Adding bevacizumab to standard first-line carboplatin and paclitaxel chemotherapy therapy against ovarian cancer prolonged progression-free survival in two separate, complementary, phase III clinical trials reported in the Dec. 29 issue of the New England Journal of Medicine.
Bevacizumab (Avastin) did not interfere with chemotherapy. Although it raised the rate of toxic effects, this did not impair patients’ quality of life in either study. Both trials received industry support.
The GOG Study
In the Gynecologic Oncology Group (GOG) study, 1,873 women were treated at 336 medical centers in the United States, Canada, South Korea, and Japan. All had previously untreated, incompletely resectable, stage III or stage IV epithelial ovarian, primary peritoneal, or fallopian-tube cancer, for which they had undergone debulking surgery, said Dr. Robert A. Burger of the Fox Chase Cancer Center, Philadelphia, and his associates.
Dr. Robert A. Burger
The cohort as a whole had a relatively poor prognosis, and factors that could influence treatment outcome were evenly distributed among the treatment groups. Patients were randomly assigned in a double-blind fashion to one of three regimens:
• 15 mg/kg bevacizumab added to chemotherapy cycles 2-22.
• 15 mg/kg bevacizumab added only to cycles 2-6, plus placebo added to cycles 7-22.
• Placebo added to chemotherapy cycles 2-22 (the control group).
A monoclonal antibody, bevacizumab targets the vascular endothelial growth factor (VEGF), which is known to promote angiogenesis and progression of ovarian cancer.
At the primary data analysis after a median of 17.4 months of follow-up, median progression-free survival, the primary end point, was 14.1 months when bevacizumab was given throughout the chemotherapy course. This was longer than the 11.2-month median when bevacizumab was given only at the beginning of the chemotherapy course and significantly longer than the 10.3-month median when it wasn’t given at all.
Thus, the addition of bevacizumab throughout the entire chemotherapy course prolonged progression-free survival by a median of 4 months, compared with chemotherapy alone, Dr. Burger and his colleagues said (New Engl. J. Med. 2011;365:2473-83).
In a further analysis of progression-free survival "in which data for patients with increased CA-125 levels were censored, as required by regulatory agencies, the median progression-free survival was 12.0 months in the control group but 18.0 months in the bevacizumab-throughout group," they added.
This benefit in progression-free survival was consistent across all subgroups of patients, regardless of prognostic factors such as cancer stage, lesion size, the tumor’s histologic type, the patient’s performance status, or the patient’s age, the researchers noted.
There was no significant benefit in overall survival, but the ability to detect such a benefit was limited by the lack of control for subsequent treatments, including crossover to bevacizumab or other anti-VEGF agents, they noted.
Regarding adverse effects, there were no significant differences among the three groups in quality-of-life scores on the Functional Assessment of Cancer Therapy–Ovary survey.
The frequency of hypertension was significantly higher with the addition of bevacizumab, which was not unexpected. But it was easily controlled with medication and led to discontinuation of the drug in only 2.4% of affected patients.
There were no significant differences among the three treatment groups in rates of other adverse events, including some that have been reported with previous monoclonal antibody therapy (gastrointestinal perforation or fistula; proteinuria; neutropenia, especially febrile neutropenia; venous or arterial thrombosis; and wound disruption).
"Rates of gastrointestinal perforation and fistula in the two bevacizumab groups were almost twice those in the control group but were still less than 3%, consistent with rates seen in metastatic nongynecologic tumors," the investigators said.
Fatal adverse events occurred in 1% of the control group, in 1.6% of those who took bevacizumab only at the beginning of chemotherapy, and in 2.3% in those who took bevacizumab throughout the entire course of chemotherapy.
The ICON7 Study
The other phase III trial, the ICON7 (International Collaboration on Ovarian Neoplasms) study led by the U.K. Medical Research Council clinical trials unit, involved women with advanced-stage ovarian cancer but no visible residual disease, as well as some women with high-risk early-stage disease.
This trial examined the efficacy and safety of a lower dose of bevacizumab (7.5 mg/kg) for a shorter interval (5 or 6 cycles with chemotherapy, and up to 12 cycles afterward), said Dr. Timothy J. Perren of the Institute of Oncology at St. James’s University Hospital in Leeds, England, and his associates
The 1,528 study subjects were treated at 263 medical centers in the United Kingdom, Germany, France, Canada, Australia, New Zealand, Denmark, Finland, Norway, Sweden, and Spain. They were randomly assigned to receive either standard carboplatin-plus-paclitaxel chemotherapy every 3 weeks for 6 cycles (764 patients), or the same chemotherapy plus concurrent 7.5 mg/kg bevacizumab, with the monoclonal antibody alone extended for 12 additional cycles (764 patients).