The benefit of adding bevacizumab (Avastin, Genentech & Roche) to a taxane in the first-line treatment of metastatic breast cancer has been confirmed in a second trial. Results from the AVADO study, reported here at the American Society of Clinical Oncology 44th Annual Meeting, show a significant improvement in progression-free survival, echoing the results of the E2100 study published earlier this year. Both studies were sponsored by Roche.
The E2100 study formed the basis for the approval of bevacizumab in the treatment of metastatic breast cancer in both Europe and the United States. The approval in the United States was accelerated rather than full, and at the time the Food and Drug Administration (FDA) said that it was awaiting data from the AVADO study and from a third company-sponsored trial (RIBBON-1).
The accelerated approval was considered rather controversial because it was based on progression-free and not overall survival data, and because the Oncologic Drug Advisory Committee (ODAC) had narrowly voted (5 to 4) not to recommend approval, as previously reported by Medscape Oncology.
This controversy was addressed during the session in which the AVADO results were presented. Patricia Cortazar, MD, from the FDA, said that overall survival is the gold standard in metastatic breast cancer. However, she continued, progression-free survival can be an acceptable end point if measured properly and if it is of sufficient magnitude, but overall survival should also be measured to ensure that it is not reduced.
Elaborating in a separate presentation, Kathy Albain, MD, from Loyola University, in Chicago, Illinois, who sits on ODAC and acts as a consultant to the FDA, said that a discussion with 40 or so colleagues led them to a consensus view that a “meaningful” progression-free survival would have a hazard ratio (HR) of about 0.70, with an absolute benefit of around 6 months and a significance level of .01 or less. They also considered it necessary to have 2 separate trials and a mandatory crossover design.
Data are Confirmatory But Not as Robust
Results from the AVADO trial confirm those from the E2100 study, lead researcher David Miles, MD, from Mount Vernon Cancer Center, in Middlesex, United Kingdom, told the meeting. Both studies added bevacizumab to a taxane, but E2100 used paclitaxel and AVADO used docetaxel and had a placebo group. The trial also used different bevacizumab doses: E2100 used 10 mg/kg; and AVADO compared a high dose of 15 mg/kg and a low dose of 7.5 mg/kg.
After a median follow-up of 11 months, the AVADO trial showed a statistically significant difference in progression-free survival between women taking either dose of bevacizumab plus docetaxel and those taking docetaxel alone; stratified HR was 0.69 (P = .0035) for the low dose and 0.61 (P = .0001) for the high dose. In other words, the risk for disease progression was reduced by 21% with the low dose and by 28% with the high dose, Dr. Miles commented. The median time to disease progression was 8 months with docetaxel alone, compared with 8.7 months with docetaxel plus low-dose bevacizumab, and 8.8 months with docetaxel plus high-dose bevacizumab.
The overall response rate, a secondary end point, was 44 with docetaxel alone, 55 with low-dose bevacizumab (P = .0295), and 63 with high-dose bevacizumab (P = .0001). This latter response is “pretty impressive,” Dr. Miles commented, and overall, the high dose had better efficacy than the low dose.
At the median follow-up of 11 months, 80% of the patients were still alive. This means that the overall survival data are still immature, Dr. Miles said, but so far, numerically, the data should trend in the right direction. There were 50 deaths (21%) with docetaxel alone, 49 (20%) with low-dose bevacizumab, and 37 (15%) with high-dose bevacizumab, which gives a 1-year survival of 73%, 78%, and 83%, respectively. A final analysis of overall survival data will not be available until April 2009, Dr. Miles said.
“Safety is the biggest message from this trial,” according to Dr. Miles. There was no new safety signal, and “we can be very reassured that bevacizumab is adding little toxicity to the chemotherapy that we are already using.”
Discussing the latest results after their presentation, Dr. Albain pointed out that although the improvement in progression-free survival seen with bevacizumab in the AVADO trial was significant, it was smaller than that seen in the E2100 study (N Engl J Med. 2007;357:2666-2676).
The E2100 study, conducted with 722 patients, found that bevacizumab added to paclitaxel nearly doubled median progression-free survival, to 11.3 months with the combination and to 5.8 months with paclitaxel alone (HR, 0.48; P <.0001).
One reason for this discrepancy might be the different taxane regimen used, Dr. Albain said. E2100 used a weekly regimen of paclitaxel that “probably has in and of itself an antiangiogenic effect, so you get a double hit,” she said. This could also explain the higher frequency of serious adverse effects in this trial, she added.
The improvement in progression-free survival seen in E2100 is “certainly very robust,” Dr. Albain commented, adding, “there are now supporting data from AVADO.” Both trials also showed a significant improvement in response rates, and both have shown a trend toward improvement in overall survival.
In the E2100 trial, overall survival was 26.5 months for bevacizumab plus paclitaxel and 24.8 months for paclitaxel alone (HR, 0.87; P = .14). The AVADO trial is unlikely to yield a statistically significant difference in overall survival because it had a crossover design and the HR was lower than that in the E2100 trial, commented Eric Winer, MD, from Harvard Medical School, in Boston, Massachusetts, during a press briefing.
“There is no question that overall survival is the most important outcome and is more important than progression-free survival, and there is no question that we all want the patient to live longer,” Dr. Winer told Medscape Oncology. “But there is a benefit and a utility from an improvement in progression-free survival,” he added. Patients have said that progression-free survival is a worthwhile achievement; it offers time without developing further symptoms, and delays the move to more toxic therapy, Dr. Albain commented
“Bevacizumab is an advance in metastatic breast cancer,” Dr. Winer said, “but not as big an advance as it would be if it had shown an effect on overall survival.”
Both trials have also shown that the addition of bevacizumab is “generally safe,” Dr. Albain commented, and the drug has been added to the armamentarium of treatment for metastatic breast cancer.
One question that remains, she said, is whether bevacizumab is beneficial when added to chemotherapy other than taxanes. This is being addressed in the ongoing company-sponsored RIBBON-1 trial, where investigators are using the chemotherapy of their choice along with bevacizumab.
Results are positive but somewhat disappointing.
Commenting during a “highlights of the day” presentation, Joseph Sparano, MD, from the Albert Einstein Cancer Center, in the Bronx, New York, said the results from AVADO were “positive but somewhat disappointing” because the absolute benefit (improvement in disease-free survival was 0.8 months for the higher dose) was not nearly as impressive as it was in the E2100 trial (5.5 months).
Dr. Sparano concluded that the regimen used in E2100 (weekly paclitaxel with biweekly bevacizumab) showed a greater benefit, making it a reasonable and, indeed, approved choice of first-line therapy for metastatic breast cancer, but the regimen of docetaxel plus bevacizumab used in AVADO is a also reasonable option.
American Society of Clinical Oncology (ASCO) 44th Annual Meeting: Abstract LBA1011. Presented June 1, 2008.
Reviewed by Ramaz Mitaishvili, MD
