Nintedanib* extended survival beyond one year for advanced adenocarcinoma patients after prior first-line chemotherapy

Boehringer IngelheimNew analysis of data from the LUME-Lung 1 Phase III clinical trial showed that the novel investigational compound nintedanib*, an oral triple angiokinase inhibitor that targets three receptors crucially involved in angiogenesis and tumour growth, provided a significant and clinically relevant overall survival benefit for advanced non-small cell lung cancer (NSCLC) patients with adenocarcinoma histology.(1) The results were presented at the European Cancer Congress in Amsterdam.

"Adenocarcinoma is the most common form of non-small cell lung cancer and as the majority of patients with an advanced stage of the disease will ultimately progress after initial therapy, effective second-line treatments are vital," said Dr. Anders Mellemgaard, Department of Oncology, Herlev University Hospital, Copenhagen. "Recent treatment advances for this sizeable patient population have been limited, but we have reached an important milestone with nintedanib. LUME-Lung 1 showed that nintedanib, when added to chemotherapy, was effective in extending overall survival by 2.3 months for advanced non-small cell lung cancer patients with adenocarcinoma histology and could become an important second-line option for these patients."

LUME-Lung 1 showed nintedanib* plus docetaxel provided a statistically significant increase in median overall survival from 10.3 months in the placebo arm to 12.6 months in the nintedanib* arm (HR: 0.83, p-value: 0.04).1 In addition, the data demonstrated that the earlier adenocarcinoma patients failed first line chemotherapy, the bigger the benefit that nintedanib* provided.1 Compared to the overall adenocarcinoma patient population, patients with advanced adenocarcinoma who progressed within 9 months after start of their first-line treatment (T<9months) achieved a larger median overall survival benefit of 3 months (10.9 with nintedanib* plus docetaxel vs. 7.9 months with placebo plus docetaxel).(1)

The analysis of the overall survival benefit observed in adenocarcinoma T<9 months patients suggests T<9months to be a predictive clinical biomarker of nintedanib* benefit in second-line, advanced NSCLC patients with adenocarcinoma histology.(1,2)

The most common adverse events (AEs) in LUME-Lung 1 were gastrointestinal side effects and reversible liver enzyme elevations which were manageable by supportive treatment or dose reduction (adverse events placebo vs. nintedanib*: nausea 18% vs. 24%, vomiting 9% vs. 17%, diarrhoea 22% vs. 42% and liver enzyme elevation 8% vs. 29%). Withdrawal due to adverse events was similar in both arms, as were Grade 3, bleeding or thromboembolic events.1 The trial results demonstrated that despite the observed adverse events, patients benefited from the additional efficacy of nintedanib*, when added to docetaxel, without significantly further impacting their quality of life.

Boehringer Ingelheim endeavours to make nintedanib* available to patients around the world. Submissions worldwide are currently under preparation.

About the LUME-Lung 1 trial
LUME-Lung 1 was a randomised, double-blind, Phase III study comparing nintedanib* plus docetaxel in patients with locally advanced/metastatic NSCLC after first-line therapy, with placebo plus docetaxel. The study included 1,314 patients, in Europe, Asia and South Africa, randomised to receive nintedanib* 200 mg twice daily plus docetaxel 75mg/m2 once a day, for 3 weeks (n=655) or placebo plus docetaxel (n=659).

LUME-Lung 1 is part of the wider Boehringer Ingelheim LUME-Lung Phase III programme for nintedanib*, investigating the safety and efficacy of nintedanib* in NSCLC patients after first line chemotherapy treatment. 1,773 patients were enrolled, making this one of the largest Phase III study programmes in this NSCLC patient population to date.

About Nintedanib*
Nintedanib* is an oral triple angiokinase inhibitor that targets three growth factor receptors simultaneously: vascular endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors (PDGFR alpha and beta), and fibroblast growth factor receptors (FGFR 1-3).(3) All three receptors are crucially involved in the formation and maintenance of new blood vessels (angiogenesis); their blockade may lead to the inhibition of angiogenesis, which plays a critical role in tumour growth and spread.(4,5)

Nintedanib* is currently being investigated in patients with various solid tumours including advanced NSCLC, ovarian cancer, liver cancer (hepatic cell carcinoma), kidney cancer (renal cell carcinoma), and colorectal cancer.

About Lung Cancer
Lung cancer is one of the most common and most deadly forms of cancer in the world, it accounts for 1.6 million new cancer cases annually.(6) Because of its poor prognosis, 1.38 million deaths each year are attributable to lung cancer.6 Overall, lung cancer is the cause of 18% of all cancer deaths.(6) Approximately 228,190 (13%) of all new cases of cancer are lung cancers(7) nd smoking is attributed as the main cause.

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's commitment to oncology is underpinned by using advances in science to develop a range of targeted therapies for 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. In the EU, Taiwan and Mexico, afatinib is approved under the brand name GIOTRIF®, and in the U.S. under the brand name GILOTRIFTM for use in patients with distinct types of NSCLC. Afatinib is under regulatory review by health authorities in Asia and other countries. Nintedanib*, an angiogenesis inhibitor is currently in Phase III clinical development in NSCLC and ovarian cancer. In the area of cell-cycle kinase inhibition, volasertib* is in Phase III development for acute myeloid leukaemia.

Boehringer Ingelheim's oncology pipeline is evolving and demonstrates the company's continued commitment to advance the disease area.

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 140 affiliates and more than 46,000 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel medications of high therapeutic value for human and veterinary medicine.

Social responsibility is a central element of Boehringer Ingelheim's culture. Involvement in social projects, caring for employees and their families, and providing equal opportunities for all employees form the foundation of the global operations. Mutual cooperation and respect, as well as environmental protection and sustainability are intrinsic factors in all of Boehringer Ingelheim’s endeavours.

In 2012, Boehringer Ingelheim achieved net sales of about 14.7 billion euro. R&D expenditure in the business area Prescription Medicines corresponds to 22.5% of its net sales.

*Nintedanib and volasertib are investigational compounds and are not yet approved. Their safety and efficacy has not yet been fully established.

1. Mellemgaard A, Kaiser R, Douillard J-Y et al. Analysis of overall survival in adenocarcinoma NSCLC patients receiving 2nd line combination treatment with nintedanib (BIBF-1120) + docetaxel in the LUME-Lung 1 trial: a randomised, double-blind, placebo-controlled phase 3 study. Oral presentation on 29 September 2013 at 09.00 at The European Cancer Congress 2013 Abstract. no 3409.
2. Kaiser R, Barrueco J, Reck M et al. Identification of a clinical biomarker for 2nd line combination with nintedanib in adenocarcinoma non-small cell lung cancer (NSCLC) patients in two phase III trials. Poster presentation on 29 September 2013 at 14.00 at The European Cancer Congress 2013. Abstract no. 3479.
3. Hilberg F, Roth GJ, Krssak M, et al. BIBF1120: triple angiokinase inhibitor with sustained receptor blockade and good anti-tumor efficacy. Cancer Res 2008;68: 4774-82.
4. Folkman N. Clinical applications of research on angiogenesis. N Engl J Med 1995;333: 1757-63.
5. Bousquet C, Lamande N, Brand M, et al. Suppression of angiogenesis, tumor growth, and metastasis by adenovirus-mediated gene transfer of human angiotensinogen. Mol Ther 2006;14:175-82.
6. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893-917.
7. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2010, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2010/, based on November 2012 SEER data submission, posted to the SEER web site, 2013.

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