG , Natale RB , Herbst RS et al. A phase II trial of ZD1839 (Iressa) in advanced non-small cell lung cancer (NSCLC) patients who had failed platinum and docetaxel based regimens (IDEAL 2). Proc Am Soc Clin Oncol 2002; 21: 292a-292a (abstract 1166).

29.

Negoro S , Nakagawa K , Fukuoka M et al. Final results from a phase I intermittent dose escalation trial of ZD1839 (Iressa) in Japanese patients with various solid tumors. Proc Am Soc Clin Oncol 2001; 20: 324a-324a (abstract 1292).

30.

Busam KJ , Capodieci P , Motzer R et al. Cutaneous side-effects in cancer patients treated with the antiepidermal growth factor receptor antibody C225. Br J Dermatol 2001; 144: 1169-1176.

31.

Hidalgo M , Siu LL , Nemunaitus J et al . Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 2001; 19: 3267-3279.

32.

Albanell J , Rojo F , Averbuch S et al. Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition. J Clin Oncol 2002; 20: 110-124.

33.

Inoue A , Saijo Y , Maemondo M et al. Severe acute interstitial pneumonia and gefitinib. Lancet 2003; 361: 137-139.

34.

AstraZeneca Pharmaceuticals LP. Iressa (gefitinib tablets) package insert. Wilmington, DE, USA, 2003.