Lung Cancer, Not One Disease: Diverse Patients Need Personalized Treatments, Two New Studies Show

Data Presented at American Society of Clinical Oncology (ASCO) on two Boehringer Ingelheim Phase III Oncology Compounds, Afatinib* and Nintedanib*, Show Progression Free Survival in Patients with Advanced Non-Small Cell Lung Cancer

BURLINGTON, ON, May 16, 2013 /CNW/ - New research taking place right here on Canadian soil is shedding light on the nation's number one cancer killer,ⁱ lung cancer.  Boehringer Ingelheim (Canada) Ltd. today announced data from Phase III clinical trials involving two different investigational oncology treatments - afatinib* and nintedanib* - in two distinct groups of patients with advanced non-small cell lung cancer (NSCLC).  The research is further proof that lung cancer is not just one disease - it can affect anyone, not just smokers.

In fact, the face of lung cancer is changing: we now know that people who have never smoked, women and East Asians are all groups that are at a higher risk for a specific genetic mutation - the epidermal growth factor receptor (EGFR) gene mutation - that happens in approximately 20 per cent of all lung cancer cases.ⁱⁱ But this is just one type of lung cancer; as research shows there are many different types, each requiring a unique approach to treatment.

Boehringer Ingelheim is conducting clinical trials on afatinib and nintedanib, two drugs that are being researched in Canada to address the unmet needs of two distinct lung cancer patient populations. Results from both trials, each of which met its primary endpoint of progression-free survival^{iii iv}(the length of time during which the disease does not get worse while on treatment - or PFS), will be presented at the 49^th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago, May 31-June 4, 2013.

"Personalized medicine has changed the way we treat lung cancer and we now know what treatment a patient will respond to best based on their genetic make-up," says Dr. Normand Blais, medical oncologist at the Centre Hospitalier de l'Université de Montréal (CHUM) in Montreal. "It is encouraging as an oncologist to see new options in development that can help us devise individualized treatment approaches.  This needs to be the way of the future for lung cancer treatment in Canada because until recently there have not been many options other than chemotherapy."

Top-line results from LUX-Lung 6 and LUME-Lung 2 trials:

• Afatinib was evaluated in the LUX-Lung 6 trial as a first-line treatment in Asian patients with epidermal growth factor receptor (EGFR) mutation-positive advanced NSCLC. Patients treated with afatinib lived for almost a year before their tumour started to grow again, as compared with just under half a year for patients treated with chemotherapy.^v The LUX-Lung 6 trial is the second Phase III trial involving afatinib in this patient population to meet its primary endpoint, and now incorporates health-related quality of life measures into the study design.
  
  
• Nintedanib was evaluated in combination with chemotherapy in the LUME-Lung 2 trial as a second-line treatment in patients with advanced NSCLC after first-line initial chemotherapy had failed. Results showed improvements in median PFS when nintedanib was combined with chemotherapy as compared to chemotherapy alone.  LUME-Lung 2, is a part of comprehensive clinical trial program that is exploring the potential of nintedanib in various lung cancer treatment settings. Highly anticipated results from the LUME-Lung 1 trial will be revealed in a late-breaking announcement at ASCO on June 3rd, 2013.

"These positive study results support why it's important to explore tailored treatment options," said Dr. Mathias Knecht M.D., Vice President Medical and Regulatory Affairs, Boehringer Ingelheim (Canada) Ltd. "Lung cancer is difficult to treat and we are committed to researching and developing new therapies for these patients and others. These results represent some of the latest advancements from Boehringer Ingelheim's robust oncology pipeline."

