Lapatinib (Tykerb/Tyverb) to be investigated in landmark early breast cancer trial

GlaxoSmithKline (GSK)GlaxoSmithKline (GSK), in collaboration with the Breast International Group (BIG), a leading academic breast cancer research network, and one of its member groups, the Spanish Breast Cancer Cooperative Group (SOLTI), announced the start of a global Phase III study that will examine the role of lapatinib (Tykerb®/Tyverb®)in the treatment of early breast cancer (EBC). Neo-ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) will evaluate and compare the rate at which cancer cells disappear in the breast following treatment with lapatinib and/or trastuzumab before surgery in women with early-stage ErbB2-positive (HER2-positive) positive breast cancer. This type of treatment is referred to as neo-adjuvant therapy. Lapatinib is an investigational drug and has not yet been approved for this indication.

"The evolution seen in breast cancer care has been tremendous in the last few last decades," said Dr. José Baselga, Co-Chair on Neo-ALTTO and Scientific Chair of the SOLTI Group, Spain. "Surgery, in the form of a radical mastectomy of the breast, was traditionally the first line treatment offered to patients with little or no improvement in overall survival. Now we have a range of sophisticated targeted treatments that can significantly delay disease progression and increase survival. Through trials such as Neo-ALTTO, oncologists may be better able to optimise the use of these agents."

One in four women diagnosed with early breast cancer have tumours that are ErbB2-positive.[1] It is well recognised that these women have a higher risk of their cancer returning - either at the location of the original tumour (local recurrence), or when the cancer spreads to other organs (distant recurrence) – even after receiving additional therapies.[1]

"The launch of Neo-ALTTO is extremely exciting, as this study will help physicians answer important clinical questions relating to the neoadjuvant treatment regimen of ErbB2-positive breast cancer," said Dr. Martine Piccart, investigator on Neo-ALTTO and Chairperson of the Breast International Group, Institute Jules Bordet, Brussels. "All too often clinicians and patients face the problem of disease recurrence, and women with high levels of ErbB2 protein are at a greater risk of this occurring. It is vital that early stage breast cancer is treated effectively from the outset with the right combination or sequence of therapies."

Neo-ALTTO is a three-arm, randomised, multi-centre, open-label Phase III study of neoadjuvant lapatinib, neoadjuvant trastuzumab, and a combination of neoadjuvant lapatinib and trastuzumab in women with ErbB2-positive primary breast cancer. After treatment for six weeks, the same targeted therapy will be repeated for 12 weeks with the addition of paclitaxel. Surgery will be performed on all patients, after which each patient will receive three courses of chemotherapy followed by the same targeted therapy for 34 weeks. The primary objective of Neo-ALTTO is to evaluate and compare the rate of pathological complete response (or complete eradication of the tumour) at the time of surgery, as well as understand the biological difference of the three treatment regimens using a neoadjuvant approach. Secondary objectives include measurements of safety and tolerability, tumour response rate, disease-free survival and overall survival. Target enrolment is 450 patients with 130 clinical trial centres planned across 26 different countries.

It is hoped that Neo-ALTTO will lead to the discovery of new molecular biomarkers that help to better identify the benefits of lapatinib or trastuzumab.

"GSK is proud to collaborate with such esteemed research groups as BIG and SOLTI for the study of lapatinib in this early breast cancer setting," said Paolo Paoletti, MD, Senior Vice President, Oncology Medicines Development Centre of GSK. "This important global Phase III study, which has begun enrolling within a year of the FDA approval of lapatinib, demonstrates the confidence that the oncology community has in lapatinib and the importance of identifying the most effective treatment regimen for patients with early stage ErbB2-positive breast cancer."

