Drug Combo Extends Progression-Free Survival in Breast Cancer

By Todd Neale
INDIANAPOLIS, Dec. 27 -- Adding bevacizumab (Avastin) to paclitaxel (Taxol) prolonged progression-free survival as initial treatment for metastatic breast cancer, researchers said.
request to recommend approval of bevacizumab for treatment of metastatic breast cancer.
Patients receiving the combination had a median progression-free survival of 11.8 months compared with 5.9 months with paclitaxel alone (hazard ratio for progression: 0.60, P<0.001), Kathy Miller, M.D., of the Indiana University Cancer Center here, and colleagues, reported in the Dec. 27 issue of the New England Journal of Medicine.
But overall survival, which Richard Pazdur, M.D., head of oncology drugs at the FDA's Center for Drug Evaluation and Research, believes to be the more important endpoint, did not differ significantly between the two groups (median, 26.7 months for the combination group versus 25.2 months for the paclitaxel-alone group, HR: 0.88, P=0.16).
Citing the lack of benefit in overall survival and added toxicities associated with the drug, the FDA's Oncology Drugs Advisory Committee rejected Genentech's request to recommend approval of bevacizumab for treatment of metastatic breast cancer earlier this month.In this open-label, randomized, phase 3 trial, Dr. Miller and colleagues recruited 722 women with breast cancer -- 614 with HER2-negative disease -- from December 2001 through May 2004. Patients were not allowed to participate in the trial if they had received prior cytotoxic therapy for metastatic disease or if they suffered from clinically significant cardiovascular disease.
The researchers assigned 368 patients to receive 90 mg of paclitaxel per square meter of body-surface area on days one, eight, and 15 of a 28-day cycle. The remaining 354 patients received the same treatment, plus 10 mg IV of bevacizumab per kilogram of body weight on days one and 15.
The two groups of patients were similar except that there were more patients with visceral involvement and measurable disease in the paclitaxel-alone group than in the combination group.
At study end, paclitaxel plus bevacizumab increased the objective response rate in all patients (36.9% versus 21.2%, P<0.001) and in the subgroup of patients with measurable disease at baseline (49.2% versus 25.2%, P<0.001) compared with paclitaxel alone.
The combination also increased the one-year survival rate for all patients (81.2% versus 73.4%, P=0.01).
In patients who had received taxane-based adjuvant therapy, the combination extended progression-free survival from three to 12 months (HR: 0.46, P<0.001).
When age was treated as a continuous variable, the effect of bevacizumab declined significantly (P=0.04) as patients grew older.
The researchers stopped collecting survival data on June 7, 2007. At that time, 483 patients had died, with the vast majority (88.8%) succumbing to progressive disease.
Toxic effects of both paclitaxel and bevacizumab led to cessation of treatment in some patients. The following adverse events were significantly more common in the combination group than in the paclitaxel-alone group: grade 3 or 4 neuropathy (23.6% versus 17.6%, P=0.03), infection (9.3% versus 2.9%, P<0.001), and fatigue (8.5% versus 4.9%, P=0.04).
Treatment was halted at least three weeks before disease progression because of adverse events in 117 (35.9%) patients in the paclitaxel-alone group and 178 (51.3%) patients in the combination group.
Patients receiving paclitaxel plus bevacizumab were also significantly more likely to have cerebrovascular ischemia (1.9% versus 0%, P=0.02) and grade 3 or 4 headaches (2.2% versus 0%, P=0.008).
A previous phase 3 study had found that the addition of bevacizumab to capecitabine increased the objective response, but neither progression-free nor overall survival (J Clin Oncol 2005; 23: 792-799).
Dr. Miller and colleagues conjectured that differences between the patient populations could account for the different results found in this recent study.
"All patients in the earlier study had received previous anthracycline and taxane therapy," they wrote, "and most (more than 85%) had received chemotherapy for metastatic disease. In contrast, 35.3% of our patients had not received any previous chemotherapy, and only 13.2% had received both an anthracycline and a taxane as adjuvant therapy."
The authors also presented the possibility that "perhaps paclitaxel is uniquely synergistic with bevacizumab."
They concluded that, "although benefit was seen across a number of clinically important subgroups, our results would be strengthened by the ability to identify patients most likely to benefit from VEGF-directed therapies."
Funding for this study came from the National Cancer Institute and Genentech, maker of bevacizumab. Genentech provided the bevacizumab for this study.
Dr. Miller reported receiving lecture fees and consulting fees for service on breast cancer advisory boards from Roche. Other co-authors reported receiving lecture or consulting fees from Genentech, Roche, GlaxoSmithKline, Bristol-Myers Squibb, and sanofi-aventis.
Primary source: New England Journal of MedicineSource reference:Miller K, "Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer" N Engl J Med 2007; 357: 2666-76.