The New Face of Lung Cancer
NSCLC accounts for more than 85 per cent of all lung cancer diagnoses.^vi Between 10 and 15 per cent of Caucasians and approximately 40 per cent of Asians with NSCLC have EGFR mutations.^vii The EGFR mutation happens in approximately 20 per cent of all lung cancer cases.^viii

One recent Canadian study found that almost half of East Asians with NSCLC had the EGFR mutation.^ix Other studies show never-smoking women of East Asian descent are at even higher risk, with 80 per cent of patients in one study having the EGFR mutation.^x

EGFR mutations are also more common in never smokers compared to former or current smokers.^xi  As many as 15 per cent of people diagnosed with lung cancer have never smoked.^xii  Non-smoking women are more likely to be diagnosed with lung cancer than non-smoking men.^xiii

Detailed Summary of the LUX-Lung 6 Clinical Trial of Afatinib
The LUX-Lung 6 trial is the largest randomized, open-label Phase III trial conducted to date in the EGFR mutation-positive advanced (stage IIIb or IV) NSCLC patient population. The trial evaluated afatinib, an irreversible ErbB Family blocker, (n=242) compared to standard chemotherapy (gemcitabine and cisplatin) (n=122) as a first-line treatment in 364 Asian patients.^xiv

The trial met its primary endpoint of PFS; within the general study population, patients treated with afatinib lived for a median of 11.0 months before their tumour started to grow again versus 5.6 months for patients treated with chemotherapy (HR=0.28, p0.0001).^xv

The most common (> grade 3) drug-related adverse events observed in the afatinib treatment arm were rash/acne (14.6%), diarrhea (5.4%) and stomatitis/mucositis (5.4%).^xvi The most common (> grade 3) drug-related adverse events observed in the gemcitabine/cisplatin treatment arm were neutropenia (17.7%), vomiting (15.9%) and leukopenia (13.3%).^xvii Overall, 5.9 percent of patients treated with afatinib discontinued treatment compared with 39.8 percent of patients treated with chemotherapy.^xviii

The analysis of lung cancer-related symptoms (cough, dyspnea or shortness of breath, and pain) showed:

• A higher proportion of patients in the afatinib arm, compared with those in the chemotherapy arm, reported 10 point or more improvements in cough (76% versus 55%; p=0.0003), dyspnea (71% versus 48%; p0.0001) and pain (64% versus 47%; p=0.003)
• Afatinib-treated patients experienced a significant delay in the worsening (time to deterioration) of cough (HR=0.45; p=0.0001), dyspnea (HR=0.54; p0.0001) and pain (HR=0.70; p=0.03) compared to those treated with chemotherapy
• Mean symptom scores (a measurement of symptom severity) over time also significantly favoured afatinib over chemotherapy for all three symptoms measured ^xix

Detailed Summary of the LUME-Lung 2 Clinical Trial of Nintedanib
This randomized, double-blinded study evaluated nintedanib - a triple angiokinase inhibitor - plus pemetrexed compared to pemetrexed plus placebo in patients with advanced non-squamous NSCLC not responding to, or who progressed after, first-line chemotherapy.^xx LUME-Lung 2 did not pass the pre-defined interim futility analysis from external independent experts which resulted in the premature halting of enrolment (after 713 patients). At the point of the futility analysis, PFS did not appear to be significantly improved compared to the comparator arm; no safety issues were identified.^xxi

However, results from the first 713 patients who were already enrolled in the study showed significant improvement in the primary endpoint of PFS even though enrolment was stopped prematurely.^xxii Patients treated with nintedanib/pemetrexed (n=353) lived for a median of 4.4 months before their tumour started to grow again (PFS), compared to 3.6 months for patients assigned to the pemetrexed/placebo arm (n=360) (HR=0.83, p=0.04).^xxiii

A higher incidence of (> grade 3) elevated ALT (23% versus 7%) and AST (12% versus 2%) - which are types of enzymes measured to determine liver health^xxiv- as well as diarrhea (3% versus 1%) were observed in patients treated with nintedanib and pemetrexed.^xxv Hypertension, bleeding, thrombosis, mucositis and neuropathy (> grade 3) were comparable between the two treatment arms.^xxvi There was no increase in serious adverse events or grade five adverse events reported in patients who received the combination of nintedanib and pemetrexed.^xxvii

Notes to Editors:

About Afatinib
Afatinib is an investigational, oral, once-daily irreversible ErbB Family Blocker that specifically inhibits epidermal growth factor receptor (EGFR or ErbB1), human epidermal receptor 2 (HER2 or ErbB2) and ErbB4. It is currently in Phase III clinical development in advanced NSCLC and head and neck cancer. Afatinib is not approved by Health Canada; its safety and efficacy have not been established.

