- 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
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
In both Study 3 and Study 6, ZD6474 was generally well tolerated.
Common side effects included rash, diarrhoea and asymptomatic QT
ZACTIMA(TM) is a trademark of the AstraZeneca group of companies.
Notes to Editors:
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
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 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
AstraZeneca is a major international healthcare business engaged
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It is one of the world's leading pharmaceutical companies with
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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
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
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