MAY 2005 

Recent press releases from the National Cancer Institute and from Genentech and Roche pharmaceutical companies have announced the early stopping of four randomized, prospective Phase III clinical trials on two new breast cancer treatments. In each case, the early stopping was prompted by better-than-expected results for the women getting the experimental treatments in the trials.

Both of the drugs under investigation in these trials, Bevacizumab (Avastin)¹ and Trastuzumab (Herceptin)², are considered to be "targeted" therapies - that is, drugs that attack specific cancer cells. Details and data from the trials will not be available before mid-May when they will be presented to the scientific community at the annual meeting of the American Society of Clinical Oncologists. For the time being, the following information has been released.

ECOG E2100 trial
Bevacizumab is a monoclonal antibody designed to inhibit vascular endothelial growth factor (VEGF). It interferes with the blood supply necessary for tumor growth and metastasis. This trial, which began enrolling patients in December, 2001, looked at use of bevacizumab in first line therapy for 722 women with recurrent or metastatic breast cancer who had not received previous chemotherapy for this diagnosis and whose tumors tested negative for the HER2/neu protein.

At the time of the first interim data analysis, which led to the early stopping decision, the group of patients getting bevacizumab were found to have gone at least 4 months longer without tumor progression than those getting chemotherapy alone. The National Cancer Institute reports that compared with patients getting standard paclitaxel treatment alone, those receiving the combination of bevacizumab and paclitaxel had slightly more problems in peripheral nerve function, abnormally high blood pressure; and a condition in which urine contains an abnormal amount of protein.

NSABP B-31, NCCTG N-9831, and BIG HERA trials
Trastuzumab is an antibody that targets the HER2/neu protein, which is overexpressed in approximately 25% of breast cancers. It has not been shown to be effective in women with HER2 negative tumors. These three trials, conducted independently of one another, all looked at the use of trastuzumab in combination with chemotherapy in Stage III node positive or high-risk node negative breast cancer. The three trials began enrolling patients in 2000 and 2001, and details about the patient populations and the chemotherapy and trastuzumab regimens vary between the trials.

In an unusual move, data from the NSABP B-31 and parts of the NCCTG N-9831 trials were pooled for a joint interim analysis of results from a total of 3,300 women³. These trials are reported to have met their primary endpoints of increasing disease-free survival (producing a 52% reduction in relative risk of recurrence) for women getting chemotherapy plus trastuzumab when compared with those getting chemotherapy alone. The North American NSABP and NCCTG trials are also reporting an increase in overall survival, but the magnitude of this effect has not been released.

In the European HERA study (with 5100 patients in 39 countries), patients getting a variety of chemotherapy regimens were compared with patients who got those therapies combined with trastuzumab. The disease-free survival results in the first interim analysis are reported to be very similar to those reported in the NSABP B-31 and the NCCTG N-9831 trials. No data on overall survival have been released yet.

A 3-4% absolute increase in rate of "cardiac dysfunction" is being reported for the women getting the AC plus trastuzumab treatment, compared to those getting AC alone.

NBCCF Concerns
Successful application of targeted breast cancer therapies promises better treatment that is tailored to an individual woman's disease. However, much more information will be needed before we can evaluate the real import of these studies.

Data: The announcements of the decisions to stop these clinical trials early have included none of the data necessary to determine the size or the clinical significance of the reported results. While a 53% relative risk reduction noted in the combined analysis of two of the trastuzumab studies, information on the more important absolute risk has not yet been provided. [See NBCCF fact sheet: "What is Meant by Breast Cancer Risk?"]. In addition, the appropriateness and adequacy of the unprecedented joint analysis of data generated from two separate studies will need to be evaluated carefully to determine whether the conclusions drawn from it can be trusted statistically.

Endpoints: Primary endpoints other than overall survival provide insufficient means to determine whether a new treatment will extend the lives of women with breast cancer. While disease free survival or time to disease progression may correlate with longer overall survival, that outcome cannot be taken for granted. [See NBCCF fact sheet: "Outcomes in Breast Cancer Clinical Trials"].

Early stopping: When clinical trials are stopped early, important information about the long-term effects of the treatments involved may not come to light for many more years and in that time, more women are exposed to the treatment. If women are advised, on the basis of these studies, to consider these treatments, they will be doing so without the benefit of much of the data that prospective randomized clinical trials are designed to provide. [See NBCCF fact sheet: "Early Stopping of Clinical Trials"].

Footnotes

¹ Bevacizumab is already approved by the FDA for treatment of colorectal cancer.

² Trastuzumab is already FDA approved for use in women with metastatic breast cancer who have tumors that overexpress the HER2 protein.

³ Both trials included control groups treated with either taxol or taxol+AC, and groups that got one of those treatments combined with trastuzumab. A third group, included in the NCCTG N-9831 trial but not the NSABP B-31 trial, was to get taxol or taxol+AC followed later by trastuzumab. Data from this group were not included in the joint analysis. With the decision to stop the trial early, some patients from this group will now be eligible to begin getting trastuzumab treatments earlier instead of waiting until the end of their chemotherapy as originally planned.