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: fibroblast growth factor (FGF) receptor, platelet-derived growth factor (PDGF) receptor, and vascular endothelial growth factor (VEGF) 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.  Nintedanib is not approved by Health Canada; its safety and efficacy have not been established.

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 program to discover and develop innovative cancer treatments.  Working in close collaboration with the international scientific community and a number of the world's leading cancer centers, 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 hematological cancers. The current focus of late-stage research includes compounds in three areas: signal transduction inhibition, angiogenesis inhibition and cell-cycle kinase inhibition. The company is also evaluating a robust and growing pipeline of early-stage oncology compounds in areas including growth/survival signaling, immunotherapy and epigenetics.

About Boehringer Ingelheim (Canada) Ltd.
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.

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 endeavors.

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

The Canadian headquarters of Boehringer Ingelheim was established in 1972 in Montreal, Quebec and is now located in Burlington, Ontario.  Boehringer Ingelheim employs more than 550 people across Canada.  For more information please visit www.boehringer-ingelheim.ca.

References
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ⁱ Canadian Cancer Society's Steering Committee on Cancer Statistics. Canadian Cancer Statistics 2012. Toronto, ON: Canadian Cancer Society; 2012, Page 9.
ⁱⁱ Pao W, Miller VA. Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions. J Clin Oncol 2005;23:2556-2568, Page 2561.
ⁱⁱⁱ Wu, Y., MD.  LUX-Lung 6: A randomized, open-label, Phase III study of afatinib (A) vs gemcitabine/cisplatin (GC) as first-line treatment for Asian patients (pts) with EGFR mutation-positive (EGFR M+) advanced adenocarcinoma of the lung.  Poster discusison (Abstract #8016) at American Society of Clinical Oncology, Chicago, June 2, 2013 Page. 2
^iv Hanna, N., MD. LUME-Lung 2: A multicenter, randomized, double-blind, phase 3 study of nintedanib plus pemetrexed vs placebo plus pemetrexed in patients with advanced non-squamous non-small cell lung cancer (NSCLC) after failure of first-line chemotherapy. Poster discussion (Abstract #8034) at American Society of Clinical Oncology, Chicago, June 2, 2013. Page. 1
^v  Wu, Y., MD.  LUX-Lung 6: A randomized, open-label, Phase III study of afatinib (A) vs gemcitabine/cisplatin (GC) as first-line treatment for Asian patients (pts) with EGFR mutation-positive (EGFR M+) advanced adenocarcinoma of the lung.  Poster discusison (Abstract #8016) at American Society of Clinical Oncology, Chicago, June 2, 2013. Page. 2
^vi  American Cancer Society.  Cancer Facts and Figures: 2012.  Available at: http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-031941.pdf.  Last accessed April 27, 2012. Pg. 16
^vii  Quest Diagnostics. Lung Cancer Mutation Panel (EGFR, KRAS, ALK). Available at: http://questdiagnostics.com/hcp/intguide/jsp/showintguidepage.jsp?fn=Lung/TS_LungCancerMutation_Panel.htm . Last accessed May 18, 2012. Page. 2
^viii Pao W, Miller VA. Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions. J Clin Oncol 2005;23:2556-2568, Page 2561.
^ix Peter M. Ellis. Late Breaking Abstract Supplement, available at the 14th World Conference on Lung Cancer.Poster Session 4 - Pathology Thursday, 7 July 2011 10:00-12:30  P4.199 IMPLEMENTATION OF A NATIONAL EGFR TESTING STRATEGY IN A PUBLICLY FUNDED HEALTH SYSTEM, Page 1.
^x Lynette M. Sholl. Lung Adenocarcinoma with EGFR Amplification Has Distinct Clinicopathologic and Molecular Features in Never-Smokers. Published OnlineFirst October 13, 2009; doi: 10.1158/0008-5472.CAN-09-2477 Cancer Res November 1, 2009 69; 8341, Page 5.
^xi Pao W, Miller VA. Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions. J Clin Oncol 2005;23: Page 2561.
^xii Torok et al. "Lung cancer in never smokers." Future Oncology. 2011. Oct; 7(10): 1195-211. Page 1195.
^xiii Subramanian and Govindan (2007).  "Lung Cancer in Never Smokers: A Review." Journal of Clinical oncology. Page 561
^xiv Wu, Y., MD.  LUX-Lung 6: A randomized, open-label, Phase III study of afatinib (A) vs gemcitabine/cisplatin (GC) as first-line treatment for Asian patients (pts) with EGFR mutation-positive (EGFR M+) advanced adenocarcinoma of the lung.  Poster discusison (Abstract #8016) at American Society of Clinical Oncology, Chicago, June 2, 2013. Page. 2
^xv Ibid.
^xvi Ibid.
^xvii Ibid.
^xviii Ibid.
^xix Geater, S.L., MD.  LUX-Lung 6: Patient reported outcomes (PROs) from a randomized open-label, Phase III study in 1st-line advanced NSCLC patients (pts) harboring epidermal growth factor receptor (EGFR) mutations. Poster (Abstract #8061) at American Society of Clinical Oncology, Chicago, June 1, 2013. Page. 2
^xx Hanna, N., MD. LUME-Lung 2: A multicenter, randomized, double-blind, phase 3 study of nintedanib plus pemetrexed vs placebo plus pemetrexed in patients with advanced non-squamous non-small cell lung cancer (NSCLC) after failure of first-line chemotherapy. Poster discussion (Abstract #8034) at American Society of Clinical Oncology, Chicago, June 2, 2013.
^xxi Ibid.
^xxii Ibid.
^xxiii Ibid.
^xxiv Ibid.
^xxv Ibid.
^xxvi Ibid.
^xxvii Ibid.

