Zactima (ZD6474) is an orally available Tyrosine Kinase Inhibitor (TKI) under development by AstraZeneca for the treatment of solid tumours. Following promising results in early clinical trials, Zactima has now progre ed to phase III development in Non-Small Cell Lung Cancer ( CLC), its primary indication.
If phase III trials prove succe ful, analysts believe Zactima could be on the market by 2008 and help to fill the void left by recent setbacks with Ire a (gefitinib), its first TKI for lung cancer.
At the begi ing of the year, AstraZeneca withdrew its marketing a lication for Ire a in Europe. This followed the release of new long-term data that showed it to be no better than placebo in prolonging patients\' lives.
Meanwhile, in the US Ire a will soon be available only to existing CLC patients who have already shown treatment benefit and will not be prescribed to new patients. While Ire a has stalled in Europe and the US, it is a roved in more than 30 countries elsewhere.
TYROSINE KINASE INHIBITORS (TKI) - A GROWING CLA OF ANTI-CANCER AGENTS
Protein tyrosine kinases are enzymes that provide a central switch mechanism in cellular signal tra duction pathways. As such they are involved in many cellular proce es such as cell proliferation, metabolism, survival and apoptosis. Several protein tyrosine kinases are known to be activated in cancer cells and to drive tumour growth and progre ion. Blocking tyrosine kinase activity therefore represents a rational a roach to cancer therapy.
Zactima is an orally active inhibitor of Vascular Endothelial Growth Factor (VEGF) receptor-2 (KDR) tyrosine kinase with additional activity agai t Epidermal Growth Factor Receptor (EGFR) tyrosine kinase, a property it shares with Ire a (gefitinib). VEGF is a pro-angiogenesis factor that binds to receptors on blood ve els and stimulates the growth of new blood ve els, an important proce in tumour di emination (metastasis).
By inhibiting the action of VEGF, Zactima also acts as an angiogenesis inhibitor. Thus, Zactima exerts its anti-tumour effects by a variety of mechanisms. In this re ect it differs from Ire a, which is a selective EGFR-TKI.
ZACTIMA ADVANCES TO PHASE III TRIALS IN CLC
In July 2005, AstraZeneca a ounced pla for phase III development of Zactima in CLC. This followed succe ful outcome in a phase II trial in which Zactima was combined with docetaxel in patients with locally-advanced or advanced CLC.
The preliminary results of the phase II trial were presented at the American Society of Oncology a ual meeting in May 2005, and showed that Zactima in combination with docetaxel, increased progre ion-free survival in this patient population. Although the combination regimen did not increase overall survival, the secondary clinical endpoint, it was suggested that this might have been due to the relatively small number of patients studied.
IMPROVING TREATMENT OPTIO FOR LUNG CANC