Results of Key Phase II Studies Demonstrate Progression Free Survival Advantage for ZD6474 (ZACTIMA) in Lung Cancer

Atlanta (ots/PRNewswire) - - Enrolment to a Pivotal Phase III Study of ZD6474 in Advanced Non-Small Cell Lung Cancer (NSCLC) is Also Underway AstraZeneca today announced at the annual meeting of the American Society of Clinical Oncology (ASCO) further results of two key Phase II studies of the novel once-daily oral anti-cancer drug ZD6474 (ZACTIMA(TM)), in locally advanced or metastatic non-small cell lung cancer (NSCLC). Both Phase II studies - Study 6 and Study 3 - met their primary endpoint of increased progression free survival (PFS). The presentation of these new data follows the start of enrolment into the first Phase III study with ZD6474 in advanced NSCLC, Study 32, which is expected to enrol more than 1,200 patients worldwide. Principal Investigator of Study 32, Roy Herbst MD, PhD, Professor of Medicine at The University of Texas M. D. Anderson Cancer Center, USA, commented, "Lung cancer is not a single entity but, a heterogeneous disease making it difficult to treat. The ability to selectively target multiple key signalling pathways involved in tumour growth and spread with new agents such as ZD6474 may provide better anti-tumour activity than single-target lung cancer drugs, thereby offering new hope for patients." ZD6474 in combination with chemotherapy in advanced NSCLC Study 6 evaluated PFS with ZD6474 100mg or 300mg compared to placebo in 127 patients with advanced NSCLC receiving standard chemotherapy treatment with docetaxel after failure of first-line platinum-based chemotherapy. Results showed that adding ZD6474 100mg or 300mg to docetaxel increased median PFS to 19 weeks (HR [95% CI] = 0.64 [0.38-1.05], P=0.074), and 17 weeks (HR [95% CI] = 0.83 [0.50-0.36], P=0.461) respectively, compared with 12.0 weeks for docetaxel plus placebo.(1) Furthermore, exploratory subgroup analyses suggested advantages in PFS for ZD6474 plus docetaxel compared with docetaxel plus placebo both for adenocarcinoma and for other lung cancer histologies, including squamous carcinoma.(1) ZD6474 monotherapy in advanced NSCLC A second, two-part trial, Study 3, compared the anti-tumour effects of ZD6474 300mg monotherapy with gefitinib (IRESSA(TM)) 250mg monotherapy in 168 patients with advanced NSCLC after the failure of first and/or second line chemotherapy.(2) - In Part A of the study, patients receiving ZD6474 300mg had a significant prolongation of PFS compared with gefitinib 250mg with a mean PFS of 11.9 weeks compared to 8.1 weeks respectively (HR [95% CI] = 0.69 [0.50-0.96], P=0.025). Furthermore disease control for more than 8 weeks was achieved in 45% (37/83) of patients receiving ZD6474 and in 34% (29/85) of those receiving gefitinib. - In Part B, where eligible patients had the option to switch to the alternative treatment, disease control for more than 8 weeks was achieved in 43% (16/37) of patients who switched to ZD6474 (from gefitinib) and in 24% (7/29) of those who switched to gefitinib (from ZD6474). Study 6 investigator John Heymach MD, PhD, University of Texas M. D. Anderson Cancer Center, USA, commented, "ZD6474 is the first multi-targeted agent to show anti-tumour activity both when used in combination with standard chemotherapy and as a single agent. Given the poor prognosis in lung cancer, an increase in PFS is meaningful for patients. In Study 6, adding ZD6474 to docetaxel significantly improved PFS compared to docetaxel alone, and the data suggests that this improvement occurred in patients with adenocarcinoma as well as non-adenocarcinoma subtypes. tumour-types. These promising data have led to the initiation of Phase III evaluation of ZD6474." In both Study 3 and Study 6, possibly due to the small number of patients involved and the fact that survival data was potentially confounded by subsequent therapies, there was no significant effect of ZD6474 on overall survival. Both progression free survival and survival outcomes will be investigated in Phase III trials.