Results from the phase III CLEOPATRA study showed that women with HER2-positive metastatic breast cancer (mBC) lived significantly longer (overall survival) when treated with the combination of pertuzumab (Perjeta?, Genentech/Roche), trastuzumab (Herceptin?, Genentech/Roche) and docetaxel chemotherapy, compared to trastuzumab and docetaxel chemotherapy alone. in the Phase III . These data will be submitted for presentation at an upcoming medical meeting.

Pertuzumab is designed specifically to prevent the HER2 receptor from pairing (or dimerizing) with other HER receptors (EGFR/HER1, HER3 and HER4) on the surface of cells, a process that is believed to play a role in tumor growth and survival. Binding of pertuzumab to HER2 may also signal the body’s immune system to destroy the cancer cells. The mechanisms of action of pertuzumab and trastuzumab are believed to complement each other, as both bind to the HER2 receptor, but to different places. The combination of pertuzumab, trastuzumab and docetaxel chemotherapy is thought to provide a more comprehensive blockade of HER signaling pathways.

Untreated HER2-positive mBC
The CLEOPATRA study (CLinical Evaluation Of Pertuzumab And TRAstuzumab), an international, Phase III, randomized, double-blind, placebo-controlled study, included 808 women with previously untreated HER2-positive mBC or with HER2-positive mBC that had recurred after prior therapy in the adjuvant or neoadjuvant setting.

HER2 positivity
Breast cancer is the most common cancer among women worldwide. [1] According to the American Cancer Society, approximately 229,000 people will be diagnosed with breast cancer, and 40,000 will die from the disease in 2012. Worldwide,about 1.4 million new cases of breast cancer are diagnosed each year, 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 (HER2) are present on the surface of the tumor cells. This is known as HER2 positivity and affects approximately 25% of people with breast cancer.[2] HER2-positive cancer is a particularly aggressive form of breast cancer.[3]

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Improvement in survival
“Pertuzumab helped people with HER2-positive metastatic breast cancer live longer and lengthened the time they lived without their disease worsening,” said Hal Barron, M.D., chief medical officer and head, Global Product Development. “The improvement in survival seen in the CLEOPATRA study is great news for patients and doctors, and reinforces our belief that pertuzumab will improve the outlook for people with this devastating disease.”

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Personalized medicine
Pertuzumab is a personalized medicine that targets the HER2 receptor, a protein found in high quantities on the outside of cancer cells in HER2-positive cancers. Pertuzumab is believed to work in a way that is complementary to Herceptin, as the two medicines target different places on the HER2 receptor.

FDA Approval
The FDA recently approved pertuzumab in combination with trastuzumab and docetaxel chemotherapy for the treatment of people with HER2-positive mBC who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease, based on the results of the CLEOPATRA study. Roche has also submitted a Marketing Authorization Application to the European Medicines Agency (EMA) for pertuzumab for people with previously untreated HER2-positive mBC.

Study Results
This analysis of overall survival in the CLEOPATRA study crossed the pre-specified boundary showing that the combination of pertuzumab, trastuzumab and docetaxel chemotherapy significantly improved overall survival in people with HER2-positive mBC, compared with Herceptin and chemotherapy. Overall survival is a secondary endpoint of the CLEOPATRA study.

Progression-free survival
The final progression-free survival (PFS, the primary endpoint) and safety profile data from the CLEOPATRA study were published in December 2011 in the New England Journal of Medicine and demonstrated that people who received pertuzumab in combination with trastuzumab and docetaxel chemotherapy had a statistically significant 38% reduction in the risk of their disease worsening or death (PFS, HR=0.62, p-value less than 0.0001) compared to people who received trastuzumab and chemotherapy plus placebo. The median PFS improved by 6.1 months from 12.4 months for people who received trastuzumab and chemotherapy plus placebo to 18.5 months for those who received pertuzumab, trastuzumab and chemotherapy.[4]

In CLEOPATRA, the most common adverse reactions (rate greater than 30%) seen with pertuzumab in combination with trastuzumab and docetaxel chemotherapy were diarrhea, hair loss, low white blood cell count with or without fever, upset stomach, fatigue, rash and peripheral neuropathy (numbness, tingling or damage to the nerves). The most common Grade 3-4 adverse reactions (rate greater than 2%) were low white blood cell count with or without fever, decrease in a certain type of white blood cell, diarrhea, damage to the nerves, decrease in red blood cell count, weakness and fatigue.

The primary endpoint of the study was PFS as assessed by an independent review committee. Secondary endpoints were overall survival, PFS by investigator assessment, safety profile, overall response rate (ORR), duration of response and time to symptom progression.

For more information:
Full Prescribing Information: Trastuzumab (Herceptin).

References
[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 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. Available from: http://globocan.iarc.fr.
[2] Wolff A.C et al. American Society of Clinical Oncology/ College of American Pathologists Guideline Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer. Arch Pathol Lab Med?Vol 131, January 2007.
[2] Slamon D et al. Adjuvant Trastuzumab in HER2-Positive Breast Cancer. N Engl J Med 2011; 365:1273-83.
[4]Baselga J, Cortes J, Sung-Bae K, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med.2012; 366:109?119.

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