Bevacizumab solution in combination with Paclitaxel
On November 14, 2014, the U. S. Food and Drug Administration approved bevacizumab solution for intravenous infusion (Avastin, Genentech, Inc.) in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for the treatment of patients with platinum-resistant, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.
The approval is based on the results of an international, randomized, two-arm trial (AURELIA) with the primary comparison of investigator-assessed progression-free survival (PFS). This trial compared bevacizumab plus chemotherapy versus chemotherapy alone. The trial enrolled 361 patients: 179 patients were assigned to receive bevacizumab plus chemotherapy, and 182 patients were assigned to receive chemotherapy alone. The chemotherapy included paclitaxel, pegylated liposomal doxorubicin, or topotecan.
Treatment continued until disease progression, unacceptable toxicity, and/or consent withdrawal. All enrolled patients had received no more than two prior chemotherapy regimens, had ECOG performance status of 0 to 2 and had recurred within less than six months from the most recent platinum‑based therapy.
The PFS assessment demonstrated a statistically significant improvement in patients who received bevacizumab plus chemotherapy compared to those who received chemotherapy alone (HR=0.38; 95% CI: 0.30, 0.49; p<0.0001, stratified log-rank test). The median PFS of patients who received bevacizumab plus chemotherapy was 6.8 months (95% CI: 5.6, 7.8) compared to 3.4 months (95% CI: 2.1, 3.8) for those receiving chemotherapy alone. There was no significant difference in overall survival (OS) (median OS: 16.6 vs. 13.3 months; HR 0.89; 95% CI: 0.69, 1.14).
The trial was stratified by chemotherapy regimen. Exploratory analyses were performed by comparing the addition of bevacizumab to each chemotherapy regimen. The addition of bevacizumab to paclitaxel provided the largest improvement, resulting in a 5.7 month improvement in median PFS (9.6 versus 3.9 months; HR 0.47; 95% CI: 0.31, 0.72), an improvement in the overall response rate of 23% (53% versus 30%), and a 9.2 month improvement in median OS (22.4 versus 13.2 months, HR 0.64; 95% CI: 0.41, 1.01). Ninety-seven per cent of patients in the paclitaxel regimen had received paclitaxel with previous chemotherapy regimens. These exploratory analyses suggest that patients who have received prior treatment with paclitaxel may benefit from bevacizumab plus weekly paclitaxel.
The most common adverse reactions (greater than or equal to 15%) in patients treated with bevacizumab plus chemotherapy were neutropenia, peripheral sensory neuropathy and hypertension. Gastrointestinal perforations were reported in 1.7% of bevacizumab-treated patients. Patients who had evidence of rectosigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction were excluded from this trial. These exclusions may have contributed to the relatively low rate of perforation compared to reports from one earlier investigation of bevacizumab in platinum-resistant ovarian cancer. Fistulae occurred in 2% of bevacizumab‑treated patients and no patients receiving chemotherapy alone.
The recommended bevacizumab dose is 10 mg/kg every 2 weeks in combination with one of the following intravenous chemotherapy regimens: paclitaxel, pegylated liposomal doxorubicin, or weekly topotecan. Bevacizumab, 15 mg/kg every 3 weeks, may be combined with topotecan (every three weeks). The chemotherapy regimens follow below.
- Paclitaxel 80 mg/m2 on days 1, 8, 15 and 22 every 4 weeks
- Pegylated liposomal doxorubicin 40 mg/m2 on day 1 every 4 weeks or
- Topotecan 4 mg/m2 on days 1, 8 and 15 every 4 weeks or 1.25 m/m2 on days 1-5 every 3 weeks
Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: AVASTIN (PDF - 1MB)
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at MedWatch Online Voluntary Reporting Form, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).