Boehringer Ingelheim announced promising results from two clinical trials of its investigational cancer compound afatinib (BIBW 2992) presented at the 35th 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 showed1:

* 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 deaths2 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.

Afatinibs 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 year4. It is the leading cause of cancer deaths in women worldwide, resulting in more than 500,000 deaths per year. Breast cancer accounts for around a third of all cancers diagnosed in women, making it the most commonly diagnosed tumour type in females5.

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 neck6 and is the sixth most frequently occurring cancer worldwide7. Most head and neck cancers are squamous cell carcinomas8 over 90% of which express EGFR9 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 year11. One of the greatest challenges in the management of ovarian cancer is that the majority of cases are not found at an early stage11 (when definitive cure is possible by surgery) since the tumour usually causes only non-specific symptoms, commonly attributed to non-serious causes.

Boehringer Ingelheim announced promising results from two clinical trials of its investigational cancer compound

afatinib (BIBW 2992) presented at the 35th 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 showed1:

* 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 deaths2 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.

Afatinibs 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 year4. It is the leading cause of

cancer deaths in women worldwide, resulting in more than 500,000 deaths per year. Breast cancer accounts for around a

third of all cancers diagnosed in women, making it the most commonly diagnosed tumour type in females5.

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 neck6 and

is the sixth most frequently occurring cancer worldwide7. Most head and neck cancers are squamous cell carcinomas8

over 90% of which express EGFR9 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 year11. One of the greatest challenges in the management of ovarian cancer is that

the majority of cases are not found at an early stage11 (when definitive cure is possible by surgery) since the

tumour usually causes only non-specific symptoms, commonly attributed to non-serious causes.

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