Investor Update

Basel, 30 May 2008

Pertuzumab with Herceptin shows impressive results in women with advanced HER2-positive breast cancer

New data from a Phase II trial presented at the American Society of Clinical Oncology (ASCO) 2008 meeting in Chicago show that half of the patients with advanced, HER2-positive metastatic breast cancer whose disease had progressed during a Herceptin-containing regimen benefited from a combination of Herceptin and pertuzumab1. Pertuzumab inhibits the pairing of HER2 with other HER receptors, a key mechanism of tumour growth. A combination of Herceptin with pertuzumab may lead to a more powerful blockade of the signalling pathways of HER2-positive breast cancer.

“This efficacy is the best I have observed with HER2-targeted therapy without chemotherapy, and represents significant promise for women with breast cancer in the future”, said Dr Jose Baselga (Vall d’Hebron University Hospital, Barcelona, Spain), lead investigator of the Phase II trial.

“Its potential lies in its ability to target and block the most relevant pathways for tumour growth. We are hopeful the combination of Herceptin and pertuzumab used with chemotherapy will be even more effective if used to treat women newly diagnosed with advanced cancer. This combination is being investigated in the Phase III CLEOPATRA study, which is currently recruiting patients.”

In the Phase II study, nearly one in four patients saw their tumours disappear (complete tumour response, 8 %) or shrink (partial tumour response, 16 %). A further 25% of patients saw their cancer, which had been progressing, stabilise for at least 6 months. The combination of pertuzumab and Herceptin was well tolerated in this group of patients and no patients were withdrawn from the trial with treatment-related adverse events.

These results are important as, unfortunately, metastatic breast cancer cannot be cured and so patients need improved and new treatment options. The need for improved treatment options is particularly important for women suffering from advanced aggressive HER2-positive breast cancer.

The combination of Herceptin plus pertuzumab combined with chemotherapy is being evaluated in first-line metastatic breast cancer patients in another study, CLEOPATRA (CLinical Evaluation Of Pertuzumab and TRAstuzumab). This phase III study began recruiting patients in January 2008 and is underway in 18 countries worldwide. If this study is successful, this combination of Herceptin plus pertuzumab and chemotherapy has the potential to become a new standard of care in HER2-positive metastatic breast cancer.

About breast cancer
Breast cancer is the most common cancer among women worldwide2.  Each year more than one million new cases of breast cancer are diagnosed worldwide, and nearly 400,000 people will die of the disease annually. In HER2-positive breast cancer, increased quantities of the HER2 protein are present on the surface of the tumour cells. This is known as ‘HER2 positivity’. High levels of HER2 are present in a particularly aggressive form of the disease which responds poorly to chemotherapy. Research shows that HER2-positivity affects approximately 20–30% of women with breast cancer.

About pertuzumab
Pertuzumab is the first in a class of innovative targeted agents known as HER2-dimerisation inhibitors (HDIs).Pertuzumab is a humanised monoclonal antibody designed to bind to the HER2 receptor and inhibit the ‘pairing’ or dimerisation of HER2 with other HER family receptors (HER1, HER2, HER3 and HER4). This pairing is believed to play an important role in the growth and formation of several different cancer types. Synergy observed in nonclinical studies of pertuzumab and Herceptin suggests that the complementary mechanisms of action of the two compounds lead to increased efficacy. Genentech and Roche are evaluating pertuzumab in solid tumours (breast and ovarian cancers) and in combination with other therapies. Pertuzumab is currently being investigated in the Phase III CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab) study in patients with previously untreated HER2-positive metastatic breast cancer, as well as in other clinical studies.

About the Phase II study
This was a Phase II, open-label, single-arm trial of pertuzumab and Herceptin in HER2-positive metastatic breast cancer. Patients were eligible if their disease had progressed on Herceptin-based therapy as their most recent treatment, and they may have received up to three lines of previous therapy including Herceptin and chemotherapy given as adjuvant treatment for breast cancer. Patients had to have good cardiac function and no evidence of declining cardiac function when given Herceptin previously.

