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Afatinib (BIBW 2992) triples progression free survival in phase III study in lung cancer patients

Boehringer IngelheimBoehringer Ingelheim announced promising results from two clinical trials of its investigational cancer compound afatinib (BIBW 2992) presented at the 35 th European Society for Medical Oncology (ESMO) Congress in Milan, Italy. Results from the "LUX-Lung 1" trial suggest that afatinib (BIBW 2992) is highly active in late-stage patients with NSCLC1, while in the LUX-Lung 2 phase II trial afatinib demonstrated encouraging activity in advanced NSCLC patients that have a mutated EGF Receptor.

Afatinib, which is taken as a tablet, is a next generation inhibitor of the epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) tyrosine kinase (TK) and unlike first generation TKIs irreversibly binds to EGFR/HER2. The compound is under development in several solid tumour types.

The LUX-Lung 1 trial (phase II b/III) compared afatinib to placebo in over 580 patients with advanced NSCLC whose disease has progressed after receiving chemotherapy and a first-generation EGFR Tyrosine Kinase Inhibitor (gefitinib or erlotinib) - results showed (1):

  • Even though the LUX-Lung 1 trial did not meet the primary endpoint of prolonging overall survival (OS), afatinib significantly extended the time before the tumour progressed; specifically it led to a three-fold extension of progression-free survival (PFS, key secondary endpoint) from 1.1 months to 3.3 months over placebo.
  • The PFS benefit was apparent as a robust effect across all patient subgroups and has been confirmed by independent review.
  • There was a significantly higher rate of tumour control or shrinkage in those patients who took afatinib (disease control rate: 58%) versus those taking placebo (disease control rate: 19%); also independently verified.
  • Afatinib significantly improved the lung-cancer related symptoms cough, dyspnea (shortness of breath) and pain, and delayed the time to deterioration of cough, individual dyspnea items and chest pain significantly.
  • There were no new or unexpected safety findings; the main side effects were diarrhea and rash.

The results of LUX-Lung 1 in a special patient population whose cancers probably have a high incidence of EGFR mutations have substantially contributed to better understanding of the biology of these tumours. Conclusions from the trial will be relevant for the design of further clinical studies, which will evaluate further patient populations and their mutation status.

Lung cancer is the most common and most deadly form of cancer in the world, accounting for 1.6 million new cancer cases annually and 1.4 million deaths (2) from lung cancer. Lung cancer remains an area of high unmet need, especially in its advanced stages where it is particularly aggressive and patients have limited treatment options. No approved therapy is currently available for patients with advanced lung cancer who have failed chemotherapy and progressed after treatments with EGFR TKI.

"In clinical practice, it is of high relevance to patients to have improvement in key lung cancer related symptoms such as cough, shortness of breath and pain" commented Dr Vera Hirsh, investigator of the trial, and Chair of the Lung Cancer Committee, McGill University, Canada. "Furthermore, the time to deterioration, meaning the time before the symptoms get worse, was significantly extended for some of these symptoms in the LUX Lung 1 study."

This is the first time that a compound has demonstrated in a controlled study, a clinically meaningful improvement in PFS in patients with NSCLC who have progressed on first generation EGFR TKIs.

Encouraging results were also presented for LUX-Lung 2, a phase II trial studying patients with advanced NSCLC who harbour EGFR mutations. This result shows that the use of afatinib led to a high rate of tumour size reduction (overall response rate of 61%) and a long delay in the progression of cancer by over 1 year (PFS of 14 months) (3). These results help to underline afatinib's potential benefit as a first or second line treatment in patients with EGFR mutations. Two phase III trials, LUX-Lung 3 and LUX-Lung 6 are currently underway to further evaluate afatinib as a first-line treatment in this patient group.

"Both of these recent trials demonstrate the promise of afatinib as a next-generation treatment option in NSCLC patients in different settings" says Prof. Klaus Dugi, Senior Vice President Medicine at Boehringer Ingelheim. "We are convinced that afatinib could provide a benefit for patients with NSCLC, and we remain fully committed to its ongoing development in lung cancer and in other solid cancer types."

Afatinib's clinical trial programme: LUX Trial Programme
The LUX-trial programme is a comprehensive and robust programme that comprises more than ten trials conducted across the globe, investigating afatinib in a variety of different solid tumour types, including NSCLC, breast and head and neck cancer.

LUX-Lung 1 is a phase III trial investigating afatinib plus best supportive care (BSC) versus placebo plus BSC in NSCLC patients who were previously treated with chemotherapy and first generation EGFR-TKIs, erlotinib or gefitinib.

LUX-Lung 2 is a phase II trial evaluating afatinib in NSCLC patients with EGFR mutations, either chemotherapy naïve or after one line of chemotherapy.

In two further ongoing global phase III trials, LUX-Lung 3 and LUX-Lung 6, the efficacy and safety profile of afatinib is compared to standard chemotherapy for first-line treatment of NSCLC patients with EGFR mutations in different geographical regions.