Worldwide, breast cancer is by far the most frequent cancer affecting women, with over one million new cases each year, and the leading cause of female cancer-related deaths.[2] Approximately 20 to 85 percent of patients (depending on initial stage, tumour biology, and treatment strategy) diagnosed with early breast cancer will develop recurrent and/or metastatic disease.[3]

About BIG
The Breast International Group (BIG), based in Brussels, Belgium, is an international non-profit organisation for academic breast cancer research groups from around the world. By encouraging interaction and cooperation between its members and related cancer networks, and by collaborating with, but working independently from, the pharmaceutical industry, BIG's mission is to facilitate the conduct of large and difficult breast cancer clinical trials and to reduce the wasteful duplication of efforts. Created by leading European opinion leaders in 1996, BIG now constitutes a network of 41 groups in Europe, Canada, Latin America, Australia / New Zealand and Asia. These research entities, which coordinate the BIG trials, are in turn tied to approximately 3,000 specialised hospitals and research centres round the world. In 2004 BIG founded a complementary network for translational research, which involves 39 partners in 21 countries and is partially supported by the European Commission; to optimise research collaboration globally, BIG has also forged strong ties with North American collaborative groups. Through these efforts BIG hopes ultimately to advance knowledge about breast cancer and better serve the women whose lives are affected by this disease.

About SOLTI
SOLTI is a non-for-profit organization under Spanish law, made up of a network of around 30 medical oncology departments from some of the most important university hospitals across Spain and Portugal, with an operations office located near to Barcelona. SOLTI's mission is to encourage, design and develop clinical trials in breast cancer and in other solid tumours to answer relevant questions about cancer treatment. The group is involved in a number of multicentre, international clinical trials on breast cancer. Its partners are other international academic groups and pharmaceutical and research companies. SOLTI is the sponsor, or the representative of the sponsor, in both domestic and multinational Phase Ib to III trials. The performance of the network of oncologists at SOLTI ranks among the top of international cooperative groups, after benchmark trials such as HERA, SOFT, ECTO II, NOAH and AZURE, among others.

About GlaxoSmithKline
GlaxoSmithKline - one of the world's leading research-based pharmaceutical and healthcare companies - is committed to improving the quality of human life by enabling people to do more, feel better, and live longer. For company information, visit GlaxoSmithKline at www.gsk.com.

GSK in Oncology
GSK Oncology is dedicated to producing innovations in cancer that will make profound differences in the lives of patients. Through GSK’s revolutionary “bench to bedside” approach, we are transforming the way treatments are discovered and developed, resulting in one of the most robust pipelines in the oncology sector. Our worldwide research in oncology includes collaborations with more than 160 cancer centres. GSK is closing in on cancer from all sides with a new generation of patient focused cancer treatments in prevention, supportive care, chemotherapy and targeted therapies.

About Lapatinib
Lapatinib is the first oral, small molecule dual targeted therapy that works by getting inside the cancer cell to inhibit both ErbB1 (EGFR) and ErbB2 (HER2), two receptor proteins which are responsible for tumour growth.[4] It is currently being investigated in a range of other solid tumours that overexpress ErbB1 and/or ErbB2. The current indication is based on Phase III results of lapatinib plus capecitabine which show significant increase in the time to disease progression compared to capecitabine alone in women with ErbB2-positive metastatic breast cancer that have progressed following prior therapy, including trastuzumab in the metastatic setting.[5] The most frequent side-effects related to lapatinib from clinical trials to date are gastrointestinal (diarrhoea, nausea and vomiting) and skin disorders (rash and hand and foot syndrome). Lapatinib has also been associated with reports of decreases in left ventricular ejection fraction (LVEF) and also with reports of pulmonary toxicity. Advice to doctors is contained in the prescribing information.[6]

References
[1] Baselga J, et al. Adjuvant trastuzumab: a milestone in the treatment of HER-2-positive early breast cancer. Oncologist. 2006;11 Suppl 1:4-12.
[2] Parkin DM, et al. Global cancer statistics, 2002. C A Cancer J Clin. 2005 Mar-Apr;55(2):74-108
[3] C. Bernard-Marty et al. Facts and Controversies in Treatment of Systemic Metastatic Breast Cancer. The Oncologist. 2004:9:617-632
[4] Konecny et al. Activity of dual kinase inhibitor Lapatinib (GW572016) against HER-2 Overexpressing and Trastuzumab-Treated Breast Cancer Cells. Cancer Res 2006;66:1630-9
[5] Cameron D, et al. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat 2008; [Epub ahead of print]
[6] GSK data on file. Ongoing studies to 15 November 2005

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