ASCO 2013: New Phase III data reveal targeted treatment with afatinib* or with nintedanib* improves progression-free survival in patients with advanced NSCLC

Ingelheim, Germany, 16 May 2013 – Boehringer Ingelheim today announced data from two separate Phase III clinical trials, involving investigational oncology compounds with a different mode of action – afatinib* and nintedanib* – in two distinct populations of patients with advanced non-small cell lung cancer (NSCLC).

The LUX-Lung 6 trial results show that patients with epidermal growth factor receptor (EGFR or ErbB1) mutation-positive advanced NSCLC treated first-line with afatinib* lived for almost a year before their tumour started to grow again (progression-free survival, or PFS) compared with just under half a year for patients treated with chemotherapy. In addition, 47 percent of afatinib*-treated patients are alive and progression-free after one year of treatment compared to only 2 percent on chemotherapy. Tumour shrinkage induced by afatinib* translated into improvements in disease-related symptoms. Patients´ global health-related quality of life (QoL) was significantly improved with afatinib* compared to chemotherapy. The delay in tumour growth in the LUX-Lung 6 trial compares well with data from the registration trial LUX-Lung 3, substantiating the efficacy of afatinib* and the robustness of the data.

The LUME-Lung 2 trial evaluated the triple angiokinase inhibitor nintedanib* in combination with chemotherapy pemetrexed in patients with advanced NSCLC after initial chemotherapy has failed. The trial did not pass the pre-defined interim analysis from external independent experts and was prematurely halted. However, the final results showed a significant improvement of the primary endpoint, centrally assessed PFS.²

Overall, both afatinib* and nintedanib* significantly improved PFS, the primary study endpoints, in their respective study populations. The most common grade 3 adverse events (AEs) associated with afatinib* in LUX-Lung 6 were diarrhoea, rash and stomatitis/mucositis (inflammation of the mouth and throat). These side effects are as expected with EGFR inhibition, consistent with previous studies, and were predictable, manageable and reversible. The most common adverse events in LUME-Lung 2 were gastrointestinal side effects, mostly of mild or moderate intensity, and manageable with supportive treatment, and liver enzyme elevations which were reversible upon dose reduction or if needed in rare cases discontinuation. Full data will be presented at the 49th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago, May 31-June 4, 2013.

"NSCLC is a complex disease with a high mortality rate and an area of oncology where advancements are necessary to improve outcomes for patients. The positive findings from these Phase III trials demonstrate the importance of exploring new treatment approaches tailored for the various NSCLC populations," said Dr. Nick Thatcher, Christie Hospital, University of Manchester, UK.

The LUX-Lung 6 trial is the largest prospective Phase III trial conducted to date in the EGFR mutation-positive advanced NSCLC patient population. The trial evaluated afatinib* (n=242) compared to standard chemotherapy (gemcitabine and cisplatin) (n=122) as a first-line treatment in 364 Asian patients with EGFR mutation-positive advanced NSCLC.¹

Results showed the trial met its primary endpoint of PFS as assessed by independent central review; within the general study population, patients treated with afatinib* lived for a median of 11.0 months before their tumour started to grow again (PFS) versus 5.6 months for those chemotherapy-treated patients (HR=0.28, p<0.0001).1 The PFS findings were consistent across all subgroups. Results from the investigator review were similar with a median improvement in PFS of 13.7 months with afatinib* compared to 5.6 months with chemotherapy (HR=0.26, p<0.0001).¹

Secondary efficacy endpoints included objective response rate (ORR: proportion of patients with considerable tumour size reduction as predefined by response evaluation criteria) and disease control rate (DCR: proportion of patients who have achieved complete response, partial response and stable disease³). Results showed that patients treated with afatinib* experienced significantly higher ORR (66.9 vs. 23.0%, p<0.0001) and DCR (92.6 vs. 76.2%, p<0.0001) compared to patients treated with chemotherapy.¹

