AstraZeneca Annual Report and Form 20-F Information 2008

Cancer

OUR FOCUS

Our key marketed products

During 2008, our breast cancer treatment, Arimidex maintained its position as market leader in sales of branded hormonal agents, with approximately four million patient years of clinical experience. This success is largely based on the extensive long-term efficacy and safety results of the ATAC study, which showed Arimidex to be significantly superior to tamoxifen at preventing breast cancer recurrence during and beyond the five-year treatment course. (Breast cancer recurrence is defined as loco-regional recurrence, distant recurrence or contra-lateral breast cancer).

Arimidex continues to be the leading branded hormonal therapy for new patients in the US, Japan and France, and is also approved in a number of markets in Europe for a switch indication for patients who have already received two to three years of tamoxifen.

Faslodex, now approved in more than 60 markets, offers an additional hormonal therapy for patients with hormone-sensitive, advanced breast cancer, delaying the need for cytotoxic chemotherapy. It is a once-monthly injection approved for the second-line treatment of hormone-receptor positive, advanced breast cancer in post-menopausal women.

Casodex is used as a 50mg tablet for the treatment of advanced prostate cancer, and as a 150mg tablet for the treatment of locally advanced prostate cancer. European sales declined due to generic erosion following patent and/or marketing exclusivity expiries in July 2008. Sales growth continued in Japan, where Casodex is available as an 80mg tablet and is approved for all stages of prostate cancer. In the US, the FDA granted an additional six months’ paediatric extension providing marketing exclusivity in the US to April 2009.

Zoladex is approved in 120 countries. It is approved for the treatment of prostate cancer, breast cancer and gynaecological disorders. In non-metastatic prostate cancer, Zoladex is the only luteinising hormone-releasing hormone (LHRH) agonist shown to improve overall survival both when used in addition to radical prostatectomy and when used in addition to radiotherapy. The 10-year follow-up results of a study for the European Organisation for Research and Treatment of Cancer confirmed the long-term survival benefits of Zoladex when used as adjuvant to radiotherapy in patients with locally advanced prostate cancer.

In breast cancer, Zoladex is widely approved for use in advanced breast cancer in pre-menopausal women. In a number of countries, Zoladex is also approved for the adjuvant treatment of early stage pre-menopausal breast cancer as an alternative to and/or in addition to chemotherapy. Zoladex offers proven survival benefits for breast cancer patients with a favourable tolerability profile.

Competition in the LHRH agonist market is expected to increase in Europe during 2009, with the anticipated launches of generic goserelin. This follows the announcement of the approval of generic goserelin (one-month depot) in Germany in December.

Iressa is approved in 36 countries and is the leading epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in the Asia Pacific region where it continues to be marketed for pre-treated advanced NSCLC. Based on data from the Phase III INTEREST study comparing Iressa with docetaxel, a marketing authorisation application for Iressa has been submitted to the European Medicines Agency.

Outside the US, we have various distribution and marketing arrangements for branded Ethyol. As of June 2008, our two main distribution partners are Pinnacle Biologics for Western Europe, Turkey and Israel, and Schering-Plough International for Rest of World.

Clinical trial developments

Results from the Phase III pan-Asian IPASS study evaluating the efficacy of Iressa as first-line treatment of NSCLC, were also announced. The IPASS study exceeded its primary objective, demonstrating superior progression-free survival (PFS) for Iressa compared with two chemotherapies (carboplatin/paclitaxel) in clinically selected patients. AstraZeneca is consulting with relevant health authorities regarding the IPASS data. Further Phase II trials are continuing to evaluate the potential benefits of Iressa in NSCLC and other EGF receptor-driven tumours.

In the pipeline

Zactima (vandetanib) is a potential new oral anti-cancer therapy, which has a unique anti-cancer profile through two clinically proven mechanisms. It blocks the development of a tumour’s blood supply (anti-angiogenesis) and blocks the growth and survival of the tumour itself (anti-EGFR). Zactima also inhibits RET-kinase activity, an important growth driver in certain types of thyroid cancer.

During 2008, we announced results from two Phase III clinical studies of Zactima in combination with chemotherapy agents, docetaxel (ZODIAC) and pemetrexed (ZEAL), and one monotherapy clinical study (ZEST) in pre-treated advanced NSCLC. The observed safety profile in these three Phase III studies was consistent with previous studies with Zactima in NSCLC.

Results from the ZODIAC and ZEAL studies showed advantages for Zactima in combination with standard chemotherapy, compared to chemotherapy alone. The addition of Zactima to chemotherapy prolonged PFS, the primary endpoint, which achieved statistical significance in the ZODIAC study, but not in the smaller ZEAL study. Clinical benefits were seen in secondary endpoints. Both studies showed that adding Zactima to chemotherapy significantly improved objective response rate, which is a measurement of tumour shrinkage. Additionally, positive trends in prolonging overall survival (OS) were seen, although these did not reach statistical significance and the data are still immature. Importantly, the studies also showed that adding Zactima to chemotherapy controlled the symptoms of lung cancer better than chemotherapy alone, allowing patients to maintain their quality of life for significantly longer.

