CHICAGO—In recurrent or metastatic breast cancer, the addition of bevacizumab(Drug information on bevacizumab) (Avastin) significantly improved progression-free survival over treatment with docetaxel(Drug information on docetaxel) (Taxotere) alone, European investigators reported at ASCO 2008 (abstract LBA-1011).
The randomized, double-blind, multicenter AVADO study included 736 patients from 24 countries who had locally advanced or metastatic breast cancer, HER2-negative disease, and no prior treatment for advanced disease.
Patients were randomized to three arms: docetaxel 100 mg/m2 plus placebo, and docetaxel plus bevacizumab 7.5 mg/kg or 15 mg/kg, all given every 3 weeks until disease progression or unacceptable toxicity.
At a median follow-up of 11 months, PFS was significantly superior for both arms containing bevacizumab. With lower-dose bevacizumab, patients were 21% less likely to have progression, compared with docetaxel alone (P = .0318) in an unstratified analysis. The higher dose was associated with a 28% reduction in risk (P = .0099), reported David Miles, MD, of Mount Vernon Cancer Center, London, United Kingdom.
Stratified analysis showed risk reductions of 31% (P = .0035) and 39% (P = .0001), respectively.
“We believe that the hazard ratio is the more important measure . . .”
— Dr. David Miles
Median PFS was 8.8 months with bevacizumab 15 mg and 8.0 months with docetaxel alone.
“These PFS times are not what we had hoped for, compared to E2100 [11.8 vs 5.9 months; P < .0001], but in many respects, we believe that the hazard ratio is the more important measure, because it is measuring the treatment effect over the whole study period and not at one single point. I ask you to consider the hazard ratio in preference, reflecting the entire treatment effect,” Dr. Miles said at an ASCO press conference.
Previous studies have shown benefit for bevacizumab plus paclitaxel(Drug information on paclitaxel) in metastatic disease.
“This study shows that the antiangiogenic approach to treating breast cancer is effective, regardless of which drug it is combined with,” Dr. Miles said. “Our belief is that the higher dose of bevacizumab will probably be better.”
Eric Winer, MD, of Dana-Farber Cancer Center, noted as moderator of the press conference that 15 mg is the FDA-approved dose for treatment in conjunction with paclitaxel.
Bevacizumab was associated with a slightly higher rate of grade 3-4 toxicity: (approximately 75% with either dose vs 67% with docetaxel alone). Hypertension, which has been a concern with bevacizumab, occurred in 3.2% of the higher-dose bevacizumab arm, 0.4% in the lower-dose arm, and 1.3% with docetaxel alone. Bowel perforation and thrombosis were not different among the groups.
“Bevacizumab added limited incremental toxicity relative to control, and this was treatable with medication,” Dr. Miles said. “I am most reassured about the absence of new safety signals, and the fact that some toxicities that we may have been concerned about are not worrisome and are equal across the treatment arms.”
|Kathy S. Slbain, md|
FDA Made ‘The Rght Decision’ on Avastin
AVADO “adds to the mix” of studies evaluating taxanes and bevacizu-mab (Avastin), said Dr. Albain, professor of medicine, Loyola University Chicago Stritch School of Medicine.
While both E2100 and AVADO found benefit for adding bevacizumab to a taxane, in E2100 (which evaluated bevacizumab and weekly paclitaxel), the median progression-free survival was improved by nearly 6 months with the combination vs paclitaxel alone. Somewhat surprisingly, in AVADO—bevacizumab and every-three-week docetaxel (Taxotere)—the absolute benefit was less than 1 month, she noted.
“Why so small an increase in PFS in AVADO, albeit significant, vs E2100?” she asked. It is likely that weekly paclitaxel in E2100, in and of itself, is antiangiogenic and makes a “dual hit” on the pathway. It is also possible (though not supported by data) that the docetaxel every 3 weeks control arm was more effective than weekly paclitaxel. It could also be the “play of chance,” she added.
In spite of the less impressive differences seen in the current study, the “very robust” PFS seen in E2100, and the supporting data from AVADO, along with a generally safe profile (in the right population), suggests that the FDA approval of bevacizumab in the metastatic setting was “the right decision,” she maintained.
The next question to answer is whether bevacizumab only works with taxanes in metastatic breast cancer, or whether it can be beneficial when added to other agents. The RIBBON 1 trial will address this question by pairing bevacizumab with chemotherapy first-line and upon progression.