The CLEOPATRA trial, a multicenter international clinical Phase III study, designed to evaluate the efficacy and safety of pertuzumab with trastuzumab and docetaxel vs. placebo with trastuzumab and docetaxel in previously untreated Her2-positive metastatic breast cancer (mBC), has met its primary endpoint: progression-free survival.

Pertuzumab is a monoclonal antibody being studied in early-stage and metastatic HER2-positive breast cancer. It is an investigational HER2-targeted medicine called a HER2 dimerisation inhibitor (HDI). HER dimerisation (pairing) is believed to play an important role in the growth and formation of several different cancer types.

Inhibiting cancer cell growth
Pertuzumab is the first investigational medicine developed to specifically prevent the HER2 receptor from pairing with other HER receptors (EGFR/HER1, HER3 and HER4). In doing so, pertuzumab is thought to block cell signalling, which may inhibit cancer cell growth or lead to the death of the cancer cell. The mechanisms of action of pertuzumab and trastuzumab (Herceptin?, Roche / Genentech), are believed to complement each other as both bind to the HER2 receptor but on different regions. The goal of combining pertuzumab with trastuzumab and chemotherapy is to determine if the combination may provide a more comprehensive blockade of HER signalling pathways.

Study results
The study showed that people with HER2-positive metastatic breast cancer (mBC) who received the combination of two targeted medicines, pertuzumab and trastuzumab, plus docetaxel chemotherapy lived significantly longer without their disease getting worse (progression-free survival, PFS) than people who received only trastuzumab and docetaxel.

Consistent adverse events
No new safety signals were observed and adverse events were consistent with those seen in previous studies of pertuzumab and trastuzumab, either in combination or alone. Data from CLEOPATRA will be submitted for presentation at an upcoming medical meeting.

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Incurable and agressive
Despite significant progress, HER2-positive metastatic breast cancer remains an incurable disease.

Breast cancer is the most common cancer among women worldwide [1]. Each year about 1.4 million new cases of breast cancer are diagnosed worldwide, and over 450,000 women will die of the disease annually [1]. In HER2-positive breast cancer, increased quantities of the human epidermal growth factor receptor 2 or HER2 are present on the surface of the tumour cells. This is known as ?HER2 positivity? and affects approximately 15-25% of women with breast cancer [2]. HER2-positive cancer is a particularly aggressive form of breast cancer [3].

Personalized options
?These results with pertuzumab combined with Herceptin and docetaxel are very encouraging and represent our commitment to developing potential new personalised options for people with this aggressive disease,? said Hal Barron, M.D., chief medical officer and head, Global Product Development. ?We plan to submit the study results for global regulatory approval this year.?

Treatment schedules
The two-arm study enrolled 808 people with previously untreated HER2-positive mBC from 19 countries worldwide. Participants in the pertuzumab arm received docetaxel 75-100 mg/m2 every three weeks for six cycles or until progression and trastuzumab 8 mg/kg loading dose followed by 6 mg/kg every three weeks and pertuzumab 840 mg loading dose followed by 420 mg every three weeks.

Participants in the trastuzumab plus docetaxel arm received docetaxel 75-100 mg/m2 every three weeks for six cycles or until progression and trastuzumab 8 mg/kg loading dose followed by 6 mg/kg every three weeks.

Progression-free survival
The primary study endpoint was PFS as assessed by an independent review. Secondary endpoints are overall survival (OS), safety profile, overall response rate (ORR), duration of remission, quality of life and correlation of biomarkers with clinical outcomes.

Regulatory status
Based on the outomes of the study, Roche Holding AG earlier today said it will file pertuzumab for approval in both Europe and the U.S. later this year.

For more information
[1]Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM GLOBOCAN 2008, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 10. Lyon, France: International Agency for Research on Cancer; 2010. Last accessed July 15, 2011.
[2] Harries M, Smith I. The development and clinical use of trastuzumab (Herceptin). Endocr Relat Cancer 9: 75-85, 2002.
[3] Macmillan Cancer Support. HER2 and breast cancer. Last accessed June 15, 2011.

Clinical Trial:
A Study to Evaluate Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated Her2-Positive Metastatic Breast Cancer (CLEOPATRA)[NCT00567190]

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