Phase III Trials

The standard first treatment for patients with advanced NSCLC is combination chemotherapy with a platinum-based, two-drug regimen (e.g. cisplatin or carboplatin combined with gemcitabine, docetaxel or paclitaxel). Based on preclinical studies which showed that Iressa enhanced the efficacy of individual cytotoxic agents against a range of human tumour cell lines and xenografts—independent of the level of EGFR expression (Ciardiello et al. 2000; Sirotnak et al. 2000)—two phase III studies (Iressa NSCLC Trials Assessing Combination Treatment, INTACT 1 and 2) investigated Iressa combination with chemotherapy in more than 2,000 previously untreated NSCLC patients. Patients in INTACT 1 received cisplatin and gemcitabine, while patients in INTACT 2 received carboplatin and paclitaxel, and in both trials the chemotherapy was combined with Iressa 250 mg/day, Iressa 500 mg/day, or placebo. In both studies, addition of Iressa to chemotherapy failed to improve response rate, disease-free survival, or overall survival compared with chemotherapy given alone (Giaccone et al. 2004; Herbst et al. 2004). However, these placebo-controlled studies confirmed the favourable safety profile of Iressa reported in the IDEAL trials. Except for addition of dose-dependent diarrhoea and skin rash, which was less frequent in the 250-mg/day group, the toxicity profile was similar to that in patients receiving chemotherapy alone. The failure to translate the added benefit of combining Iressa and chemotherapy, anticipated from animal model studies (Ciardiello et al. 2000; Sirotnak et al. 2000), into the clinical setting in the INTACT trials is disappointing but should not be interpreted to mean that such combinations will be inappropriate in all settings (other stages of disease/other tumours/other agents). No animal studies were performed examining concurrent treatment with two cytotoxic agents and Iressa.

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