BEVACIZUMAB IN BREAST CANCER

June 15, 2009 (Orlando, Florida) — A large trial, the third in a row, has confirmed the benefits of using bevacizumab (Avastin) with chemotherapy in patients with metastatic breast cancer. Results from the RIBBON-1 study show a significant improvement in progression-free survival, similar to that seen in the previous 2 trials, even though each trial added bevacizumab to a different chemotherapy regimen.

"There is a modest but consistent effect of bevacizumab on progression-free survival, no matter which chemotherapy is used," said Clifford Hudis, MD, chief of the Breast Cancer Medical Service at Memorial Sloan-Kettering Cancer Center in New York City, "However, there is consistently no effect on overall survival."

Dr. Hudis was discussing the trial during a Highlights of the Day session here at the American Society of Clinical Oncology 45th Annual Meeting. The trial was formally presented at the meeting, although top-line results had been released by the company in a November 2008 press release.

The RIBBON-1 trial is important to Genentech, the manufacturer of bevacizumab, because the company plans to submit the data to the US Food and Drug Administration (FDA), along with data from the second study (the AVADO trial), to convert the drug's accelerated approval into full approval.

Accelerated Approval for Breast Cancer

The FDA granted accelerated approval for bevacizumab use in metastatic breast cancer in February 2008 on the basis of 1 study (the E2100 trial); at that time the company agreed to submit further data when they became available.

That decision to grant accelerated approval was considered to be controversial because it was based on an improvement in progression-free survival and not overall survival. The Oncologic Drugs Advisory Committee was almost split in its opinion, eventually voting 5 to 4 in favor of recommending approval.

However, breast cancer experts welcomed the approval, saying that progression-free survival was a reasonable end point, as reported at the time by Medscape Oncology.

The E2100 trial used bevacizumab in addition to weekly paclitaxel; the results were published in the New England Journal of Medicine (2007;357:2666-2676). E2100 found that, in the 722 patients studied, bevacizumab added to paclitaxel nearly doubled median progression-free survival (to 11.3 months from 5.8 months with paclitaxel alone).

"This was a practice-changing trial," reported Dr. Hudis, "and most of us who use bevacizumab in metastatic breast cancer do so on the basis of this study."

The second study was the AVADO trial, which was presented at last year's ASCO annual meeting, and reported in detail at the time by Medscape Oncology. AVADO, in which bevacizumab was added to docetaxel, also showed a significant improvement in progression-free survival, although it was of a smaller magnitude than was seen in the E2100 trial.

The addition of bevacizumab to docetaxel improved the median progression-free survival to 8.7 to 8.8 months (depending on dose), compared with 8 months with docetaxel alone.

Now the RIBBON-1 trial, conducted in 1237 patients, has shown that bevacizumab significantly improves progression-free survival when added to various chemotherapy regimens. These patients, with HER2-negative disease, were divided into 2 randomized cohorts. One cohort was treated with capecitabine (Xelox) and the other was treated with a taxane or an anthracycline; each cohort then received either bevacizumab or placebo.

The increase in progression-free survival was statistically significant for both cohorts, reported lead investigator Nicholas Robert, MD, from Fairfax Northern Virginia Hematology Oncology. In the capecitabine group, progression-free survival increased from 6.2 months to 9.8 months with the addition of bevacizumab; in the taxane/anthracycline group, it increased from 8.3 months to 10.7 months. (These data come from an assessment done by an independent review committee.)

No Effect on Overall Survival

However, Dr. Robert noted that there was no significant difference in overall survival, which was a secondary end point. In the capecitabine group, median overall survival was 21.2 months vs 29 months with bevacizumab, and in the taxane/anthracycline group, median overall survival was 23.8 vs 25.2 months with bevacizumab.

When asked by physicians in the audience about this lack of effect on overall survival and the fact that this is the third trial not to find an effect, Dr. Robert explained that "overall survival as an end point is a challenge." To have overall survival as the primary end point would require much larger numbers of patients, he said. Also, there was a confounding factor in the second-line therapy that was given to patients when they progressed, he said. Sixty percent of patients receiving placebo and 50% of those receiving bevacizumab were given chemotherapy with bevacizumab on progression of their disease.

The data from this postprogression phase have not yet been reported, but "I think they are unlikely to yield any meaningful or useful information," noted Kathy Miller, MD, associate professor at Indiana University in Indianapolis, in her discussion of this study. She agreed, however, that the use of subsequent therapy in these patients "obscures the benefit of the first-line therapy." She also agreed that each individual trial was underpowered for overall survival, but suggested that now that all 3 have been completed, it would be useful to conduct a meta-analysis.

However, it might be that there is no effect on overall survival, Dr. Miller said. It might be that tumors that become resistant to bevacizumab represent more aggressive disease, or it might be that there is a rapid regrowth of vasculature after stopping bevacizumab.

Nonetheless, there are now 3 trials showing an improvement in progression-free survival, and they confirm that bevacizumab is an important component of initial chemotherapy for metastatic HER2-negative breast cancer, Dr. Miller concluded.

In the future, it will be interesting to see how this approach fits alongside anti-HER2 therapies and alongside endocrine therapy for HER2-positive disease, she commented, noting that trials exploring these questions are currently underway.

The RIBBON-1 and AVADO trials were funded by Genentech. The E21000 trial was supported by grants from the National Cancer Institute and Genentech. Dr. Hudis reports receiving consultancy fees from Genentech, GlaxoSmithKline, Novartis, Merck, Amgen, Bristol-Myers Squibb, Infinity, and Johnson & Johnson; honoraria from Roche and Sanofi-Aventis; and research funding from Kosan Biosciences. Dr. Robert and coauthors report receiving consultancy fees, honoraria, and research funding from Genentech, and some coauthors are company employees. Dr. Miller reports receiving consultancy fees and honoraria from Genentech, and was the principal investigator of the E2100 study.

American Society of Clinical Oncology (ASCO) 45th Annual Meeting: Abstract 1005. Presented June 1, 2009.