Gefitinib

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Abstract
Gefitinib (Iressa™), the first commercially available epidermal growth factor receptor-tyrosine kinase (EGFR-TK) inhibitor, is indicated in the management of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). However, approved uses differ between countries; in most markets, gefitinib is approved for third-line use only (e.g. the US, Canada and Switzerland), although in some it is approved for both second- and third-line use (e.g. Japan and Australia) and, additionally, in patients considered unsuitable for chemotherapy (e.g. Indonesia and the Philippines). Few third-line treatment options exist for patients with inoperable advanced NSCLC who have failed both platinum-based and docetaxel chemotherapies. Gefitinib represents a significant advance in the treatment of this population; a once-daily, oral dosage of 250 mg/day was well tolerated, produced objective tumour responses and disease stabilisation, and improved disease-related symptoms and quality of life. It also produced overall survival outcomes that compared favourably with historical outcomes in a similar group of patients treated with three or four different chemotherapy regimens. These findings have been supported by observations from a global compassionate-use programme. Ongoing or planned clinical trials are designed to confirm and/or further define the role of the drug in the above and other clinical settings. Gefitinib is a low molecular weight inhibitor of EGFR-TK, an enzyme that regulates intracellular signalling pathways implicated in the pathogenesis of many solid tumours. The drug demonstrates antitumour activity in preclinical models of NSCLC including platinum-and docetaxel-resistant cell lines and xenografts. Preliminary human data suggest that the majority of responses to gefitinib (i.e. ≥50% tumour shrinkage) correlate with the presence of EGFR-TK somatic mutations. Orally administered gefitinib is absorbed moderately slowly; peak plasma concentrations are typically achieved 3–5 hours after administration (50–700 mg/ day) in patients with solid tumours. The drug has a bioavailability of ≈60%, which is unaffected by food. Steady-state plasma concentrations are reached in 7–10 days. Gefitinib is mainly cleared by hepatic metabolism (cytochrome P450 3A4 pathway) and mostly excreted in the faeces (86% of the administered dose). The average elimination half-life was 48 hours after administration (50–700 mg/day) in patients with solid tumours. Two phase II trials (IDEAL [Iressa Dose Evaluation in Advanced Lung Cancer]-1 and -2), evaluated the efficacy of gefitinib 250 and 500 mg/day in 210 (IDEAL-1) and 216 (IDEAL-2) patients with advanced NSCLC who had received one or two (IDEAL-1) or two or more (IDEAL-2) previous chemotherapy regimens. In both trials the two dosages were found to be similarly effective; however, 250 mg/day was better tolerated and is, therefore, the recommended dosage. Response rates with the recommended dosage of gefitinib 250 mg/day in IDEAL-1 and -2, respectively, were as follows: objective tumour response (all partial), 18% and 12%; disease control (i.e. objective tumour response + stable disease), 54% and 42%; symptom improvement, 40% and 43%; and quality-of-life improvement, 24% and 34%. Patients survived for a median of 7.6 and 7 months, and 1-year survival rates were 35% and 29%. Interestingly, a post hoc analysis of the IDEAL-1 results found that of the patients who had previously received (and failed) platinum-based and docetaxel chemotherapies, 24% had an objective tumour response when treated with gefitinib 250 mg/day. Responses to gefitinib were rapid (≈70% of objective tumour responses achieved within the first month; median onset of symptom improvement 8–10 days) and sustained (median duration of objective tumour response 7−13 months). Survival duration was correlated with tumour response and symptom improvement in both trials. Findings from the global Expanded Access Programme (EAP) with gefitinib 250 mg/day monotherapy in advanced NSCLC are supportive of the results of phase II trials. Median survival duration was 5.3 months and 1-year survival was 29.9% among US participants (n = 21 064). Objective tumour response rates ranged from 4.5% to 9.6% and disease control rates ranged from ≈44% to 55% in individual series of pretreated patients participating in the European EAP (n =40-124). In chemotherapy-naive patients with advanced NSCLC, gefitinib dosages of 250 and 500 mg/day combined with platinum-based chemotherapy (gemcitabine/ cisplatin or paclitaxel/carboplatin) did not show greater efficacy compared with chemotherapy alone in two large, randomised, placebo-controlled, multicentre phase III trials (n > 1000). In other investigations in the first-line setting, gefitinib 250 or 500 mg/day monotherapy demonstrated antitumour activity (i.e. objective response or disease stabilisation) in chemotherapy-naive patients with advanced NSCLC, including those with bronchioalveolar carcinoma and individuals unwilling or unable to receive chemotherapy. Adverse effects were less frequent and milder in patients receiving monotherapy with gefitinib 250 mg/day compared with those receiving 500 mg/day, leading to fewer treatment withdrawals, dose modifications or dose interruptions. Mild-to-moderate (National Cancer Institute Common Toxicity Criteria grade 1 or 2) skin changes and gastrointestinal symptoms were the most frequent adverse drug reactions in patients receiving gefitinib 250 mg/day in IDEAL-1 and -2. These events, which typically occurred within the first month of treatment, were noncumulative and manageable. Results from the overall safety database (>92 000 patients treated in pre-and postmarketing studies, including the EAP, prior to September 2003) suggest that gefitinib at a dosage of 250 mg/day is not associated with haematological, neurological or nephrological toxicities...