Adding Bevacizumab to Paclitaxel-Carboplatin in Recurrent Platinum-Sensitive Ovarian Cancer
In a phase III trial (NRG Oncology/Gynecologic Oncology Group GOG-0213 trial) reported in The Lancet Oncology, Coleman et al found evidence of an overall survival advantage with the addition of bevacizumab (Avastin) to paclitaxel-carboplatin in recurrent platinum-sensitive ovarian cancer. The significant survival benefit was observed in a sensitivity analysis performed after incorrect platinum treatment–free interval stratification had been identified in a subgroup of patients. The trial includes both the bevacizumab component and a surgical cytoreduction component, the latter of which is ongoing and not represented in the current report.
Study Details
In the open-label trial, patients with recurrent measurable or evaluable epithelial ovarian, primary peritoneal, or fallopian tube cancer, clinical complete response to primary platinum-based chemotherapy, and a disease-free interval of ≥ 6 months following the last platinum cycle were randomized to receive six 3-weekly cycles of paclitaxel at 175 mg/m² and carboplatin AUC 5 with or without bevacizumab at 15 mg/kg every 3 weeks and continued as maintenance every 3 weeks until disease progression or unacceptable toxicity. Patients participating in both the bevacizumab and ongoing surgical components of the trial were randomized 1:1:1:1 to receive either of the two chemotherapy regimens with or without prior secondary cytoreductive surgery. Randomization in the bevacizumab component was stratified by platinum treatment–free interval (6–12 months and > 12 months) and participation in the surgical component. The primary endpoint was overall survival in the intent-to-treat population.
In the bevacizumab component, 674 patients from 67 sites in the United States, Japan (1 site), and South Korea (1 site) were randomized between December 2007 and August 2011 to the bevacizumab group (n = 337) or standard-therapy group (n = 337). Overall, patients had a median age of 60 years, 80% were white and 14% Asian, most had stage III (73%–77%) or IV (11%) disease, and most tumors were high grade (74%–75%) and of serous histology (81%). Features of first-line therapy prior to enrollment, which were balanced between groups, included intraperitoneal chemotherapy in 18%, maintenance therapy following initial chemotherapy in 13%, and prior bevacizumab in 10%.
For the stratification factors, 16% of patients in each group were considered surgical candidates and were randomized to surgery vs no surgery (8% vs 8% in each group). Initially, 69% of patients in each group reported a treatment-free interval > 12 months. Review of electronic case-report forms identified an error in which treatment-free interval was calculated from the last cycle of any therapy (eg, maintenance) rather than from the last cycle of primary platinum therapy in 45 patients. After correction, the treatment-free interval was > 12 months in 73% of the bevacizumab group and 75% of the standard-therapy group.
Overall Survival
Median follow-up for the bevacizumab component of the trial was 49.6 months in each treatment group. Prior to correction of stratification data, median overall survival was 42.2 months (95% confidence interval [CI] = 37.7–46.2 months) in the bevacizumab group vs 37.3 months (95% CI = 32.6–39.7 months) in the standard-chemotherapy group, with a hazard ratio (HR) of 0.829 (P = .056). In the sensitivity analysis after correction, the hazard ratio was significant at 0.823 (P = .0447). The effect of bevacizumab on overall survival was consistent across prespecified subgroups.
Median progression-free survival was 13.8 months vs 10.4 months (adjusted HR for surgery and treatment-free interval for progression or death = 0.628, P < .0001). An exploratory post-hoc analysis of investigator-assessed objective response among 509 patients (76%) with measurable disease and available serial imaging data showed response rates of 78% vs 59% (P < .0001), including a complete response in 32% vs 18%.
Adverse Events
Grade ≥ 3 adverse events occurred in 96% of the bevacizumab group vs 86% of the standard-chemotherapy group, with the most common treatment-related events in the bevacizumab group vs standard-chemotherapy group being hypertension (12% vs 1%), fatigue (8% vs 2%), and proteinuria (8% vs 0%). Serious adverse events occurred in 28% vs 11%, with the most common being febrile neutropenia (5% vs 2%). Hypersensitivity reactions of any grade occurred in 27% vs 25%, with grade 3 reactions in 9% of both groups. Adverse events led to discontinuation of any study drug in 25% vs 11%. Death considered related to treatment occurred in nine patients (3%) in the bevacizumab group (due to infection in one, febrile neutropenia in one, myelodysplastic syndrome in one, secondary malignancy in one, death—disease progression in three, sudden death in one, and death—not specified in one) and in two patients (1%) in the standard-chemotherapy group (due to infection in one and myelodysplastic syndrome in one).
The investigators concluded: “The addition of bevacizumab to standard chemotherapy, followed by maintenance therapy until progression, improved the median overall survival in patients with platinum-sensitive recurrent ovarian cancer. Although the intention-to-treat analysis for overall survival was not significant, our sensitivity analysis based on corrected treatment-free interval stratification indicates that this strategy might be an important addition to the therapeutic armamentarium in these patients.”
The study was funded by the National Cancer Institute and Genentech.
Robert L. Coleman, MD, of The University of Texas MD Anderson Cancer Center, is the corresponding author of The Lancet Oncology article.
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