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Gefitinib (IRESSA, ZD1839) Demonstrates Clinical Activity In A Variety Of Tumours: Presented at ASCO

CHICAGO, IL -- June 2, 2003 -- New data add to the evidence of efficacy of gefitinib (IRESSA™, ZD1839) and demonstrate its potential to have anti-tumour activity across a broad range of common cancers. Encouraging data from Phase ll trials in advanced colorectal cancer1, non-small cell lung cancer (NSCLC)2,3, breast cancer,4,5, glioblastoma6,7 and head and neck cancer8 - presented June 1 at the American Society of Clinical Oncology meeting in Chicago - add to the growing body of evidence supporting gefitinib's current and future role as an efficacious agent in the fight against cancer. Furthermore, the data demonstrate that gefitinib has an acceptable safety profile and is generally well tolerated across all tumour types.

Dr George Blackledge, Medical Director of Oncology at AstraZeneca commented: "These data provide clinical evidence that confirm gefitinib is an effective and generally well tolerated cancer treatment. The potential for gefitinib to provide clinical benefit in multiple cancers is very exciting and we are very committed to researching and identifying the biomarker changes associated with gefitinib sensitivity. Gefitinib has given hope to many patients with advanced NSCLC who previously had no other treatment options available, and we are optimistic we may be able to extend this hope to patients and families living with other debilitating cancers."

Encouraging data in advanced colorectal cancer
Very encouraging early Phase II data1 indicate that the addition of gefitinib to the triple combination chemotherapy known as Folfox* for advanced colorectal cancer could lead to improvements in clinical outcomes. Data from a National Cancer Institute (NCI) sponsored study were presented by Dr Cheryl Cho and Dr B. I. Sikic, Stanford University Medical Center, Stanford, USA:
ˇ The data reported that 75% of previously untreated colorectal cancer patients achieved a partial response - where their tumour had shrunk by at least half - when they received gefitinib in combination with Folfox
ˇ 29% of patients whose cancer progressed on prior chemotherapy responded when given Folfox plus gefitinib

Previous studies have shown that Folfox alone gives an overall response rate of approximately 50%9 in previously untreated patients, while for patients who have received prior therapy; the response rate is around 9%10. The data show the combination with gefitinib to be generally well tolerated with the most reported side effects being diarrhoea and nausea. Dr Sikic's results are encouraging because they suggest the addition of oral gefitinib to the triple Folfox combination could lead to further improvements in clinical outcomes for patients in the fight against this devastating disease. Colorectal cancer is the second most common cancer in the world.

Confirmed clinical benefit in NSCLC
New findings from the IDEAL** 2 study2 demonstrate that patients experience improvement in the debilitating symptoms from their cancer when taking gefitinib monotherapy once daily and are more likely to achieve better outcomes in terms of their overall survival rates and tumour shrinkage if their symptoms improve:
ˇ Patients who experienced early disease symptom improvement were significantly more likely to experience disease stabilisation or tumour shrinkage and live longer, than those who did not experience relief from their lung cancer symptoms (p=0.0001)
ˇ The association between early symptom improvement and improved overall survival was also seen among patients whose disease continued to progress despite treatment
ˇ Median overall survival was found to be considerably longer for those patients who experienced symptom improvements than those who did not, 11.8 months and 3.7 months respectively

The results from the IDEAL studies11,12 demonstrate gefitinib has proven and unprecedented anti-tumour activity in advanced NSCLC. The results of both studies demonstrate that gefitinib has a favourable tolerability profile with most common side effects being skin rash and diarrhoea. More than 40 per cent of patients gained life-enhancing benefit (tumour shrinkage + stabilised disease, associated with symptom relief) from treatment with gefitinib. Furthermore, the IDEAL results demonstrate that responses to gefitinib are long-lasting, as approximately 30% of patients, all of whom had a very poor prognosis, were alive one year after starting treatment.12

A separate retrospective analysis3 of NSCLC patients who received gefitinib once daily on a compassionate use basis, also revealed that those who had failed at least one previous chemotherapy treatment achieved good disease control when treated with gefitinib. Gefitinib also demonstrated an acceptable safety profile with the most frequent side effects observed being skin rash and diarrhoea. Out of 72 evaluable patients, who had failed previous treatments, 43% achieved disease control where their cancer had stopped progressing or they experience tumour shrinkage.

Clinical activity in breast cancer
Early data from two Phase ll trials4,5 in patients with advanced breast cancer who had failed previous treatment options, confirmed previously reported clinical activity of gefitinib monotherapy in recurrent breast cancer.
ˇ The first study assessed antitumour activity and tolerability of gefitinib in 31 patients with advanced breast cancer4. Data reported confirm that ten patients (32%) experienced stable disease (SD) for at least three months, including six patients who had SD for > 4 months and three patients for >6 months. Gefitinib was generally well tolerated with the majority of adverse events being mild (grade 1/2).
ˇ A study of 33 patients with advanced breast cancer demonstrated gefitinib was generally well tolerated and had antitumour activity in patients with ER-negative tumours and ER-positive tumours who had been treated with tamoxifen but had developed resistance to the drug. 27 patients were evaluable at six months - nine patients were tamoxifen resistant and 18 were ER-negative. Of the 9 patients who were tamoxifen resistant, six patients gained clinical benefit: one patient's tumour shrunk by at least half (defined as a partial response) and the other five had stable disease. Of the 18 patients who were ER-negative one experienced a partial response and one experienced stable disease.