ZEST, which evaluated the efficacy of Zactima monotherapy versus erlotinib, did not meet the primary objective of demonstrating a statistically significant prolongation of PFS for Zactima. However, Zactima and erlotinib showed equivalent efficacy for PFS and OS in a pre-planned non-inferiority analysis. We plan to file a regulatory submission in the second quarter of 2009 following discussion with regulatory agencies for combination therapy. Full results from studies ZODIAC, ZEAL and ZEST will be presented at an international medical congress in 2009.

Results from the Phase III ZETA study in hereditary and sporadic medullary thyroid cancer are expected in the second quarter of 2009.

The anti-cancer activity of Zactima continues to be evaluated in NSCLC and other tumour types, including colorectal, glioma, head and neck, breast and prostate cancers.

Recentin (cediranib) is a highly potent and selective-inhibitor of vascular endothelial cell growth factor (VEGF) receptor signalling in solid tumours, which inhibits all three VEGF receptors irrespective of activating ligand, and is suitable for once-daily oral dosing. It is currently in Phase III development in first-line colorectal cancer (CRC) and recurrent glioblastoma (rGBM).

In early 2008, our HORIZON III Phase II/III head-to-head study of Recentin with chemotherapy versus Avastin^™ with chemotherapy in patients with first-line metastatic CRC progressed directly into Phase III. Patient recruitment was subsequently completed for both HORIZON III and HORIZON II, our Phase III study of Recentin with chemotherapy versus chemotherapy alone. The Phase III REGAL trial in rGBM comparing Recentin monotherapy versus lomustine +/- Recentin began enrolling patients in the fourth quarter of 2008.

Following the announcement that the National Cancer Institute of Canada Clinical Trial Group’s (NCIC CTG) Recentin BR24 NSCLC trial would not be progressing straight into Phase III, we worked in close collaboration with the NCIC CTG to understand the BR24 data further and to assess the potential of Recentin in this disease area. Subsequently the NCIC CTG announced it would now investigate Recentin at 20mg plus carboplatin/paclitaxel versus carboplatin/paclitaxel alone in the BR29 study, which is expected to start recruitment in early 2009.

Encouraging Phase II data for Recentin from completed and continuing studies to investigate renal, rGBM, ovarian and prostate cancers were also presented in 2008.

ZD4054 is an oral once-daily potent and specific endothelin A-receptor antagonist in Phase III development. Data from Phase II studies suggested that ZD4054 10mg has the potential to increase median overall survival time by approximately seven months in men with metastatic hormone-resistant prostate cancer (HRPC), with the benefit of a generally well-tolerated side effect profile and a convenient once-daily tablet. The Phase III ENTHUSE studies are investigating efficacy in metastatic HRPC, both as monotherapy and in combination with docetaxel, and in non-metastatic HRPC.

In December 2008, we ceased our collaboration with Infinity Pharmaceuticals for the development and commercialisation of Infinity’s drug candidates IPI-504 (MEDI-561) and IPI-493 for the treatment of cancer and related conditions. This decision was taken after reviewing the potential opportunity for these projects and to take account of competing R&D investment priorities.

Our early oncology pipeline includes a range of novel compounds that target signalling pathways believed to be pivotal in cancer cell growth, invasion DNA repair and survival, with nine products in Phase II and 15 others in Phase I development. Phase II data from AZD6244, a potent MEK inhibitor licensed from Array BioPharma, showed biological activity in lung cancer and melanoma and studies will now focus on its use in combination with standard and other novel therapies, rather than its development as monotherapy. Phase II studies with the poly-ADP-ribose-polymerase (PARP) inhibitor AZD2281 have started and will initially focus on BRCA-mutated breast and ovarian cancer as well as other cancers where DNA repair could be defective.

The dual-specific Src/Abl kinase inhibitor, AZD0530, has shown a dramatic effect on biomarkers of cell motility and bone resorption and has started Phase II studies in ovarian cancer with others to follow. Among the compounds from the early portfolio continuing in development are AZD4877, a novel inhibitor of cell cycle; AZD7762, a tumour-selective chemosensitiser; and AZD8931. AZD1152, an aurora kinase inhibitor, has shown activity in acute myelogenous leukaemia and will commence Phase II/III studies in 2009. We are also developing potential new cancer treatments using biological approaches with highly defined molecular targets for patient populations with unmet medical needs.

CAT-8015 is an immunotoxin fusion protein that targets CD22, which is a receptor expressed on the surface of a wide variety of B-cell malignancies. CAT-8015 has orphan drug designation for hairy cell leukaemia in the US and EU. In 2008, the enrolment for studies continued in the CAT-8015 Phase I development programme.

Blinatumomab (MEDI-538) is a recombinant single-chain bi-specific T-cell engager (BiTE^™) molecule that is being studied for use in certain patients suffering from certain lymphomas and leukaemias. Exclusive rights to develop and commercialise blinatumomab in North America have been granted from Micromet.

The US Phase I programme with blinatumomab was suspended during 2008 in order to make appropriate modifications to the dosing regimen based on preliminary results from the EU studies.

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