The most common grade 3 adverse events (AEs) associated with afatinib* in LUX-Lung 6 were diarrhoea, rash and stomatitis/mucositis (inflammation of the mouth and throat). These side effects are as expected with EGFR inhibition, consistent with previous studies, and were predictable, manageable and reversible. The most common AEs associated with chemotherapy were neutropenia (an abnormally low level of neutrophils, a type of white blood cell), vomiting and leukopenia (a decrease in the number of white blood cells). The discontinuation rate due to AEs related to treatment was 5.9 percent of patients on the afatinib* arm and 39.8 percent of patients on the chemotherapy arm. Importantly only 2 percent of patients on afatinib* decided to discontinue due to rash and none for diarrhoea.¹

Patient-reported outcomes (PROs) were evaluated as secondary endpoints of the LUX-Lung 6 trial. Based on the reported outcomes, the improvement in PFS seen with afatinib* was associated with significantly better health-related QoL and significantly longer control of life-restricting lung cancer-related symptoms compared with chemotherapy.⁴

Health-related QoL was measured using the EORTC QLQ-C30 questionnaire, which evaluated global health status/QoL (overall well-being) in addition to physical, cognitive, role, social and emotional functioning. Based on review of these six measurements, afatinib*-treated patients experienced improvements in their global health-related QoL and physical, role and social functioning compared to chemotherapy (p<0.05).⁴

"The data to be presented from the LUX-Lung 6 trial show a meaningful improvement in progression-free survival with first-line afatinib* treatment for patients with EGFR mutation-positive advanced non-small cell lung cancer," said Prof Yi-Long Wu from the Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangong Academy of Medical Sciences, Guangzhou, China and principal investigator of the LUX Lung 6 trial. "This is now the second largest Phase III trial involving afatinib* to confirm a high level of activity accompanied by improved health-related quality of life in this patient population."

This study evaluated nintedanib* plus pemetrexed (n=353) compared to pemetrexed plus placebo (n=360) in 713 patients with advanced non-squamous NSCLC who relapsed after, first-line chemotherapy.² Although prematurely halted, the trial showed a significant improvement in centrally assessed PFS, the primary endpoint of the trial; within the general study population, patients treated with nintedanib*/pemetrexed lived for a median of 4.4 months before their tumour started to grow again, compared to 3.6 months for patients assigned to the pemetrexed/placebo arm (HR=0.83, p=0.04).

The combination of nintedanib* and pemetrexed was not associated with an increase in serious adverse events or fatal events. A higher incidence of grade three or more elevated ALT (23 vs. 7%) and elevated AST (12 vs. 2%) – which are types of enzymes measured to determine liver health – as well as grade three diarrhoea (3.5 vs. 1%) were observed in patients treated with nintedanib* and pemetrexed. Grade three or more hypertension, bleeding, thrombosis, mucositis and neuropathy were comparable between the two treatment arms.²

"This study is part of the comprehensive LUME-Lung clinical trial program that is exploring the potential of nintedanib* in various lung cancer treatment settings. Boehringer Ingelheim is looking forward to sharing the data from the LUME-Lung 1 Phase III trial including overall survival data, which has been accepted as a late-breaker and will be presented on June 3rd at ASCO," said Prof. Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim. "The Phase III trial results in NSCLC for both afatinib* and nintedanib* represent the latest advancements from Boehringer Ingelheim’s robust oncology pipeline and our commitment to researching and developing new therapies for patients with cancer that are to this day difficult to treat."

Notes to Editors

About Afatinib*
Afatinib* is an irreversible ErbB Family Blocker which irreversibly blocks EGFR (ErbB1) as well as the other relevant members of the ErbB Family that are known to play a critical role in the growth and spread of the most pervasive cancers and cancers associated with high mortality (lung, breast, and head & neck cancers). Afatinib* is currently in Phase III clinical development in NSCLC and head & neck cancer.

Afatinib* has been submitted to the FDA, EMA, regulatory authorities in Asia and other countries for treatment of EGFR mutation-positive locally advanced and metastatic NSCLC patients. Afatinib* received priority review status in the US.