Within 9 weeks of their last dose of Herceptin, patients received:

  • Herceptin, 2 mg/kg IV every week or 6 mg/kg IV every 3 weeks
  • Pertuzumab, 840 mg IV day 1, then 420 mg every 3 weeks.


The study took place in two stages according to a modified Simon design, with the primary endpoints of:

  • objective response rate
  • clinical benefit rate

and secondary endpoints of:

  • time to response
  • duration of response
  • time to progression
  • progression-free survival

Results from the first stage were presented at ASCO last year3.

No patients withdrew from the trial with treatment-related or cardiac adverse events and the treatment was well-tolerated.

About CLEOPATRA
CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab) is a Phase III randomised, double-blind, placebo-controlled clinical trial evaluating the efficacy and safety of pertuzumab, Herceptin and chemotherapy versus Herceptin and chemotherapy in previously untreated HER2 positive metastatic breast cancer.

CLEOPATRA is currently recruiting in in 225 sites in 18 countries (Argentina, Brazil, China, Costa Rica, Finland, France, Germany, Hong Kong, Italy, Korea, Mexico, Philippines, Poland, Russia, Singapore, Spain, Thailand and the UK).

About Herceptin (trastuzumab)
Herceptin is a humanised antibody, designed to target and block the function of HER2, a protein produced by a specific gene with cancer-causing potential. It has demonstrated efficacy in treating both early and advanced (metastatic) breast cancer. Given on its own as monotherapy as well as in combination with or following standard chemotherapy, Herceptin has been shown to improve response rates, disease-free survival and overall survival while maintaining quality of life in women with HER2-positive breast cancer.

Herceptin received approval for use in the European Union for advanced (metastatic) HER2-positive breast cancer in 2000, and for early HER2-positive breast cancer in 2006. In the advanced setting, Herceptin is now approved for use as a first-line therapy in combination with paclitaxel where anthracyclines are unsuitable, as first-line therapy in combination with docetaxel, and as a single agent in third-line therapy. It is also approved for use in combination with an aromatase inhibitor for the treatment of post-menopausal patients with HER2 and hormone receptor co-positive metastatic breast cancer. In the early setting, Herceptin is approved for use following standard (adjuvant) chemotherapy.

Herceptin is marketed in the United States by Genentech, in Japan by Chugai and internationally by Roche. Since 1998, Herceptin has been used to treat more than 450,000 HER2-positive breast cancer patients worldwide.


About Roche
Headquartered in Basel, Switzerland, Roche is one of the world’s leading research-focused healthcare groups in the fields of pharmaceuticals and diagnostics. As the world’s biggest biotech company and an innovator of products and services for the early detection, prevention, diagnosis and treatment of diseases, the Group contributes on a broad range of fronts to improving people’s health and quality of life. Roche is the world leader in in-vitro diagnostics and drugs for cancer and transplantation, and is a market leader in virology. It is also active in other major therapeutic areas such as autoimmune diseases, inflammatory and metabolic disorders and diseases of the central nervous system. In 2007 sales by the Pharmaceuticals Division totalled 36.8 billion Swiss francs, and the Diagnostics Division posted sales of 9.3 billion francs. Roche has R&D agreements and strategic alliances with numerous partners, including majority ownership interests in Genentech and Chugai, and invested over 8 billion Swiss francs in R&D in 2007. Worldwide, the Group employs about 79,000 people. Additional information is available on the Internet at www.roche.com.

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Additional information
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References
1) Gelmon K, Fumoleau P, Verma S, Wardley A, Conte PF, Miles D, Gianni L, McNally VA, Ross GA and Baselga J. Results of a Phase II trial of trastuzumab (H) and pertuzumab (P) in patients (pts) with HER2-positive metastatic breast cancer (MBC) who had progressed during trastuzumab therapy. Proceedings from ASCO 2008, Abs TBC
2) World Health Organization, http://www.who.int/cancer/detection/breastcancer/en/
3) Objective response rate in a Phase II multicenter trial of pertuzumab (P), a HER2 dimerization inhibiting monoclonal antibody, in combination with Trastuzumab (T) in patients (Pts) with HER2 positive metastatic breast cancer (MBC) which has progressed during treatment with trastuzumab — J. Baselga. ASCO 2007 oral presentation.