New efficacy and safety data adds to evidence supporting treatment with afatinib(GIOTRIF^®) in Asian and non-Asian lung cancer patients

Ingelheim, Germany, 27 October, 2013 – Data from two pivotal large-scale Phase III registration studies, LUX-Lung 3 and LUX-Lung 6, showed superior efficacy and a manageable safety profile in both Asian and non-Asian lung cancer patients compared to chemotherapy.^2,3 A new analysis of the trials has substantiated the consistent safety profile of afatinib as a first-line treatment in Asian and non-Asian patients with EGFR mutation positive non-small cell lung cancer (NSCLC).¹

The efficacy of afatinib is further reinforced by new data in NSCLC patient subpopulations. Additional analyses from the LUX-Lung trials demonstrate the efficacy of afatinib in NSCLC patients with uncommon EGFR mutations⁴ and those with metastatic brain disease.⁵

The findings, presented at this year's World Congress on Lung Cancer (WCLC), add to a growing body of robust clinical evidence which supports the first-line use of afatinib in Asian and non-Asian patients with a distinct type of advanced lung cancer, known as Epidermal Growth Factor Receptor (EGFR) mutation positive NSCLC. The global trial LUX-Lung 3 and its companion trial LUX-Lung 6, which was conducted in China, Korea and Thailand, together represent the two largest clinical registration trials conducted to date in patients with EGFR mutation positive NSCLC. The trials have already shown patients treated with afatinib lived for almost a year before their tumour started to grow again (progression-free survival (PFS)) versus just over half a year for those on chemotherapy. Specifically, the trials demonstrated: ^2,3

• LUX-Lung 3: PFS = 11.1 vs. 6.9 months – afatinib vs. pemetrexed/cisplatin
• LUX-Lung 6: PFS = 11.0 vs. 5.6 months – afatinib vs. gemcitabine/cisplatin

(These are data from primary analyses based on independent review.)

In LUX-Lung 6, 47% of afatinib-treated patients were alive and progression-free after 1 year of treatment compared to only 2% on chemotherapy.³ The delay in tumour progression was coupled with improvements in patients' lung cancer related symptoms (e.g. shortness of breath, cough and chest pain) and quality of life as assessed by standard lung cancer questionnaires.^2,3

In Asia, lung cancer accounts for more than 14% of all cancers and over 18% 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 86,000 in Japan and over 9,000 in Taiwan.⁶As lung cancer has a poor prognosis, it is important to choose the best treatment from the start.

The new LUX-Lung 3 and LUX-Lung 6 pooled safety analysis substantiates afatinib's previously reported adverse events (AEs) and tolerability profile in Asian and non-Asian EGFR mutation positive NSCLC patients. The most common grade 3 side effects which occurred at a similar rate in both patient groups were diarrhoea, rash/acne and stomatitis (inflammation of the mouth).¹ Furthermore, there was no difference in the afatinib pharmacokinetic exposure between the two patient populations.¹ The data from LUX-Lung 3 and 6 previously showed that side effects were predictable, manageable and reversible and treatment discontinuation rates were low.^2,3

"The new sub-analysis confirms the consistent safety profile of afatinib in Asian patients compared to non-Asian patients", commented Professor James Chih-Hsin Yang, Director of the Cancer Research Center, College of Medicine, National Taiwan University, Taipei, Taiwan and lead investigator of the LUX-Lung 3 trial. "This further supports afatinib's role as a valuable treatment option for patients with EGFR mutation positive lung cancer, which is three times more frequent in Asia than in Western countries."

In a separate oral presentation, the largest data series to date of efficacy in patients with uncommon EGFR mutations pooled from three prospective clinical trials with afatinib are presented. The data shows that the activity of afatinib in certain types of rare EGFR mutations is in the same range as demonstrated for common EGFR mutations (deletion 19, L858R) patient.⁴

A subgroup analysis of LUX-Lung 3 demonstrated that afatinib was efficacious as a first line treatment option in patients with lung cancer harbouring common EGFR mutations who had metastatic brain disease. ⁵

"Afatinib has clearly demonstrated its clinical benefit in our large, robust LUX-Lung clinical trial programme, which is now further supported by strong efficacy and safety data in important subpopulations," said Prof. Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim. "The results of these analyses are very encouraging, and may make afatinib an important addition to the available treatment options for both Asian and non-Asian patients with lung cancer harbouring EGFR mutations."

