Zactima - Tyrosine Kinase Inhibitor for Treatment of Lung Cancer

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 progressed to phase III development in non-small cell lung cancer (NSCLC), its primary indication. If phase III trials prove successful, analysts believe Zactima could be on the market by 2008 and help to fill the void left by recent setbacks with Iressa (gefitinib), its first TKI for lung cancer.

In addition to NSCLC, Zactima is also being investigated as a treatment for thyroid cancers. It was granted orphan drug status by the FDA for the treatment of follicular, medullary, anaplastic, and locally advanced and metastatic papillary thyroid cancers. Phase II studies are ongoing in medullary thyroid cancer, a rare malignancy associated with poor prognosis and one for which there are very few treatment options.

TYROSINE KINASE INHIBITORS (TKI) – A GROWING CLASS OF ANTI-CANCER AGENTS

Protein tyrosine kinases are enzymes that provide a central switch mechanism in cellular signal transduction pathways. As such they are involved in many cellular processes 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 progression. Blocking tyrosine kinase activity therefore represents a rational approach to cancer therapy.

Zactima is an orally active inhibitor of Vascular Endothelial Growth Factor (VEGF) receptor-2 (KDR) tyrosine kinase with additional activity against Epidermal Growth Factor Receptor (EGFR) tyrosine kinase, a property it shares with Iressa (gefitinib). VEGF is a pro-angiogenesis factor that binds to receptors on blood vessels and stimulates the growth of new blood vessels, an important process in tumour dissemination (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 respect it differs from Iressa, which is a selective EGFR-TKI.

ZACTIMA ADVANCES TO PHASE III TRIALS IN NSCLC

In July 2005, AstraZeneca announced plans for phase III development of Zactima in NSCLC. This followed successful outcome in a phase II trial in which Zactima was combined with docetaxel in patients with locally-advanced or advanced NSCLC.

The preliminary results of the phase II trial were presented at the American Society of Oncology annual meeting in May 2005, and showed that Zactima in combination with docetaxel, increased progression-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 OPTIONS FOR LUNG CANCER PATIENTS

Since 1985, lung cancer has been the most common cancer in the world and it remains the major cause of all cancer-related deaths, especially among men. In 2002 lung cancer claimed 1.18 million deaths worldwide, 17.6% of the world total.

Cancers of the lung are of two types: NSCLC and Small-Cell Lung Cancer (SCLC). NSCLC is the most common, accounting for around 80% of all lung cancers. It is an aggressive disease, for which overall five-year survival rates are generally less than 10%.

Treatment of lung cancer has traditionally centred on the use of surgery, for operable cases, radiotherapy and chemotherapy with cytotoxic drugs. Platinum-based regimens are the mainstay of chemotherapy and include cisplatin and carboplatin. To enhance the efficacy of these agents, platinum-based agents may be combined with taxanes, such as paclitaxel and docetaxel.

Targeted agents, such as TKIs, are seen as an important development with potential to improve treatment outcomes in patients with NSCLC. Currently approved TKIs for NSCLC include Iressa (gefitinib) and Tarceva (erlotinib).

MARKETING COMMENTARY

The market for antineoplastic drugs is the third largest sector of the prescription drug market, behind cardiovascular and CNS drugs, and is currently experiencing strong growth. Significant opportunities exist for effective new treatments for lung cancer, among the most difficult cancers to treat.

Despite the disappointment with Iressa, the recent approval of Tarceva (erlotinib) for second-line use in NSCLC patients failing at least one prior chemotherapy regimen suggest that TKIs have a place in the treatment of lung cancer.

Zactima is a once-daily, oral TKI that combines the action of Iressa and Tarceva with an additional ability to deprive tumours of their blood supply via VEGFR-2-mediated antiangiogenic effects. A broader spectrum of anti-tumour activity may confer treatment advantages but this awaits confirmation in large-scale trials.