Adding Bevacizumab to Chemotherapy Improves Progression-Free Survival in Platinum-Resistant Recurrent Ovarian Cancer
Single-agent chemotherapy is standard in platinum-resistant ovarian cancer. In the open-label phase III AURELIA trial reported in the Journal of Clinical Oncology, Pujade-Lauraine et al found that the addition of bevacizumab (Avastin) to chemotherapy resulted in significant improvement in progression-free survival, the primary study endpoint, in patients with platinum-resistant ovarian cancer. The combination was also associated with improved objective response rate. However, no significant difference in overall survival was observed.
Study Details
In the trial, investigators selected chemotherapy consisting of pegylated liposomal doxorubicin at 40 mg/m2 on day 1 every 4 weeks (n = 126), paclitaxel at 80 mg/m2 on days 1, 8, 15, and 22 every 4 weeks (n = 115), or topotecan at 4 mg/m2 on days 1, 8, and 15 every 4 weeks or at 1.25 mg/m2 on days 1 to 5 every 3 weeks (n = 120) for women with measurable/assessable ovarian cancer that had progressed within 6 months of completing platinum-based therapy. Recruitment was capped for each chemotherapy cohort, with the doxorubicin cohort being the first to be fully recruited, in October 2010, and recruitment to the paclitaxel and topotecan cohorts being completed in April 2011.
Once chemotherapy was selected, patients were randomly assigned to receive chemotherapy alone (n = 182) or with bevacizumab (n = 179) at 10 mg/kg every 2 weeks or at 15 mg/kg every 3 weeks in patients receiving topotecan on the every-3-week schedule. Patients with refractory disease, history of bowel obstruction, or more than two prior anticancer regimens were ineligible.
Patients were stratified according to selected chemotherapy, prior antiangiogenic therapy, and platinum-free interval. Crossover to single-agent bevacizumab was permitted after disease progression in patients in the chemotherapy-alone group.
The bevacizumab/chemotherapy and chemotherapy-alone groups were generally balanced for age (median, 62 and 61 years), ovary as origin of cancer (93% and 86%), histology (serous/adenocarcinoma in 87% and 84%, endometrioid in 5% in both, clear cell in 2% and 7%), histologic grade (1 in 6% and 5%, 2 in 30% and 26%, 3 in 53% and 58%), prior antiangiogenic therapy (7% and 8%), receipt of two prior chemotherapy regimens (40% and 43%), platinum-free interval < 3 months (28% and 25%), Eastern Cooperative Oncology Group performance status (0 in 60% and 54%, 1 in 32% and 38%, 2 in 7% and 6%), measurable disease (80% and 79%), and presence of ascites (33% and 30%).
Progression-Free Survival Improved
Median follow-up was 13.0 months in the bevacizumab/chemotherapy group and 13.9 months in the chemotherapy-alone group. Median progression-free survival on RECIST criteria was 6.7 months vs 3.4 months (hazard ratio [HR] = 0.48, P < .001, on unstratified log-rank test; HR = 0.42, P < .001, on stratified log-rank test). The progression-free survival benefit was consistent across all subgroups evaluated.
Objective Response Rate and Overall Survival
Response was evaluable by RECIST or Gynecologic Cancer Intergroup cancer antigen (GCIC CA)-125 criteria in 350 patients. Objective response rates were 30.9% in the combination group and 12.6% in the chemotherapy-alone group (P < .001), including 27.3% vs 11.8% on RECIST (n = 287; P = .001) and 31.8% vs 11.6% on GCIG CA-125 criteria (n = 297; P < .001).
At the time of data cutoff for the final overall survival analysis, 40% of patients in the chemotherapy-alone group had received single-agent bevacizumab after progression. Median overall survival was 16.6 months in the bevacizumab/chemotherapy group and 13.3 months in the chemotherapy-alone group (HR = 0.85, P = .174).
Among patients with ascites at baseline, paracentesis was performed in 17% of those in the chemotherapy-alone group and in 2% of those in the bevacizumab/chemotherapy group (one patient, who received paracentesis on the first day of bevacizumab treatment).
Adverse Events
Adverse events of special interest with regard to bevacizumab occurred in 57.0% of the bevacizumab/chemotherapy group vs 40.3% of the chemotherapy-alone group, including grade ≥ 2 hypertension (20% vs 7%), gastrointestinal (GI) perforation (2% vs 0%), and fistula/abscess (2% vs 0%) and grade ≥ 3 hypertension (7% vs 1%), proteinuria (2% vs 0%), GI perforation (2% vs 0%), thromboembolic events (5% vs 4%), fistula/abscess (1% vs 0%), and reversible posterior leukoencephalopathy syndrome (1% vs 0%).
Rates of grade ≥ 3 bleeding (1% in both) and congestive heart failure (1% in both) were identical in the two groups, and no cases of wound healing complications or other cardiac disorders were observed in either group. Among other grade ≥ 3 adverse events, the frequency of neutropenia was similar in both groups, and leukopenia and events potentially related to tumor burden, such as fatigue, abdominal pain, vomiting and dyspnea, were more common in the chemotherapy-alone group. Hand-foot syndrome and peripheral sensory neuropathy were more common in the bevacizumab/chemotherapy group, likely reflecting the longer exposure to chemotherapy in this group associated with prolonged time to progression.
Five deaths (2.8% of patients) in each group were considered to be not primarily due to progressive disease, including death due to infection with neutropenia, GI hemorrhage, GI perforation, cardiac arrest, and shock in the bevacizumab/chemotherapy group and to infection with neutropenia, cardiac failure, septic shock, peritonitis, and GI hemorrhage in the chemotherapy-alone group.
The investigators concluded:
Adding bevacizumab to chemotherapy statistically significantly improved [progression-free survival] and [objective response rate]; the [overall survival] trend was not significant. No new safety signals were observed…. AURELIA is the first trial to our knowledge demonstrating a significant [progression-free survival] benefit of either a combination regimen or a biologic agent in platinum-resistant ovarian cancer. On the basis of the statistically significantly improved [progression-free survival], together with response rate and safety results, bevacizumab combined with chemotherapy should be considered a standard option in platinum-resistant ovarian cancer.
Eric Pujade-Lauraine, MD, PhD, of Université Paris Descartes, is the corresponding author for the Journal of Clinical Oncology article.
The study was sponsored by F. Hoffmann-La Roche (Basel, Switzerland). For full disclosures of the study authors, visit jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