Notes to Editors

About Afatinib Data Presentations at WCLC

Safety Sub-Analysis¹
The new pooled sub-analysis of the LUX-Lung 3 and LUX-Lung 6 trials was based on a total of 468 EGFR mutation positive patients (404 Asian and 64 non-Asian) that were treated with afatinib 40mg daily until progression or intolerable AEs. The afatinib dose could be escalated to 50mg daily or reduced to 30mg or 20mg based on predefined study criteria. All patients reported at least one AE, with the most common including diarrhoea, rash/acne and stomatitis (inflammation in the mouth). Drug-related AEs leading to discontinuation were 7.2% in Asian patients vs. 4.7% in non-Asian patients, however were lower than with chemotherapy (28%).

Uncommon mutations Sub- Analysis⁴
This analysis is based on data from EGFR mutation-positive patients included in the LUX-Lung 2 (Phase II), LUX-Lung 3 and LUX-Lung 6 (both Phase III) studies. Patients were classified as having common (Del19 or L858R) or uncommon (all other single or complex) mutations. Objective response rate, disease control, duration of response and progression-free survival (PFS) were assessed by independent review.

Metastatic Brain Disease Sub-Analysis⁵
In LUX-Lung 3 EGFR mutation-positive patients were randomized 2:1 to afatinib 40 mg daily or up to 6 cycles of pemetrexed/cisplatin at standard doses. Patients with stable brain metastases were allowed. Presence of brain metastases was documented by the investigator during screening. Tumour assessments were performed every 6 weeks until 48 weeks and every 12 weeks thereafter until progression.

About the LUX-Lung 3 trial²
LUX-Lung 3 is the largest global, randomised, open-label, Phase III registration study, comparing afatinib to a combination of two chemotherapy agents, pemetrexed and cisplatin, as first-line treatment for patients with stage IIIb or IV NSCLC harbouring an EGFR mutation. The study included 345 patients with EGFR mutation positive NSCLC globally. LUX-Lung 3 is the first study in patients with EGFR mutation positive NSCLC to use pemetrexed/cisplatin as a comparator.

The most common grade 3 drug-related adverse events observed in the afatinib treatment arm were diarrhoea (14%), rash (16%), and paronychia (11%). The most common drug-related grade 3 adverse events observed in the chemotherapy arm (pemetrexed/cisplatin) were neutropenia (15%), fatigue (13%), and leucopenia (8%). There was a low discontinuation rate associated with treatment-related adverse events in the trial (8% discontinuation rate for afatinib; 12% for chemotherapy). One percent of patients in the afatinib arm discontinued due to drug-related diarrhoea.

About the LUX-Lung 6 trial³
LUX-Lung 6 is the largest (n=364), prospective, registration trial to date in Asian patients with advanced EGFR mutation positive lung cancer. It is a multicentre, randomised, open-label Phase III trial, which evaluated the efficacy and safety of afatinib versus chemotherapy (cisplatin/ gemcitabine) as first-line treatment for patients with advanced and metastatic NSCLC harbouring an EGFR mutation.

In the study, 364 patients from China, the 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 on day 1 / 1000 mg/m2 on day 1 and day 8 every 21 days up to 6 cycles, n=122). The primary endpoint was progression free-survival by central independent review.

Cisplatin/gemcitabine is commonly used for the treatment of first-line NSCLC patients in China, the Republic of Korea and Thailand.

About Afatinib
In the European Union, Taiwan, Chile and Mexico, afatinib is approved under the brand name GIOTRIF^® for the treatment of patients with metastatic NSCLC whose tumours have epidermal growth factor receptor (EGFR) mutations.

In the U.S., afatinib is approved under the brand name GILOTRIF^TM for the first-line treatment of patients with metastatic NSCLC whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, as detected by an FDA-approved test.⁷

Afatinib is an irreversible ErbB Family Blocker, which 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. The covalent and, therefore, irreversible binding of afatinib is unlike other compounds which are reversible, in that it provides a sustained, selective, and complete ErbB Family Blockade, and therefore may lead to a distinct therapeutic benefit.^8,9

Afatinib is being further investigated in Phase III clinical development in NSCLC and head & neck cancer.

About Lung Cancer
Lung cancer is one of the most common forms of cancer: it accounts for 1.6 million new cancer cases annually and more than half (54%) of these occur in Asia. Overall, lung cancer is the cause of 18.5% of all cancer deaths in Asia.¹⁰ 13% of all new cases of cancer are lung cancers¹¹ and smoking is attributed as the main cause.

Between 10-15% of Caucasian and 40% of Asian NSCLC patients have tumours harbouring EGFR mutations, with approximately 90% of these accounting for two mutations (del19 or L858R).¹²

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, Mexico and Chile, afatinib is approved under the brand name GIOTRIF^®, and in the U.S. under the brand name GILOTRIF^TM 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.

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.