Two large-scale phase III trials that add bevacizumab(Drug information on bevacizumab) to standard chemotherapy regimens in advanced ovarian cancer reported results at ASCO this year. The ICON7 trial adds bevacizumab (Avastin) to a standard chemotherapy regimen for newly diagnosed ovarian cancer patients. The OCEANS trial tests the therapeutic benefit of bevacizumab in conjunction with chemotherapy followed by maintenance dosing of bevacizumab in previously-treated ovarian cancer patients. The OCEANS trial reported a 52% risk reduction in disease progression for women in the bevacizumab arm, while the ICON7 trial found that treatment-naive ovarian cancer patients had a 36% reduced risk of death among those patients that are high-risk.
The OCEANS Trial Results
"The OCEANS study is a positive study," said the presenter and lead investigator, Carol Aghajanian, MD during a press briefing. Dr. Aghajanian is a medical oncologist and the head of Memorial Sloan Kettering Cancer Center's chemotherapy program. The combination of bevacizumab and chemotherapy "provides a clinically meaningful benefit in recurrent ovarian cancer." This is the first advanced stage trial of an antiangiogenic agent that has demonstrated a clinical benefit in recurrent ovarian cancer.
The data showed that adding bevacizumab to platinum-based chemotherapy reduced the risk of progression in women with recurrent platinum-sensitive ovarian, peritoneal, or fallopian tube cancer by one-half (P < .0001). Women with added bevacizumab during their chemotherapy regimen and following chemotherapy treatment as a maintenance therapy were 52% less likely to progress than those women who were given a placebo. The median progression-free survival (PFS) was 12.4 months compared to 8.4 months for the placebo group. The PFS finding was consistently better for the bevacizumab group regardless of patient factors such as age and cytoreductive surgery for recurrence.
The objective response rate was statistically significantly higher in the combination group: 78.5% compared to 57.4% in the chemotherapy-alone group (P < .0001). The median number of chemotherapy cycles, bevacizumab, and placebo cycles completed for each study arm were 6, 12, and 10, respectively. So far, interim overall survival (OS) results favor the use of bevacizumab, with a median OS of 35.5 months for the combination compared with 29.9 months for the chemotherapy-alone arm. The OS results are not yet mature however.
Dr. Aghajanian stated that "the safety data were reassuring and consistent with the known bevacizumab side effect profile."
The OCEANS Trial Design
The OCEANS trial is a phase III, randomized, blinded and placebo-controlled trial that compares the use of carboplatin(Drug information on carboplatin) and gemcitabine(Drug information on gemcitabine) (C/G) chemotherapy with C/G plus bevacizumab in women with platinum-sensitive recurrent ovarian cancer who had not previously received chemotherapy for their recurrence. The trial was started in 2007 and 487 patients were randomized to two arms consisting of chemo every 3 weeks for 6 cycles with either bevacizumab (15 mg/kg) or placebo every 3 weeks for 6 cycles followed by maintenance with bevacizumab or placebo until disease progression. The primary outcome of the trial was PFS. According to the abstract presenter, the 15 mg/kg dose was chosen based on a previous phase II trial that compared this dose to several lower doses in ovarian cancer patients.
The ICON7 Trial Results
Mature PFS data for this study showed a 15% improvement in PFS at 12 months for patients taking bevacizumab compared with placebo (P = .0041). The overall survival interim analysis showed that at a median follow-up of 28 months, the risk of death was reduced by a significant 36% among high-risk patients. "Bevacizumab is the first new active agent for the front-line treatment of ovarian cancer in more than 15 years," according to the presenter and lead investigator of the study, Dr. Gunnar Kristensen. According to Dr. Kristensen, "we see there is an overall trend for improvement of overall survival with bevacizumab. The treatment effect is greater in high-risk patients, which may be of clinical relevance." The final overall survival results are expected in 2013.
"This treatment was tolerated well, without a substantial increase in side effects. The side effects were mild and manageable," according to Dr. Kristensen.
The ICON7 Trial Design
ICON7 is a randomized two-arm global trial that is assessing the benefits of adding bevacizumab to a standard chemotherapy regimen of carboplatin and paclitaxel(Drug information on paclitaxel) in newly diagnosed ovarian, epithelial, and fallopian tube cancer. The large-scale study started in 2006 and has since enrolled more than 1500 patients. The primary endpoint is comparing the progression-free survival of the standard chemo regimen to chemotherapy with additional bevacizumab. Patients receive paclitaxel and carboplatin (P/C) via IV every 3 weeks for 6 courses or P/C plus concurrent bevacizumab (7.5 mg/kg) as an infusion.
Future of Bevacizumab in Ovarian Cancer
Although these trials are positive, adding bevacizumab to chemotherapy regimens is still being debated by oncologists because of the incremental increase in PFS. Active ovarian oncologists and researchers are split as to whether PFS is a good enough measure and whether studies should always have overall survival as a primary endpoint. The FDA has been requiring more overall survival data, partly as a result of the increased cost of oncology drugs. Researchers acknowledge that cost plays a role in consideration of treatment options. Dr. Kristensen, for example, stated that the cost of bevacizumab and a lack of substantial survival benefit in ovarian cancer patients may result in only high-risk patients being prescribed a bevacizumab regimen. Additionally, it is not known how much of a benefit is added with a maintenance dose of bevacizumab.
How bevacizumab will be utilized by oncologists remains to be seen, but for now, there is a consistent trend of a benefit in the utilization of bevacizumab in combination with chemotherapy as well as a documented benefit as a monotherapy in ovarian cancer.