Preliminary data in glioblastomas
Two studies6,7 further suggest gefitinib may have anti-tumour activity in several types of brain cancers, including glioblastoma multiforme (GBM), one of the most common but aggressive and fatal forms of primary brain tumours. Fifty one patients6 -diagnosed with glioblastomas and who had received previous treatment -were treated with gefitinib. Of these, one patient achieved a partial response and 22 (43%) achieved stable disease at 8.4 months after beginning therapy. In a second study7, of 50 patients (35 with glioblastoma and 15 with anaplastic gliomas) five patients achieved a partial response (four patients had glioblastoma and one patient had anaplastic oligodendroglioma), when treated with gefitinib after their tumours progressed following radiation therapy. Gefitinib's tolerability profile was consistent with other trials with the most common side effects being skin rash, fatigue and diarrhoea. These data are very encouraging as they suggest gefitinib has the potential for clinical activity in this setting.

About gefitinib
Gefitinib is the first in a new class of anti-cancer drugs known as Epidermal Growth Factor Receptor (EGFR) - Tyrosine Kinase (EGFR-TK) inhibitors. Gefitinib has been approved for the treatment of advanced NSCLC by the United States Food and Drug Administration, the Australian Therapeutic Goods Administration and by the Japanese Ministry of Health, Labour and Welfare. Gefitinib is currently undergoing regulatory review with several other regulatory authorities worldwide for the treatment of advanced NSCLC. AstraZeneca is committed to further investigating the potential for this novel treatment in multiple tumour and disease settings.

IRESSA™, 'Arimidex', 'Casodex', 'Faslodex', 'Nolvadex', 'Zoladex' and Tomudex' are trademarks of the AstraZeneca group of companies.

ˇ To view netcasts of data presented at the 39th American Society of Clinical Oncology Annual Meeting, Chicago 31 May - 3 June 2003, please visit www.cancerpressoffice.com
ˇ For further information on the Epidermal Growth Factor Receptor and its potential role in cancer treatment, please visit www.EGFR-INFO.com
ˇ For further information on IRESSA™ and lung cancer, please visit www.iressa.com
ˇ For further press information regarding IRESSA™ and other AstraZeneca cancer therapies, please visit www.cancerpressoffice.com
* Folfox is a triple combination of oxaliplatin and 5-fluorouracil (5-FU) two cytotoxic chemotherapy agents with leucovorin (folinic acid)
** IDEAL = IRESSA Dose Evaluation in Advanced Lung Cancer

References
1. Cho et al. A phase II study of gefitinib (ZD1839, Iressa™ combination with Folfox-4 (IFOX) in patients with unresectable or metastatic colorectal cancer. ASCO 31 May - 3 June 2003 Abstract Number 1062
2. Cella, D. et al. Disease-related symptoms in advanced non-small cell lung cancer (NSCLC) as measured by the Lung Cancer Subscale (LCS) of the FACT-L questionnaire: clinically meaningful improvements with gefitinib (IRESSA, ZD1839). ASCO 2003. Poster Discussion, Sunday 1 June 2003, 13.00 - 17.00, Chicago Abstract No.2531
3. López Martin A, et al. IRESSA in advanced Non-Small Cell Lung Cancer (NSCLC) patients progressed to chemotherapy. ASCO 2003. Saturday 31 May Poster Session, 09:00 - 13:00 hours, Chicago Abstract No. 2695
4. Baselga, J. et al. Phase II and tumor pharmacodynamic study of gefitinib ('Iressa', ZD1839) in patients with advanced breast cancer. ASCO, 2003. Abstract No. 24
5. Robertson, J. et al. Gefitinib ('Iressa', ZD1839) is active in acquired tamoxifen (TAM)-resistant oestrogen receptor (ER)-positive and ER-negative breast cancer: results from a Phase II study. ASCO, 2003. Abstract No. 23
6. Peery T, et al. Phase II Trial of ZD1839 (Iressa) for Patients With First Relapse Glioblastoma. ASCO, 2003. Abstract No. 396
7. Lieberman, F. et al. Phase I-II study of ZD-1839 for recurrent malignant gliomas and meningiomas progressing after radiation therapy ASCO, 2003. Abstract No. 421
8. Ezra E. W. Cohen, Fred Rosen, Walter M. Stadler, Wendy Recant, Kerstin Stenson, Dezheng Huo, and Everett E. Vokes. Phase II Trial of ZD1839 in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck. JCO Vol 21, issue 10, May 15 2003: 1980-1987.
8.9. de Gramont A, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000 Aug;18(16):2938-2947
9.10. Eloxatin™ (oxaliplatin) label. FDA website (www.fda.gov/bbs/topics/NEWS/2002/NEW00825.html)
10.11. Fukuoka, M et al. Final Results From a Phase II Trial of ZD1839 (IRESSA) for Patients with Advanced Non-Small-Cell Lung Cancer (IDEAL 1). 38th Annual Meeting of the American Society of Clinical Oncology (ASCO), Orlando, US, May 2002.
12. Kris, M et al. A Phase II trial of ZD1839 (IRESSA) in advanced non-small-cell lung cancer (NSCLC) patients who had failed platinum- and docetaxel-based regimens (IDEAL 2). 38th Annual Meeting of the American Society of Clinical Oncology (ASCO), Orlando, US, May 2002.


SOURCE: Shire Health International

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