Boehringer Ingelheim Initiates Phase III Clinical Trial with Novel Oral Agent in Advanced Breast Cancer

Boehringer IngelheimBoehringer Ingelheim announced the initiation of a phase III clinical trial to investigate one of its most advanced oncology pipeline compounds, afatinib, for the treatment of patients with advanced (metastatic) breast cancer. Afatinib is an oral compound (taken as a tablet), which is a next generation, targeted therapy, that irreversibly inhibits both, the epidermal growth factor receptor (EGFR/HER1) and the human epidermal receptor HER2, which are involved in tumour growth and spread(1).

This phase III clinical trial, called the "LUX-Breast 1 Trial" is the first pivotal study to evaluate afatinib in breast cancer, and this investigation widens the scope of potential cancer types for which Boehringer Ingelheim’s oncology portfolio may be suitable. Afatinib is currently investigated in an extensive clinical trial programme, the LUX-Lung Programme in lung cancer. Results from LUX -Lung 1 are due to be reported this year.

LUX-Breast I, is a global, open-label. randomised phase III pivotal study in patients with advanced breast cancer after prior treatment with trastuzumab who have an over-expression of the HER2 protein (HER2-positive patients). The study investigates whether treatment with afatinib can extend the lives of these patients before their cancer progresses (i.e. progression-free survival, PFS) as compared to continuing treatment with trastuzumab when both are added to the standard chemotherapy treatment vinorelbine. Overall survival, tolerability and safety will also be assessed in the study.

"We have seen positive results in our proof-of-concept studies for afatinib in breast cancer and are glad to advance the programme into pivotal phase III. We are delighted to be able to initiate this important trial together with a range of leading investigators to assess the value of afatinib for women with advanced breast cancer." said Prof. Klaus Dugi, Corporate Senior Vice President Medicine at Boehringer Ingelheim.

Breast cancer is the leading cause of cancer deaths in women globally, resulting in more than 411,000 deaths each year (2). HER2-positive breast cancer is a particularly aggressive form of the disease and is associated with a greater risk of disease progression and death compared to women with HER2-negative tumours (3). It is thought that in approximately 30% of advanced breast cancer cases, women overexpress the HER2 protein (4).

The initiation of the LUX-Breast I trial represents yet another important milestone for Boehringer Ingelheim to broaden and amplify its oncology development activities beyond lung cancer, again initiating the development of a potential novel agent for the treatment of an aggressive advanced cancer type.

Advancing Boehringer Ingelheim's oncology pipeline:
Afatinib is also being investigated for non-small cell lung cancer (NSCLC) in phase III clinical trials, the most common type of cancer (5). In the LUX-Lung clinical trial programme, one of the pivotal trials, LUX-Lung 3, evaluates the efficacy and safety of afatinib compared to standard chemotherapy (cisplatin/pemetrexed) as a potential first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR mutation (6). In addition in another phase III trial, LUX-Lung 1, Boehringer Ingelheim investigates afatinib versus placebo in NSCLC patients after prior EGFR inhibitor therapy (7).

Afatinib is just one of Boehringer Ingelheim's most advanced oncology pipeline compounds along with BIBF 1120, which is in phase III development for the treatment of patients with advanced NSCLC. Furthermore, in December 2009, Boehringer Ingelheim announced the initiation of its first pivotal phase III trial of BIBF 1120 in ovarian cancer.

The ongoing phase III development of its two most advanced compounds in a number of cancer types and patient populations. Continuously, Boehringer Ingelheim's oncology pipeline is evolving and demonstrates the company's continued commitment to the disease area.

About afatinib (BIBW 2992*, planned brand name Tomtovok TM#):
Afatinib is a next generation, orally administered targeted agent that irreversibly inhibits EGFR/HER1 and HER2 tyrosine kinases (1), which are involved in tumour growth and spread.

The decision to progress afatinib into a phase III trial in breast cancer was based on previous positive study results, which indicated that the agent was well tolerated and induced promising early clinical responses in advanced HER2-positive breast cancer patients whose cancer had progressed following treatment with trastuzumab; manageable cutaneous adverse events and diarrhoea were the main side-effects (8).

