Emerging Trends in Combinations of Gefitinib and Cytotoxic Agents: New Opportunities

Accessible online at: www.karger.com/onk Fax +49 761 4 52 07 14 E-mail Information@Karger.de www.karger.com are in clinical development (table 1). Among these inhibitors, gefitinib (ZD1839, Iressa®) is one of the compounds with the largest preclinical and clinical development. Gefitinib is an oral anilinoquinazoline, a selective and reversible EGFR-TKI that blocks signal transduction pathways implicated in cancer cell proliferation and other processes connected with cancer growth. Early limited preclinical studies – with in vitro and in vivo evaluation – showed high antitumour activity against different tumour types [8–11]. Moreover, this activity was shown not only when this compound was administered as a single agent but also in combination with several cytotoxic drugs and with radiation therapy. These encouraging results led to the development of a vast clinical programme of gefitinib in many tumour types, with special emphasis on patients with non-small cell lung cancer (NSCLC). The initial phase I studies showed gefitinib to have a good safety profile, with clear clinical activity in some tumour types including NSCLC [12]. Two large randomised phase II studies demonstrated that gefitinib was active in patients with advanced NSCLC refractory to, at least, one previous chemotherapy treatment [13, 14]. The efficacy results of these two studies were consistent, leading to a fast-track approval by the FDA with the indication of treatment for patients with advanced NSCLC refractory to standard chemotherapy treatment. The next step was to demonstrate that gefitinib could improve the efficacy results of first-line treatment when combined to standard chemotherapy schedules. Some preclinical studies favoured this approach although the experiments were limited with only few tumour cell lines evaluated. The initial phase I studies combining standard chemotherapy schedules with gefitinib showed that this approach was feasible. Two well-designed phase III studies evaluated the role of the addition of gefitinib to two different first-line schedules – cisplatin/gemcitabine and carboplatin/paclitaxel. Unfortunately, these two studies failed to demonstrate any advantage with In the last 10 years, many pharmacological and biological approaches have been tested to develop novel targeted agents that are able to selectively inhibit important pathways that control cancer cell proliferation and growth [1]. The blockade of the epidermal growth factor receptor (EGFR) signal transduction pathway has emerged as one of the most successful strategies in the treatment of cancer with a wide preclinical and clinical evaluation [2]. The EGFR is a transmembrane glycoprotein with three different parts: an external ligandbinding domain, a transmembrane domain and an intracellular tyrosine kinase domain with catalytic activity [3]. Once the ligands – mainly TGF-α and EGF – bind to the receptor, a dimerisation process is induced. It results in the formation of either homodimers or heterodimers with other receptors of the HER family, producing autophosphorylation of different tyrosine residues located in the catalytic domain of the receptor, triggering different signalling transduction cascades that lead, at the end, to critical cellular processes such as proliferation, survival, angiogenesis and production of metastasis (fig. 1). The EGFR plays a critical role in most of human carcinomas. Enhanced expression of the ligands – mainly TGF-α – and the EGFR itself has been observed in these tumours and has been shown to negatively correlate with prognosis in many tumour types. EGFR overexpression has been observed in cell lines that are resistant to different cytotoxic drugs. For these and other reasons the EGFR signalling pathway has been in the forefront of the development of targeted therapies directed to control tumour growth. Several pharmacological approaches have been developed to block the EGFR itself. However, only two strategies have reached advanced clinical development: monoclonal antibodies directed to the extracellular domain that compete with the natural ligands [4–6], and low-weight molecules with tyrosine kinase inhibition capacity directed to the endodomain of the receptor [6, 7]. Several tyrosine kinase inhibitors (TKIs) directed to the EGFR Emerging Trends in Combinations of Gefitinib and Cytotoxic Agents: New Opportunities