Bevacizumab Shows Promise for High-Risk Ovarian Cancer

CHICAGO – Adding bevacizumab to chemotherapy may prolong survival in women with newly diagnosed ovarian, primary peritoneal, or fallopian tube cancer who are at high risk for poor outcomes, suggests an interim analysis from the randomized phase III ICON7 trial .

Trials results, reported at a median follow-up of 28 months, showed that when this antiangiogenic agent was added during and after chemotherapy, the risk of death was reduced by a significant 36% among high-risk patients. There was a nonsignificant 15% risk reduction among the study population as a whole.

"Bevacizumab is the first new active agent for the front-line treatment of ovarian cancer in more than 15 years," lead investigator Dr. Gunnar Kristensen said in a press briefing.

"Based on this interim analysis ... we see there is an overall trend for improvement of overall survival with bevacizumab," he said. "The treatment effect is greater in high-risk patients, which may be of clinical relevance."

Indeed, Dr. Kristensen acknowledged, cost considerations and lack of substantial survival benefit in patients who are not at high risk may ultimately guide use of bevacizumab in this context.

"Here we present our data, and then of course it is up to the doctors how they will use the drug," he said. "Personally, I ... [agree] on restricting it to the high-risk group."

The trial differs from the OCEANS trial, also reported at the meeting, in the dose and duration of bevacizumab used, and the patient population, noted moderator Dr. Andrew Seidman, an attending physician for the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center and professor of medicine at Weill Cornell Medical College, both in New York.

"However, the consistent results of these studies, in addition to a previously reported trial, the GOG-0218 trial , and the already documented efficacy of bevacizumab as a single agent in ovarian cancer, I think do all lend support to a potentially important role for bevacizumab as the first biologic agent to be used in this disease," he said.

The investigators conducted the trial among 1,528 women with newly diagnosed, high-risk early or advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. All underwent debulking surgery.

The patients were assigned in nearly equal numbers to receive six cycles of standard chemotherapy (carboplatin and paclitaxel) at 3-week intervals alone, or the same chemotherapy given concurrently with bevacizumab (Avastin, 7.5 mg/kg) followed by single-agent bevacizumab every 3 weeks for 12 additional cycles or until progression.

"This treatment was tolerated well, without a substantial increase in side effects," Dr. Kristensen reported. "The side effects were mild and manageable."

The mature progression-free survival results, previously reported at the 2010 European Society for Medical Oncology meeting, showed that the median duration of progression-free survival was 19.0 months with bevacizumab and 17.3 months without it (hazard ratio, 0.81; P = .004).

U.S. and European regulatory authorities requested an interim analysis of overall survival, in support of applications to license the drug for this indication, according to Dr. Kristensen, a senior consultant in the department for gynecologic oncology at Norwegian Radium Hospital in Oslo.

The interim analysis of overall survival, which was based on 53% of the number of events needed for the final analysis, showed that the risk of death in the entire trial population was lower with bevacizumab than without it, but not significantly so (hazard ratio, 0.85; P = .11).

However, in a preplanned subgroup analysis among the 30% of patients falling into a high-risk category – those with stage III disease whose debulking surgery was suboptimal (leaving more than 1 cm of residual tumor) and those with stage IV disease – there was a significant 36% reduction in the risk of death (hazard ratio, 0.64; P = .002). In this subgroup, the median duration of survival was 7.8 months longer with bevacizumab (36.6 vs. 28.8 months).

Final overall survival results are expected in 2013, according to Dr. Kristensen. "We have to remember that the data [are] premature. It’s an interim analysis. There are very few events in this group of patients" not at high risk, he cautioned when presenting the results in a session. "So we have to await the final analysis in 2 years before we can make conclusions about this group."

The reason for the apparent greater benefit in the high-risk group is as yet unclear, he said, while agreeing with an attendee that tumors that are more difficult to optimally debulk may be more aggressive and more susceptible to antiangiogenic therapy.

"We have just used clinical parameters here, whether they were optimally debulked or not, and we see that we have the main effect in the suboptimally debulked population. Then come all the questions about the biology," he commented. "We have an ancillary research program along with the study, but it will, of course, take time."

In the updated analysis of progression-free survival, the median duration of progression-free survival in the entire trial population continued to be better with bevacizumab, at 19.8 months, than without it, at 17.4 months (hazard ratio, 0.87; P = .039).

Dr. Kristensen reported that he is a consultant to Roche. Dr. Seidman reported being a consultant to Enzon and Wyeth; receiving honoraria from Abraxis BioScience, Genentech, and Genomic Health; and receiving research funding from Abraxis BioScience.