About Advanced Breast Cancer
Advanced breast cancer, also known as metastatic breast cancer, refers to the stage of the disease when cancer cells have broken away from the primary breast cancer site and spread to other parts of the body via the bloodstream or lymphatic system (9).

About Boehringer Ingelheim in Oncology
Building on scientific expertise and excellence in the fields of pulmonary and cardiovascular medicine, metabolic disease, neurology, virology and immunology, Boehringer Ingelheim has embarked on a major research programme to develop innovative cancer drugs. Working in close collaboration with the international scientific community and a number of the world’s leading cancer centres, Boehringer Ingelheim is committed to discovering and developing novel cancer treatments. This commitment is underpinned by using advances in science to develop a range of targeted therapies in areas of medical need, including various solid tumours and haematological cancers.

The current focus of research includes compounds in three areas: signal transduction inhibition, angiogenesis inhibition and cell-cycle kinase inhibition.Afatinib is currently in phase III clinical development in NSCLC, and was granted Fast Track designation for the treatment of NSCLC after prior EGFR inhibitor therapy by the US Food & Drug Administration. In addition, the LUME-Lung phase III clinical trial program, which is investigating BIBF 1120 in combination with standard second-line chemotherapy treatments for patients with advanced NSCLC, is ongoing. In the area of cell-cycle kinase inhibition, Boehringer Ingelheim is developing inhibitors of polo-like kinase 1 (Plk1), a protein that is involved in the processes of cell division. These molecules are in the early stages of clinical development.

About Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 142 affiliates in 50 countries and more than 41,500 employees. Since it was founded in 1885, the family-owned company has been committed for 125 Years to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

In 2009, Boehringer Ingelheim posted net sales of 12.7 billion euro while spending 21% of net sales in its largest business segment Prescription Medicines on research and development.

* Afatinib is an investigational compound, its safety and efficacy has not yet been fully established.
# not approved by FDA

* BIBF 1120 is an investigational compound, its safety and efficacy has not yet been fully established.

1. Li D et al. (2008) 'BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models', Oncogene, vol. 27, pp. 4702-4711.
2. International Agency for Research on Cancer (IARC). World Cancer Report 2008. [Online]. Available at: http://www.iarc.fr/en/publications/pdfs-online/wcr/2008/index.php [Accessed: March 2010]
3. Slamon D et al. (1987) ‘Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene', Science, vol. 235, pp. 177-87.
4. Penault-Llorca F et al. (2005) ‘Incidence and implications of HER2 and hormonal receptor overexpression in newly diagnosed metastatic breast cancer (MBC)', Journal of Clinical Oncology, vol. 23, S69.
5. Ferlay J et al. (2007) 'Estimates of the cancer incidence and mortality in Europe in 2006', Annals of Oncology, vol. 18, no. 3, pp. 581-592.
6. Boehringer Ingelheim. Clinical Trial Protocol. BIBW 2992: Trial No. 1200.32. Doc. No.: U09-1380-01. 14 May 2009.
7. Yang CH et al. (2009) 'Phase IIb/III double-blind randomized trial of BIBW 2992, an irreversible, dual inhibitor of EGFR and HER2 plus best supportive care (BSC) versus placebo plus BSC in patients with NSCLC failing 1–2 lines of chemotherapy (CT) and erlotinib or gefitinib (LUX-Lung1): a preliminary report', Journal of Clinical Oncology, vol. 27, S15
8. Hicklish T et al., 'Use of BIBW 2992, a Novel Irreversible EGFR/HER1 and HER2 Tyrosine Kinase Inhibitor to Treat Patients with HER2-positive Metastatic Breast Cancer after Failure of Treatment with Trastuzumab', Poster 5060 presented at 32nd Annual San Antonio Breast Cancer Symposium, 9-13 December 2009, San Antonio, Texas, USA.
9. MacMillan UK, 2008. Secondary breast cancer. [Online] Available at http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Breastsecondary/ Aboutsecondarybreastcancer/Secondarybreastcancer.aspx [Accessed 25 February 2010]

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