About the Afatinib* LUX-Lung 6 Trial
LUX-Lung 6 is the largest (n = 364) and most robust trial to date in patients with advanced EGFR mutation positive lung cancer. LUX-Lung 6 is a multicentre, randomised, open-label Phase III trial of afatinib* versus chemotherapy (cisplatin/gemcitabine) as first-line treatment for patients with advanced and metastatic non-small cell lung cancer (NSCLC) harbouring EGFR mutations. The study included 364 previously untreated patients with EGFR mutation positive NSCLC.1

In study, 364 patients from China, Republic of Korea and Thailand (Stage IIIB/IV, performance status 0–1, chemo-naïve) were randomised 2:1 to oral daily afatinib* 40 mg (n=242) or intravenous cisplatin / gemcitabine (75mg/m2 / 1000 mg/m2 every 21 days up to 6 cycles, n=122). In these countries, gemcitabine/cisplatin is commonly used for first-line NSCLC patients. The primary endpoint was PFS by central independent review. The most common drug-related grade 3 AEs were rash (14.6%), diarrhoea (5.4%) and stomatitis/mucositis (5.4%) with afatinib*, and neutropenia (17.7%), vomiting (15.9%) and leucopoenia (13.3%) with cisplatin/gemcitabine. Drug-related AEs led to discontinuation in 5.9 percent of afatinib* patients and 39.8 percent of cisplatin / pemetrexed patients.1

About NSCLC and EGFR Mutations
NSCLC is the most common form of lung cancer, accounting for about 85 percent of all diagnoses.5NSCLC is named for the kinds of cells found in the cancer and how they look under a microscope – the three main types of NSCLC are squamous cell carcinoma, large cell carcinoma and adenocarcinoma.6Non-small cell lung cancer can be even further categorised by looking at the genetic make-up of the cancer cells. In a non-small cell lung cancer cell there are a number of genes which may have ‘mutated’ which causes the cell to behave abnormally. One such gene is called EGFR. There are specific laboratory tests to identify these mutated genes in cancer cells. Between 10 and 15 percent of Caucasians and approximately 40 percent of Asians with NSCLC have EGFR mutations7 of which two most common types of mutations (called del19 and L858R) account for approximately 90 percent of the cases.8

About Nintedanib*
Nintedanib* (BIBF 1120) is an investigational orally-administered triple angiokinase inhibitor that targets three of the receptor tyrosine kinases shown to aid in the regulation of angiogenesis: vascular endothelial growth factor (VEGF) receptor, fibroblast growth factor (FGF) receptor and platelet-derived growth factor (PDGF) receptor.

Nintedanib* is being evaluated in various solid tumours – including advanced non-small cell lung cancer (NSCLC), ovarian cancer, liver cancer (hepatic cell carcinoma), kidney cancer (renal cell carcinoma) and colorectal cancer. The advanced NSCLC and ovarian cancer clinical trials are in Phase III development. Nintedanib* is also being investigated in Phase III trials for the treatment of Idiopathic Pulmonary Fibrosis (IPF), a progressive and severely debilitating lung disease.

About Lung Cancer
Lung cancer is the most common and most deadly form of cancer in the world.9 In Europe, it accounts for 391,000 new cancer cases annually, and 342,000 deaths each year.9 Overall, lung cancer is the cause of 19.9 percent of all cancer deaths in Europe.9 12 percent of all new cases of cancer are lung cancers9 and smoking is attributed as the main cause.10 In Asia, lung cancer accounts for more than 14 percent of all cancers and over 18 percent of all cancer deaths, however incidence varies by region. The highest rates are found in Eastern Asia; each year over half a million new lung cancer cases are diagnosed in China, over 86 thousand in Japan and over nine thousand in Taiwan.⁹

Early testing for tumour EGFR mutation status of lung cancer patients is critical in improving patient outcomes. Between 10-15 percent of Caucasian and 40 percent of Asian NSCLC patients have tumours harbouring EGFR mutations, with approximately 90 percent of these accounting for two mutations (del19 or L858R).7

About Boehringer Ingelheim in Oncology
Building on scientific expertise and research 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: angiogenesis inhibition, signal transduction inhibition and cell-cycle kinase inhibition. Nintedanib*, an angiogenesis inhibitor is currently in Phase III clinical development in NSCLC and ovarian cancer. In the area of cell-cycle kinase inhibition, Boehringer Ingelheim is developing an inhibitor of polo-like kinase 1 (Plk1), volasertib*, a protein that is involved in the processes of cell division. The compound is in Phase II 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.

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