(1,2) ZD6474 Phase III study in advanced NSCLC The Phase III trial, Study 32, will compare PFS with a combination of ZD6474 100mg plus docetaxel with docetaxel alone in patients with advanced NSCLC after failure of first-line anti-cancer therapy. The study will also assess overall survival, overall disease response and control rates, response duration, effect on disease related symptoms, quality of life assessments, and safety and tolerability as secondary endpoints. In both Study 3 and Study 6, ZD6474 was generally well tolerated. Common side effects included rash, diarrhoea and asymptomatic QT prolongation. ZACTIMA(TM) is a trademark of the AstraZeneca group of companies. Notes to Editors: ZD6474 (ZACTIMA(TM)) ZD6474 works by inhibiting both the development of the tumour's blood supply (anti-angiogenesis) and the growth and survival of the tumour itself. It also inhibits RET kinase, an important growth factor in medullary thyroid cancer. In addition to ongoing studies in NSCLC and medullary thyroid cancer, ZD6474 continues to be investigated in Phase II studies in a range of other tumours. Further data on ZD6474 being presented at ASCO Further results from Trial 008, an ongoing Phase II study in patients with hereditary medullary thyroid cancer, will be presented during a poster discussion session at ASCO on Tuesday 6 June 2005 at 11.00-12.00. Lung cancer Lung cancer is the leading cause of cancer death, accounting for around 25% of all cancer deaths in women and more than 30% in men. The 5-year relative survival rate for all stages of lung cancer combined is only 15%. Survival from lung cancer has shown little improvement for more than 20 years. For patients with refractory advanced NSCLC, prognosis is poor with a median survival of approximately six months at time of failed first treatment.(3) Thyroid cancer Thyroid cancer is a rare disease affecting approximately 290,000 people in the USA and 240,989 individuals in Europe.(4,5) Medullary thyroid cancer is a specific form of thyroid cancer that comprises 2-8% of the 50,000 new cases of the disease in the USA and Europe each year.(4,5) In approximately 40% of sporadic medullary thyroid cancer, and in up to 100% of hereditary medullary thyroid cancer cases, the cancer is caused by specific mutations in the RET proto-oncogene, a receptor tyrosine kinase, that transduces signals for cell growth and differentiation.(6) Advanced hereditary medullary thyroid cancer, a rare malignancy, has a poor prognosis and there are currently very limited therapeutic options available. Neither standard chemotherapy regimens, nor radiation therapy, provide substantial benefits for patients with advanced hereditary medullary thyroid cancer. AstraZeneca AstraZeneca is a major international healthcare business engaged in the research, development, manufacture and marketing of prescription pharmaceuticals and the supply of healthcare services. It is one of the world's leading pharmaceutical companies with healthcare sales of US$23.95 billion and leading positions in sales of gastrointestinal, cardiovascular, neuroscience, respiratory, oncology and infection products. AstraZeneca is listed in the Dow Jones Sustainability Index (Global) as well as the FTSE4Good Index. For more information about AstraZeneca, please visit: References 1. Herbst R et al. ZD6474 plus docetaxel in patients with previously treated NSCLC: results of a randomized, placebo-controlled phase II trial. Lung Cancer 2005; 49 (Suppl 2): S35. 2. Natale R et al. A comparison of the antitumour efficacy of ZD6474 and gefitinib (Iressa(TM)) in patients with NSCLC: results of a randomized, double-blind Phase II study. Lung Cancer 2005; 49 (Suppl 2): S36. 3. GLOBOCAN 2000: Cancer Incidence, Mortality and Prevalence Worldwide, Version 1.0. IARC CancerBase N0.5. Lyon, IARC Press 2001 4. J. Ferlay, F. Bray, P. Pisani and D.M. Parkin. GLOBOCAN 2000: Cancer Incidence, Mortality and Prevalence Worldwide. 5. National Cancer Institute. Genetics of Medullary Thyroid Cancer. oid/healthprofes sional. Last accessed 11 May 2006. 6. Gilliland FD, Hunt WC, Morris DM, Key CR (1997). Prognostic factors for thyroid carcinoma. A population-based study of 15,698 cases from the Surveillance, Epidemiology and End Results (SEER) program 1973 - 1991. Cancer, 79: 564-573. ots Originaltext: AstraZeneca Im Internet recherchierbar: Contact: Janet Milton-Edwards, AstraZeneca, Tel: +44-1625-515-275, Mobile: +44-7990-640-119,; Odette England, AstraZeneca, Mobile: +44-7743-927-226,

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