At the Epidermal Growth Factor Receptor Tyrosine Kinase

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A. E. Wakeling

AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK [email protected]

1 Rationale 434

2 Pharmacology 436

2.1 Enzyme Inhibition 436

2.2 Inhibition of Tumour Cell Growth In Vitro 437

2.3 In Vivo Anti-tumour Activity 438

3 Clinical Studies 439

3.1 Phase I Trials 439

3.2 Phase II Trials 440

3.3 Phase III Trials 442

4 Future Prospects 442

References 443

Abstract The epidermal growth factor receptor (EGFR) is a promising target for anti-cancer therapy because of its role in tumour growth, metastasis and angiogenesis, and tumour resistance to chemotherapy and radiotherapy. This chapter describes a low-molecular-weight EGFR tyrosine kinase inhibitor (EGFR-TKI), Iressa (gefitinib, ZD1839). Iressa is a potent EGFR-TKI which blocks EGF-stimulated EGFR autophosphorylation in tumour cells and selectively inhibits EGF-stimulated tumour cell growth. In studies with mice bearing a range of human tumour-derived xenografts, Iressa given orally, once daily, inhibited tumour growth in a dose-dependent manner. Long-term (>3 months) Iressa treatment of xenograft-bearing mice was well tolerated, and Iressa completely inhibited the growth of xenografts derived from A431 cells which highly express EGFR, and induced regression of advanced A431-derived tumours. No Iressa-resistant tumours appeared during treatment, but some tumours regrew following drug withdrawal. The level of expression of EGFR did not determine xenograft tumour sensitivity to Iressa. These preclinical studies indicated the potential utility of Iressa in the treatment of a wide range of human tumours, and established that continuous once-daily oral dosing might be a suitable therapeutic regimen. The first clinical studies with Iressa confirmed that an oral, once-daily, regimen is generally well tolerated and shows activity in cancer patients. Phase II clinical trials, in patients with advanced non-small-cell lung cancer (NSCLC) who had been previously treated with chemotherapy, demonstrated that Iressa at a daily dose of 250 or 500 mg has a favourable safety profile and has activity. The lower (250 mg/day) dose was better tolerated and as effective as the 500 mg/day dose. In these phase II studies, the level of expression of EGFR did not predict response to Iressa treat ment. In phase III clinical trials, addition of Iressa to standard two-drug chemotherapy regimens, in previously untreated NSCLC patients, failed to improve disease-free or overall survival. Studies are now underway to investigate how Iressa can be used as an alternative to or in sequence with chemotherapy in NSCLC, and to explore its efficacy in other tumours including head and neck, breast and colorectal.

Keywords Iressa ■ Gefitinib ■ ZD1839 ■ Epidermal growth factor receptor ■ EGFR tyrosine kinase inhibitor ■ NSCLC

Iressa is a trademark of the AstraZeneca group of companies. 1

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