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Boehringer Ingelheim to Study Afatinib in Patients with Difficult-to-Treat HER2-Positive Breast Cancer

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Continuing to expand the development program for its irreversible inhibitor of EGFR and HER2, afatinib, Boehringer Ingelheim Pharmaceuticals has launched two new Phase II studies — one investigating the drug as a treatment for inflammatory breast cancer and another for metastatic HER2-positive breast cancer patients who have progressed despite treatment with other HER2-targeted drugs.

Study 1200.89, also known as "Afatinib (BIBW 2992) in erbB2 (HER2)-overexpressing Inflammatory Breast Cancer," will look at the efficacy and safety of Boehringer Ingelheim's drug in HER2-positive inflammatory breast cancer, a particularly aggressive form of the disease. Patients who continue to progress despite treatment with afatinib may be given a combination of afatinib and vinorelbine, the drug firm noted. Study 1200.89, a non-randomized and open label trial, has begun recruiting patients in Australia, India, and the UK. US enrollment will begin in January 2012.

This trial plans to enroll 40 patients who have previously been treated with Roche/Genentech's HER2 drug Herceptin, and may or may not have failed on that drug. The primary endpoint of 1200.89 is clinical benefit rate assessed by complete response, partial response, and stable disease for at least six months. The secondary endpoints of the study are objective response, duration of objective response, progression-free survival, and safety.

Study 1200.98, also called the LUX-Breast 2 trial, will investigate afatinib in 120 patients with HER2-positive metastatic breast cancer who have progressed on other HER2-targeting therapies. This study, which began enrolling patients in Asia and the UK in May, is also non-randomized, open-label in design, and will evaluate afatinib as a single agent, as well as in combination with vinorelbine or paclitaxel for those patients who progress on the single treatment. The primary endpoint of the study is objective response rate; secondary endpoints include best overall response.

Both studies will include biomarker testing of tumor tissues, the company said.

Boehringer Ingelheim has embarked on a broad clinical trial program for afatinib. Last year, the company launched the Phase III LUX-Breast 1 trial looking at afatinib in HER2-positive breast cancer patients with advanced disease. The open-label, randomized study involving around 800 patients who have been previously treated with Herceptin is comparing whether afatinib plus vinorelbine can extend progression-free survival better than a Herceptin/vinorelbine regimen. Overall survival and safety are the secondary endpoints of the trial.

"We have seen positive results in our proof-of-concept studies for afatinib in breast cancer and are glad to advance the program into pivotal Phase III," Klaus Dugi, corporate senior VP of medicine at Boehringer Ingelheim, said in a statement a year ago announcing the launch of LUX-Breast 1.

According to the American Cancer Society, nearly 40,000 women are expected to die from breast cancer in this year in the US. It is estimated that women who overexpress the HER2 protein comprise approximately 30 percent of advanced breast cancer cases.

"There is a need for more treatment options for patients with aggressive HER2-positive breast cancer. These studies are important because they will help us to further explore the potential of afatinib in this difficult-to-treat group of patients," Andree Amelsberg, executive director of Boehringer Ingelheim's oncology medical affairs division, said in a statement.

Outside of the breast cancer setting, Boehringer Ingelheim is also studying the irreversible erbB tyrosine kinase inhibitor as a treatment for non-small cell lung cancer patients with EGFR mutations. A Phase III trial called LUX-Lung 3 is comparing single-agent afatinib as a first-line NSCLC treatment against a cisplatin/pemetrexed chemo regimen. Boehringer Ingelheim and Qiagen's DxS subsidiary are together working on developing an EGFR mutation test kit to identify best responders to afatinib.

At the American Society of Clinical Oncology's annual meeting in June, Boehringer Ingelheim presented data from a Phase Ib trial combining afatinib with Bristol-Myers Squibb/Merck/Lilly's Erbitux in 22 NSCLC patients with EGFR mutations who have developed resistance to a reversible tyrosine kinase inhibitor. In that study, researchers observed a tumor size reduction of up to 76 percent over a treatment period of up to five months when patients received the afatinib/Erbitux regimen.

In a similar strategy, Roche subsidiary Genentech is also looking to expand Tarceva as a NSCLC treatment in patients with EGFR mutations in the first-line setting (PGx Reporter 06/08/2011). This drug could potentially end up competing with afatinib, if both are successfully developed and launched. Earlier this month, the European Commission approved the use of Tarceva as a first-line monotherapy for non-small cell lung cancer in patients with EGFR activating mutations (see related story, in this issue).

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