FDA grants priority review to Boehringer Ingelheim's Afatinib* NDA for EGFR mutation-positive advanced NSCLC

Boehringer IngelheimBoehringer Ingelheim today announced that the New Drug Application (NDA) for its investigational oncology compound afatinib* has been accepted for filing and granted Priority Review by the U.S. Food and Drug Administration (FDA). The application for afatinib* is currently under review for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation as detected by an FDA-approved test. The FDA target action date for afatinib* will be in the third quarter of 2013.

Afatinib has demonstrated a significant delay in tumour growth versus the best-in-class chemotherapy, which resulted in 11.1 months progression free survival (PFS) vs. 6.9 months in the comparator arm. Afatinib is currently under review by the European Medicines Agency (EMA) following submission for Marketing Authorisation in Europe in August 2012.(1)

"The acceptance of the NDA filing reinforces our ongoing commitment to oncology as we take the necessary steps to seek approval for our first cancer treatment, in an area of high unmet medical need," said Prof. Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim. "We are excited that the positive clinical data for afatinib* is now currently under review by both the FDA and EMA and look forward to working diligently with both agencies in the hope that people with lung cancer can soon benefit from this new treatment."

The NDA submission is based on the comprehensive LUX-Lung clinical trial programme. Data from the pivotal LUX-Lung 3 trial, comparing afatinib* to pemetrexed and cisplatin, considered best-in-class chemotherapy for non squamous NSCLC (2), demonstrated superiority in progression-free survival (PFS) in patients with stage IIIb or IV adenocarcinoma of the lung harbouring an EGFR mutation. Patients taking afatinib* as a first-line treatment lived for almost one year without their tumour growing (PFS of 11.1 months) versus just over half a year (PFS of 6.9 months) for those on chemotherapy (pemetrexed / cisplatin).(1) Importantly, patients taking afatinib* with the most common EGFR mutations (del19 and L858R, accounting for 90% of all EGFR mutations) lived for well over a year without progression (PFS of 13.6 months) versus just over half a year (PFS of 6.9 months) for those in the comparator arm.(1)

In addition, patients treated with afatinib* experienced better and longer control and improvement of the most common lung cancer-related symptoms and better quality of life (QoL) compared to chemotherapy (pemetrexed and cisplatin). Importantly, afatinib* treatment led to improved physical, role and cognitive functioning, and overall better QoL.(3)

The most common adverse events associated with afatinib* treatment were diarrhoea and rash/acne. These adverse events were as expected with EGFR inhibition, consistent with previous studies, and were manageable and reversible. These rarely led to discontinuation of afatinib* treatment.(1)

Boehringer Ingelheim strives to make afatinib* available to patients around the world. Further submissions worldwide are currently under preparation.

About Afatinib*
Afatinib* is an irreversible ErbB Family Blocker which targets inhibition of signal transduction of all kinase receptors from the ErbB Family (4), which is 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 also in Phase III clinical development in breast cancer and head & neck cancer.

In Europe, Boehringer Ingelheim announced submission of a Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) seeking approval of afatinib* as a treatment for patients with EGFR (ErbB1) mutation-positive NSCLC in August 2012.

About LUX-Lung 3 Trial
LUX-Lung 3 is the largest (n=345) registration trial to date in patients with advanced EGFR mutation positive lung cancer.

LUX-Lung 3 is a global, randomized, open-label, Phase III trial and the first to directly compare a tyrosine kinase inhibitor (afatinib*) to the standard chemotherapy agents, pemetrexed and cisplatin. The study included 345 previously untreated patients with EGFR mutation positive NSCLC. (1)

Adverse events in LUX-Lung 3 were as expected with EGFR inhibition, consistent with previous studies, and were predictable, manageable and reversible. Importantly, adverse events rarely led to the discontinuation of afatinib treatment compared with chemotherapy (8% discontinuation rate for afatinib*; 12% for chemotherapy). One percent of patients in the afatinib* arm discontinued treatment due to diarrhoea. 1 Drug related adverse events of grade three were similar in patients treated with afatinib* (49%) vs. patients treated with chemotherapy (48%). (1) The most common drug-related grade three adverse events observed in the afatinib* treatment arm were rash/acne (14%), diarrhoea (11%), and mucositis/stomatitis (6%). The most common drug-related grade three adverse events observed in the chemotherapy arm (pemetrexed /cisplatin) were fatigue (23%), neutropenia (16%), and nausea (3%).

About Lung Cancer
Lung cancer is the most common and most deadly form of cancer in the world. (5) In Europe, it accounts for 391,000 new cancer cases annually, and 342,000 deaths each year. (6) Overall, lung cancer is the cause of 19.9% of all cancer deaths in Europe. (6) Thirteen percent of all new cases of cancer are lung cancers (7) and smoking is attributed as the main cause. (8)

Early testing for tumour EGFR mutation status of lung cancer patients is critical in improving patient outcomes. Between 10-15% of Caucasian and 40% of Asian NSCLC patients have tumours harbouring EGFR mutations, with 90% of these accounting for two mutations (del19 or L858R). (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'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 will be investigated in a Phase III study programme 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 145 affiliates and more than 44,000 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.

As a central element of its culture, Boehringer Ingelheim pledges to act socially responsible. 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 2011, Boehringer Ingelheim achieved net sales of about 13.2 billion euro. R&D expenditure in the business area Prescription Medicines corresponds to 23.5% of its net sales.

1. Abstract no: LBA7500, LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations. Oral Presentation at 48th Annual Meeting of the American Society of Clinical Oncology (ASCO) 2012.
2. Scagliotti GV, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer.J Clin Oncol 2008;26(21):3543–51
3. Abstract no: 1229PD. Sequist L. V. et al. LUX-Lung 3: Symptom and health-related quality of life results from a randomized phase III study in 1st-line advanced NSCLC patients harbouring EGFR mutations. ESMO 2012 Congress. Available at: http://abstracts.webges.com/myitinerary/session-148.html?congress=esmo2012#.UFdGtBr1LSY.gmai
4. Solca, F. et al. Target Binding Properties and Cellular Activity of Afatinib (BIBW 2992), an Irreversible ErbB Family Blocker (Fast Forward 10 August 2012) . J Pharmacol Exp Ther 2012 343 (2).
5. Ferlay J et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127 2893-2917.
6. Ferlay J et al. Estimates of cancer incidence and mortality in Europe in 2008. EJC 2010; 46 765-781.
7. Cancer Research UK. UK lung cancer incidence. CancerStats – Key Facts 2009. [Online] Available at: http://info.cancerresearchuk.org/cancerstats/types/lung/incidence/ [Last Accessed January
8. Allen J et al. J Natl Compr Canc Netw 2008;6(3): 285-293.
9. Quest Diagnostics – Lung Cancer Mutation Panel. [Online] Available at: http://www.questdiagnostics.com/hcp/intguide/jsp/showintguidepage.jsp?fn=TS_LungCancerMutation_Panel.htm [Last Accessed January 2013]

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