Benefits of Bevacizumab in Ovarian Cancer Clarified

Michael J. Birrer, MD, PhD

Professor of Medicine Harvard Medical School Director, Gynecologic Medical Oncology Director, Gynecologic Cancer Research Program Massachusetts General Hospital Cancer Center Boston, MA

Bevacizumab (Avastin) has failed to demonstrate statistically significant improvements in overall survival (OS) for women with recurrent ovarian cancer in 2 recent clinical trials, but those results may be affected by factors not related to the drug’s efficacy, according to Michael J. Birrer, MD, PhD.

“The drug works. We’ve had very dramatic responses, particularly for women with ascites, and that’s based upon the mechanism of action,” Birrer said in a recent interview. “The only real controversy is, how should we give it so that women get the maximum benefit. Should they get it up front? Should they get it in maintenance? Or should they get it in recurrence?”

Both phase III trials showed gains in progression-free survival (PFS). Key details include:

GOG218 — The Gynecologic Oncology Group study evaluated the addition of bevacizumab to standard front-line therapy in 1873 women with newly diagnosed stage III or stage IV epithelial ovarian cancer. Participants were randomized to receive chemotherapy consisting of paclitaxel and carboplatin plus either a placebo, bevacizimab as initiation treatment, or bevacizumab throughout treatment. (N Eng J Med; 2011;365(26):2473-2483). The median PFS was 14.1 months (hazard ratio [HR] = 0.717; 95% confidence interval [CI], 0.625-0.824; P <.001) with bevacizumab throughout, as compared with 11.2 months (HR = 0.908; 95% CI, 0.795- 1.040; P = .16) in the bevacizumab initiation group, and 10.3 months in the control arm.

ICON7 — The Gynaecologic Cancer InterGroup trial randomly assigned 1528 women to receive either carboplatin and paclitaxel, or that regimen plus bevacizumab. Among the participants, 90% had epithelial ovarian cancer and disease burden ranged from 9% with high-risk early-stage disease to 70% at stage IIIC or stage IV (N Engl J Med. 2011;366[26]:2484-2496). At 36 months, PFS was 21.8 months with standard therapy plus bevacizumab (HR = 0.81; 95% CI, 0.70-0.94; P = .004) compared with 20.3 months with standard therapy alone.

Birrer, who was among the key investigators in the GOG218 trial, said the crossover rate in that study likely was about 30% to 50%. “That confounds the overall survival endpoint and, unfortunately, may neutralize any effect of bevacizumab on overall survival for GOG218,” he said.

Production of Avastin in Switzerland. Photo courtesy of Roche.

ICON7, a European-led trial, had less crossover and may still show an overall survival benefit when further results are available in about 18 months, Birrer said. In ICON7, however, Birrer noted that the dosage of bevacizumab was 7.5 mg/kg, half the dosage in the GOG218 trial.

“If you look very carefully at the GOG study and the ICON7 study, the progression-free survival curves separate fairly dramatically in the middle of treatment, ” Birrer said. “They then ultimately come back together, which is why there’s no difference in overall survival. If you look at the timing of when they come back together, it’s about several months after the bevacizumab is stopped. It’s been hypothesized that bevacizumab is a drug that works by being there continuously, and once you stop it, the tumor rebounds and grows fast. So that’s still an issue to be debated.”

An OS benefit is crucial to an expanded label indication for the drug in the United States. “The FDA has made it very clear that they will not approve drugs for ovarian cancer based upon PFS alone, and they are essentially demanding a difference in overall survival,” noted Birrer, even though gains in PFS improve the quality of life for patients.

Although the drug is widely given off-protocol in recurrent ovarian cancer, an approved indication would help improve treatment, Birrer said. “When some patients recur with ovarian cancer, they’ll get very aggressive disease, they’ll get ascites, and they’re so sick you can’t give bevacizumab to them. They may have missed an opportunity to get a drug that would have been effective at prolonging their life.”

The European Commission has approved bevacizumab in combination with chemotherapy for women with late-stage ovarian cancer as first-line treatment following surgery.