New Data Highlight Increased EGFR Gene Copy Number as the Most Positive Biomarker in Determining Which Patients are Most Likely to Benefit From gefitinib (Iressa(TM))

Macclesfield, England, November 15 (ots/PRNewswire) -

- For Health Professional Press Only

- For International Journalists Only - Not for US Media

- Retrospective ISEL Study Analysis Identifies Potential Indicator
of Response to Treatment With gefitinib in Advanced NSCLC patients

Data presented today at the AACR-NCI-EORTC(x) conference provide
an insight into a potential future direction for the targeted
treatment of advanced non-small cell lung cancer (NSCLC) with the
EGFR-TKI, gefitinib (IRESSA(TM)). A retrospective analysis of tumour
samples from the ISEL study suggests that patients with a high EGFR
gene copy number, as identified by fluorescent in situ hybridisation
(FISH), may be more likely to benefit from treatment with
gefitinib[1].

Of the 370 patients with tumour samples evaluated for EGFR gene
copy number, approximately one third (31%, 114 patients) were found
to be FISH positive, and were therefore classifiable as having a high
EGFR gene copy number[1]. Among these patients with high EGFR gene
copy number, median survival appeared longer for those treated with
gefitinib compared with those who received placebo (HR=0.61, 95% CI
0.36-1.04, p=0.067) with a median survival of 8.3 months vs. 4.5
months respectively[1]. For patients with low EGFR gene copy number,
there was no difference between treatment groups (HR 1.16, 95% CI
0.81-1.64, p=0.4171). These new findings offer a further insight into
which NSCLC tumours may respond to inhibition of the EGFR pathway,
and appear consistent with findings in another placebo controlled
study of an EGFR TKI in NSCLC and with several single arm studies of
gefitinib in lung cancer.

"Of the biomarkers evaluated from ISEL, high EGFR gene copy number
appears to be the strongest biological predictor of a
gefitinib-related effect on survival, even in patients with clinical
factors associated with a poor effect," stated Fred R. Hirsch, MD,
Professor of Medicine & Pathology, University of Colorado Cancer
Center, United States, and lead investigator of the analysis. "What
these data represent is a valuable step forward in understanding
which patients suffering with this devastating, and usually fatal,
disease could benefit from treatment with gefitinib."

Further data, also presented at the conference, provide additional
evidence that EGFR mutations may also be a useful indicator of
response to gefitinib, a concept first reported by Lynch et al[2] and
Paez et al[3] in 2004. In another analysis of the ISEL data,
mutations in the EGFR tyrosine kinase domain were found in tumours
from 26 of 215 evaluable tumour samples [4]. EGFR mutations were
predominantly, but not exclusively, found in tumour samples from
patients with adenocarcinomas, patients of Asian origin, females and
patients who had never smoked. EGFR mutation-positive patients
treated with gefitinib appeared to have a higher objective response
rate and a reduction in treatment failures compared with EGFR
mutation-positive patients who received placebo[4]. Gefitinib did
not increase response rate or influence treatment failure, compared
with placebo in mutation-negative patients. Due to the low overall
incidence of mutations (12%), there were insufficient data to assess
the impact of mutations on survival. Interestingly, around two
thirds of EGFR mutations were found in patients who were also
positive for FISH and EGFR protein expression[4].

Brian Holloway, IRESSA Science Director, AstraZeneca commented,
"We are now making progress in evaluating potential biomarker
determinants of clinical benefit with gefitinib.

AstraZeneca has an on-going broad collaboration with leading
academic institutions around the world to help identify which
patients are most likely to benefit from gefitinib, and is continuing
its clinical research programme in the use of the drug in other NSCLC
treatment settings and other tumour types."

References

1. Hirsch, FR. et al. Molecular Analysis of EGFR Gene Copy Number,
EGFR Expression and Akt Activation Status in Advanced Non-small-cell
Lung Cancer (aNSCLC) Treated with Gefitinib or Placebo (ISEL trial).
AACR-NCI-EORTC 2005, Abs. A268.

2. Lynch, T.J. et al. Activating mutations in the epidermal growth
factor receptor underlying responsiveness of non-small-cell lung
cancer to gefitinib. N Engl J Med. 2004 May 20;350(21):2129-39.

3. Paez, J.G. et al. EGFR mutations in lung cancer: correlation
with clinical response to gefitinib therapy. Science. 2004 Jun
4;304(5676 ):1497-500.

4. Holloway, B. et al. Epidermal growth factor (EGFR), K-Ras and
B-Raf mutation status and clinical outcome to gefitinib (IRESSA) in a
Phase III placebo-controlled study (ISEL) in advanced non-small-cell
lung cancer (aNSCLC). AACR-NCI-EORTC 2005. Abs. A269.

Notes to Editors:

While the ISEL trial did not meet its primary endpoint of
significantly improved survival with gefitinib in the overall
population, it is important to recognise there was an increase in
survival in patients of Asian origin and in patients who had never
smoked.

(x) - AACR-NCI-EORTC International Conference on Molecular Targets
and Cancer Therapeutics: Discovery, Biology, and Clinical
Applications, Philadelphia, United States.

'IRESSA' is a trademark, the property of the AstraZeneca group of
companies.

AstraZeneca (LSE: AZN) 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 over $21.4 billion and leading
positions in sales of gastrointestinal, cardiovascular, respiratory,
oncology and neuroscience products. AstraZeneca is listed in the Dow
Jones Sustainability Index (Global) as well as the FTSE4Good Index.

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