*Afatinib and nintedanib are investigational compounds. Their safety and efficacy have not yet been fully established and are currently not authorized for sale in Canada.

Video with caption: "Video: Dr. Vera Hirsh, Associate Professor, McGill University, Department of Medical Oncology, Royal Victoria Hospital, Montreal, Canada talks about a new era of personalized medicine in lung cancer.". Video available at: http://stream1.newswire.ca/cgi-bin/playback.cgi?file=20130516_C7366_VIDEO_EN_26769.mp4&posterurl=http://photos.newswire.ca/images/20130516_C7366_PHOTO_EN_26769.jpg&clientName=Boehringer%20Ingelheim%20%28Canada%29%20Ltd%2E&caption=Video%3A%20Dr%2E%20Vera%20Hirsh%2C%20Associate%20Professor%2C%20McGill%20University%2C%20Department%20of%20Medical%20Oncology%2C%20Royal%20Victoria%20Hospital%2C%20Montreal%2C%20Canada%20talks%20about%20a%20new%20era%20of%20personalized%20medicine%20in%20lung%20cancer%2E&title=BOEHRINGER%20INGELHEIM%20%28CANADA%29%20LTD%2E%20%2D%20Lung%20Cancer%2C%20Not%20One%20Disease%3A%20Diverse%20Patients%20Need%20Personalized%20Treatments%2C%20Two%20New%20Studies%20Show&headline=Lung%20Cancer%2C%20Not%20One%20Disease%3A%20Diverse%20Patients%20Need%20Personalized%20Treatments%2C%20Two%20New%20Studies%20Show

SOURCE: Boehringer Ingelheim (Canada) Ltd.

Morgan Cates
Environics Communications
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