Another trial, LUX-Lung 5, is a global phase III trial in patients previously treated with erlotinib or gefitinib. This is the first randomised phase III trial investigating whether patients who initially benefit from treatment with afatinib alone may further benefit from afatinib beyond progression when given in combination with chemotherapy.

Further indications
Additionally, Boehringer Ingelheim has recently commenced a phase III clinical trial evaluating afatinib in advanced breast cancer (LUX-Breast 1).

Afatinib is also being investigated in head and neck cancer, glioblastoma and colorectal cancer.

Afatinib & BIBF 1120*: the two front-runner molecules within Boehringer Ingelheim's investigational oncology portfolio
Apart from afatinib, Boehringer Ingelheim's late stage oncology portfolio includes BIBF 1120, also in phase III development for the treatment of patients in two different indications, advanced NSCLC and ovarian cancer.

BIBF 1120 is a triple angiokinase inhibitor that acts on three growth factors simultaneously: vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR) - all crucially involved in the formation of blood vessels, which supply tumours with nutrients and oxygen needed for the cancer to grow.

About lung cancer
Lung cancer is the world's most common cancer and kills more people than any other cancer. In 2008, approximately 1.6 million new cases of lung cancer were diagnosed worldwide, with 1.4 million people dying from the disease.(2)

About breast cancer
There are more than one and a half million cases of breast cancer diagnosed each year(4). It is the leading cause of cancer deaths in women worldwide, resulting in more than 500,000 deaths per year(5). Breast cancer accounts for around a third of all cancers diagnosed in women, making it the most commonly diagnosed tumour type in females.

About head and neck cancer
Head and neck cancer can occur in over 30 different places in any of the tissues or organs in the head and neck (6) and is the sixth most frequently occurring cancer worldwide (7). Most head and neck cancers are squamous cell carcinomas (8) over 90% of which express EGFR (9) which is critical for tumour growth. (10)

About ovarian cancer
Each year approximately 204,000 new cases of ovarian cancer are diagnosed in women worldwide, with an estimated 125,000 dying of the disease each year. (11) One of the greatest challenges in the management of ovarian cancer is that the majority of cases are not found at an early stage (12) (when definitive cure is possible by surgery) since the tumour usually causes only non-specific symptoms, commonly attributed to non-serious causes.

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 is committed to discovering and developing novel cancer treatments. This commitment is underpinned by using advances in science to develop a range of targeted therapies in areas of medical need, including 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. Afatinib is currently in phase III clinical development in NSCLC. In addition, the LUME-Lung phase III clinical trial programme, which is investigating BIBF 1120 in combination with standard second-line chemotherapy treatments for patients with advanced NSCLC, is ongoing. In the area of cell-cycle kinase inhibition, Boehringer Ingelheim is developing inhibitors of polo-like kinase 1 (Plk1), a protein that is involved in the processes of cell division. These molecules are in the earlier stages of clinical development.

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 142 affiliates in 50 countries and more than 41,500 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

In 2009, Boehringer Ingelheim posted net sales of 12.7 billion euro while spending 21% of net sales in its largest business segment Prescription Medicines on research and development.

1. Miller et al. Phase IIb/III double-blind randomized trial of BIBW 2992, an irreversible inhibitor of EGFR/HER1 and HER2 + best supportive care (BSC) versus placebo + BSC in patients with NSCLC failing 1–2 lines of chemotherapy and erlotinib or gefitinib (LUX-Lung 1). Oral presentation at The European Society of Medical Oncology (ESMO) annual meeting, Milan, October 2010. Abstract ID: LBA11
2. Cancer Research UK. CancerStats Key Facts on Lung Cancer and Smoking. Available at http://info.cancerresearchuk.org/cancerstats/types/lung/. Last accessed 30 September 2010.
3. Yang et al. A Phase II study of BIBW 2992 in patients with adenocarcinoma of the lung and activating EGFR/HER1 mutations (LUX-Lung 2). Poster presentation at The 35th European Society of Medical Oncology (ESMO) annual meeting, Milan, October 2010. Abstract ID: 367PD
4. WHO Cancer Factsheet N°297 – updated February 2009. [Online] Available at: http://www.who.int/mediacentre/factsheets/fs297/en/index.html
5. Breast Cancer Campaign. Breast Cancer: The Facts. [Online] Available at: http://www.breastcancercampaign.org/breastcancer/breast_cancer_facts/
6. Hunter KD et al. Profiling early head and neck cancer. Nat Rev Cancer. 2005 Feb; 5 (2): 127-35
7. Viviana P. Lutzky. Biomarkers for Cancers of the Head and Neck. Clinical Medicine: Ear, Nose and Throat 2008:1
8. Grandis, J.R. and Tweardy, D.J. Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res., 1993. 53:3579–84.
9. Normanno N et al. The ErbB receptors and their ligands in cancer: an overview. Current Drug Targets.2005.  May;6(3):243-47.
10. Boyle P. et al. World Cancer Report 2008. International Agency for Research on Cancer.

*Afatinib (BIBW 2992) and BIBF 1120 are investigational compounds; their safety and efficacy have not been fully established.

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