Bevacizumab May Benefit Some Women with Ovarian Cancer
The targeted drug bevacizumab (Avastin) extends the amount of time women with advanced ovarian cancer live without their disease progressing, according to findings from two phase III clinical trials. The results were published December 29 in the New England Journal of Medicine.
In both trials, women initially received a combination of bevacizumab and standard chemotherapy, followed by bevacizumab alone for a defined period. Not enough time has passed in either trial to determine whether the approach extends lives (improves overall survival), although data from both trials suggest a possible small survival increase.
Bevacizumab is thought to work by blocking the formation of blood vessels (angiogenesis) that feed tumors. Common side effects, including severe hypertension, were more frequent in patients who received bevacizumab but were generally manageable with medications, trial investigators reported. More dangerous side effects, such as gastrointestinal perforations, were also more frequent in those receiving bevacizumab, although such complications were relatively rare. Deaths that were likely to be related to treatment were also rare, but they were more frequent in women treated with bevacizumab.
Progress over the past two decades in developing effective therapies for the initial treatment of women with advanced ovarian cancer has been limited. These trials suggest that bevacizumab could change that, at least for some women, explained Dr. Ronald Alvarez, director of the Division of Gynecologic Oncology at the University of Alabama at Birmingham.
"I think these two studies have shown that bevacizumab has some promising efficacy [in women with ovarian cancer]," Dr. Alvarez said. Whether the drug is more valuable as an initial treatment or after the disease has returned is still unclear, he continued. "But clearly bevacizumab has activity in ovarian cancer."
Similar Trials, Important Differences
Although similar, the two trials—one conducted primarily in the United States and the other in Europe—had important differences, including different enrollment criteria and different doses of bevacizumab used.
The larger trial—co-sponsored by NCI and Genentech, which manufactures bevacizumab, and led by the Gynecologic Oncology Group (GOG)—enrolled nearly 1,900 patients newly diagnosed with advanced ovarian cancer. The trial had three arms: a control arm and two experimental arms. In the control arm, initial treatment with standard chemotherapy (carboplatin plus paclitaxel) was followed by placebo. In one experimental arm, initial treatment consisted of chemotherapy plus bevacizumab, followed by placebo. The other experimental arm consisted of the same chemotherapy and an extended bevacizumab treatment.
Patients in the trial, called GOG-0218, who received bevacizumab for the extended period (a maximum of 10 months) had the longest progression-free survival, a median of approximately 14 months—nearly 4 months longer than the median time for women treated with chemotherapy alone and 3 months longer than the median time for women who received the shorter course of bevacizumab. (See Table 1.) Quality-of-life scores were similar among the trial's three treatment groups.
Table 1. Findings from the GOG-0218 Trial
|Chemotherapy plus placebo, followed by placebo||10.3 months|
|Chemotherapy plus bevacizumab (15 mg/kg), followed by placebo||11.2 months|
|Chemotherapy plus bevacizumab (15 mg/kg), followed by bevacizumab||14.1 months|
A lower dose of bevacizumab was used in the other trial, called ICON7, which was funded in part by Genentech's parent company, Roche. The more than 1,500 patients in the trial were randomly assigned to receive either standard chemotherapy or chemotherapy plus bevacizumab, followed by bevacizumab alone for a maximum of 7 months. Most women in ICON7 had advanced ovarian cancer, except for the approximately 30 percent who had earlier-stage disease but, based on several factors, were considered to be at high risk of their cancer returning after surgery.
Among all patients in ICON7, treatment with bevacizumab was associated with a median improvement in progression-free survival of less than 2 months. But in a subset of women considered at high risk of progression, there were more substantial differences in progression-free survival, as well as overall survival. (See Table 2.) This was an unplanned subset analysis, however, and such analyses are considered to be less reliable than analyses that are specified before a study's launch.
Table 2. Findings from the ICON7 Trial
|Chemotherapy plus placebo, followed by placebo||17.3 months|
|Chemotherapy plus bevacizumab (7.5 mg/kg), followed by bevacizumab||19 months|
|*Chemotherapy plus placebo, followed by placebo (high-risk patients)||10.5 months (28.8 months overall survival)|
|*Chemotherapy plus bevacizumab (7.5 mg/kg), followed by bevacizumab (high-risk patients)||15.9 months (36.6 months overall survival)|
* Unplanned subset analysis
Impact on Practice
A number of important uncertainties remain about using bevacizumab to treat ovarian cancer, several researchers said. Among the most critical, said Dr. Deborah Armstrong of the Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, is the lack of clinical or biological markers that indicate which patients are most likely to benefit from the drug or are at increased risk for serious adverse events.
Without a marker that identifies those most likely to benefit, she said, "you're just treating everybody, and the subgroup that gets the benefit gets diluted out."
Bevacizumab is currently approved by the FDA to be used as a single agent to treat glioblastoma, in combination with interferon alpha to treat kidney cancer, and in combination with chemotherapy for colorectal and lung cancer. Last fall, the FDA withdrew the drug's accelerated approval for the treatment of metastatic breast cancer based on several trials that showed that it failed to extend women's lives and was associated with potentially serious side effects.
Genentech had previously stated the company was unlikely to pursue FDA approval for bevacizumab in women with ovarian cancer based on the GOG-0218 and ICON7 results. According to a spokesperson, however, a final decision will be made after a full assessment of the trial data, including the overall survival findings.
FDA approval is likely to heavily influence the extent to which bevacizumab is used in the clinic to treat women newly diagnosed with ovarian cancer, Dr. Alvarez explained, since most insurers typically won't pay for the drug without such approval. At up to $100,000 for a year of treatment, few patients can afford to pay for it themselves. (In the European Union, the drug was recently approved as a first-line treatment for women with advanced ovarian cancer.)
Even so, bevacizumab has for many years been used outside clinical trials in women with ovarian cancer, often after their disease has returned following surgery and chemotherapy, noted Dr. Robert Burger of the Fox Chase Cancer Center, the lead investigator of the GOG-0218 trial.
Based on the available data, Dr. Burger said, he believes the drug is a good option for the initial treatment of patients who, following standard surgery, are found to have either stage III disease in which the tumor could not be removed completely, or stage IV disease. However, based on the latest data from the OCEANS trial of women with recurrent ovarian cancer, he continued, the drug "probably should be continued at least until progression in those appearing to benefit and having no unacceptable side effects."
Outside of clinical trials, Dr. Armstrong said, she typically uses bevacizumab only in women whose cancer has recurred, and then only by itself, not in combination with chemotherapy. As an initial treatment, she believes there are still too many unknowns.
"[Bevacizumab] doesn't improve survival. In that situation, should it be embraced as a standard of care?" she asked. Factors including the drug's cost and potentially serious side effects require serious consideration. "I think those are things we have to look at," she said.
Numerous clinical trials are testing bevacizumab with different therapies and at various schedules to treat ovarian cancer. Many other promising agents are being investigated in phase III trials as well, Dr. Burger noted, including drugs such as AMG386, BIBF 1120, pazopanib, and cediranib, which target angiogenesis in different ways than bevacizumab.