Report of the Expert Advisory Panel on the Use of Avastin™ in Metastatic Breast Cancer

March 15^th, 2011

The Expert Advisory Panel on Avastin™ was convened at the request of the Biologics and Genetic Therapies Directorate (BGTD), Health Canada. The panel's mandate was to provide advice to BGTD on the benefit-risk analysis of Avastin™ for the treatment of metastatic HER2-negative breast cancer, and the value of continuing to make Avastin™ in combination with paclitaxel available as an option for these patients in Canada. The drug manufacturer, Hoffmann-La Roche, submitted the results of two confirmatory clinical studies, AVADO and RIBBON I, to fulfill the conditions in the Notice of Compliance with Conditions (NOC/c) for the metastatic breast cancer indication for Avastin™.

The panel was convened via a teleconference on March 15th 2011. In advance of the teleconference, the panel was provided with the terms of reference, three questions posed by BGTD, and background materials provided by BGTD and the drug manufacturer. The background materials included information intended to address BGTD and Hoffmann-La Roche's perspectives on the interpretation of the clinical data to support the issues raised by the three questions. The panel was tasked with conducting an unbiased scientific review of the information and data provided on safety and efficacy in order to provide independent and objective advice to BGTD. The final regulatory decision on Avastin™ remains with BGTD.

The Panel members were:

• Ms. Diana M. Ermel
• Dr. Kong Khoo
• Ms. Dianne Moore
• Dr. Lynne Nakashima
• Dr. Wendy R. Parulekar
• Dr. Ian F. Tannock
• Dr. Maureen E. Trudeau (Chair)

This teleconference was attended by the seven panel members, representatives from Health Canada, Hoffmann-La Roche and its subsidiary company, Genentech, and observers from the US Food and Drug Administration (FDA). Panel members provided verbal declarations of their affiliations and interests at the beginning of the teleconference. These declarations had been previously provided in writing to BGTD on the Affiliations and Interests Forms.

BGTD summarized the submission history of the application for the metastatic breast cancer indication for Avastin™ (bevazucimab). BGTD also summarized the safety and efficacy concerns related to the clinical data from studies E2100, AVADO, and RIBBON I. BGTD's assessments based on the thorough review of the data from the drug manufacturer were provided.

Hoffmann-La Roche addressed the issues related to the safety and efficacy concerns raised by BGTD. Reviews of the benefit/risk profiles for bevacizumab in combination with paclitaxel in the pivotal study E2100 and the confirmatory studies, AVADO and RIBBON I, were presented. Hoffmann-La Roche affirmed its position on the use of bevacizumab in combination with paclitaxel for the first-line treatment of Canadian patients with metastatic breast cancer. At the end of the presentations, BGTD, Hoffmann-La Roche and Genentech answered questions from the panel members.

The panel discussed the three questions posed by BGTD; the panel discussion was attended only by Health Canada representatives and US FDA observers. The following are the Expert Advisory Panel's advice and recommendations on the questions.

Question 1: Based on the progression-free survival (PFS) benefit obtained from a single clinical trial, its lack of survival benefit, and its toxicity profile, does Avastin™ in combination with paclitaxel have any meaningful clinical value as first-line treatment for HER2-negative metastatic breast cancer?

The panel noted that the aim of any metastatic breast cancer treatment is to improve overall survival (OS) or to improve quality of life (QoL). Progression free survival (PFS) has been used as the primary end point in many cancer trials. However, this outcome measure is only valid if it is shown to be a surrogate for improved survival or QoL. The AVADO and RIBBON I studies showed no significant improvement in OS, no improvement in QoL, slight improvement in PFS, and increased side effects. These side effects are tolerable in most patients and are comparable to other anti-cancer drugs.

It was further noted that the term "clinically meaningful" is a rather ambiguous term as it is not meaningful by itself. When a doctor says to a patient that this drug will be able to prolong the time period for which he/she will not have disease progression, this is quite a different discussion than to say that the patient's overall survival will not improve and there are more associated toxicities. The AVADO and RIBBON I trials have showed an increased PFS that did not translate to overall survival, but showed increased side effects.

Panel Recommendation:
The Expert Advisory Panel unanimously concluded that Avastin™ in combination with paclitaxel does not have any meaningful clinical value as first-line treatment for HER2-negative metastatic breast cancer.

Question 2: The drug manufacturer states that crossover treatment administered to patients after disease progression in the control arm may confound any potential overall survival benefits of Avastin™ for metastatic breast cancer. However, if this were true, and since no differences were detected between the groups, it means that the subsequent crossover treatment is as effective as the first-line use of Avastin™. Therefore, should Avastin™ be used as a first-line therapy at all based on the current benefit/risk profile?

In order to determine whether a drug should be used as a first-line or second-line therapy, the clinical trial evidence must demonstrate improved overall survival or improved quality of life. The clinical trials have consistently showed an increase in progression free survival. However, the studies showed no overall survival benefit, but the side effects are increased for patients with metastatic breast cancer.

The panel discussed that Avastin™ has biologic activity; however, at this time, it is not understood why this does not translate positively into overall survival benefit in patients. Since the clinical data does not show an increase in overall survival, there is a possibility that this therapy could harm as many patients as it helps. A confirmatory trial with a biomarker component could help identify the specific population of patients who may be the most likely to benefit from this drug. If the mechanisms of action of this drug were better understood, there might be an important role for this therapy in the future. At this time, the group of patients with metastatic breast cancer who would benefit from Avastin™ has not yet been identified.

Panel Recommendation:
The Panel unanimously concluded that Avastin™ should not be used as either a first-line or second-line therapy based on its risk-benefit profile.

Question 3: Depending on the outcome of this consultation, are there further risk mitigation measures that can be recommended by the panel to BGTD / Health Canada and that could be reflected in the Product Monograph, in addition to those already included in the label for Avastin™?

The panel commented that risk mitigation was not the problem. The fundamental problem is that there is a lack of efficacy. Therefore, until the lack of efficacy is addressed, no further risk mitigation measures could be considered for Avastin™. The confirmatory studies, AVADO and RIBBON I, were conducted to fulfill the conditions in the Notice of Compliance with Conditions (NOC/c) of this indication. However, these clinical studies failed to confirm overall survival of Avastin™ in combination with chemotherapy for patients with HER-2 negative metastatic breast cancer.

As discussed in Question 2 above, a confirmatory trial with a biomarker component might help identify the specific population of patients who may be the most likely to benefit from the Avastin™ and Paclitaxel combination. At this time, this group of patients has not yet been identified.

Panel Recommendation:
The panel unanimously recommended that no changes in the product monograph could address the fundamental issue of the drug's lack of efficacy (improved overall survival or quality of life) to treat patients with HER2-negative metastatic breast cancer.

Report submitted by Dr. Maureen Trudeau on behalf of the Panel.
April 29, 2011