Bevacizumab Is a 'New Way to Control' Ovarian Cancer
By Nick Mulcahy
Medscape Medical News
December 28, 2011 — Two phase 3 trials have demonstrated that bevacizumab (Avastin, Genentech/Roche) slows the progression of ovarian cancer in women with advanced disease, and thus offers clinicians a new class of treatment. Both trials were published in the December 29 issue of the New England Journal of Medicine.
Data from these 2 trials formed the basis of the recent approval in Europe of bevacizumab for use in women with advanced ovarian cancer.
The complementary trials differed in a number of ways, but both investigated the addition of bevacizumab to standard chemotherapy in the first-line treatment of ovarian cancer.
"Bevacizumab blocks the growth factor [vascular endothelial growth factor], which is important in the process of ovarian cancer progression," said Robert A. Burger, MD, one of the bevacizumab investigators, in a press statement. He is director of the Women's Cancer Center at Fox Chase Cancer Center in Philadelphia, Pennsylvania.
Dr. Burger was the lead investigator of the Gynecologic Oncology Group (GOG) study 0218. The 1873-patient study took place at 336 sites located primarily in the United States, but also in Canada, South Korea, and Japan.
In the GOG0218 study, the use of bevacizumab during and up to 10 months after carboplatin and paclitaxel chemotherapy extended the median progression-free survival (PFS) by 3.8 months in patients with advanced epithelial ovarian cancer.
Specifically, the median PFS was 10.3 months in the chemotherapy-alone control group and 14.1 months in the group that received chemotherapy plus bevacizumab for a prolonged maintenance period. This prolonged, "bevacizumab-throughout" group had a hazard ratio (HR) for progression or death of 0.717 (95% confidence interval [CI], 0.625 - 0.824; P < .001). The median follow-up was 17.4 months.
"This approach can be looked upon as a third major component of treatment for ovarian cancer," summarized Dr. Burger, referring to the use of bevacizumab in addition to the current standard of chemotherapy and debulking surgery. (All of the women in both studies first received surgery.) "This represents a new way for us to control the disease," he added.
This represents a new way for us to control the disease.
In the second study, PFS (restricted mean) at 36 months was 20.3 months with standard therapy and 21.8 months with standard therapy plus bevacizumab (HR for progression or death with bevacizumab added, 0.81; 95% CI, 0.70 - 0.94; P = .004). Overall, the treatment difference was described as "modest" by the study authors, led by Timothy Perren, MD, from the University of Leeds in the United Kingdom.
This study, known as the Gynecologic Cancer InterGroup International Collaboration on Ovarian Neoplasms 7 (ICON7) trial, involved 1528 women and took place at 263 international sites.
The ICON7 investigators noted that the treatment effect was maximized earlier in the study, at 12 months, coinciding with the end of the bevacizumab treatment. In fact, the effect disappeared at 24 months, which led the investigators to use the novel statistical method of restricted mean difference for their calculations at 36 months. The method accounts for "nonproportional hazards."
The fact that the addition of bevacizumab was most effective at 12 months, with a resounding 15.1% (95% CI, 10.7 - 19.5) improvement in PFS compared with standard therapy, led the investigators to speculate about possible continuous maintenance treatment. They said that the findings raised the "possibility that prolonged therapy beyond 12 months, perhaps until disease progression, might further improve outcome."
The GOG0218 investigators called bevacizumab a "front-line treatment option," but also said that much more work is needed in evaluating bevacizumab in this setting. They cited the need to optimize duration and timing of treatment, examine cost-effectiveness, and "perhaps most important, identify potential tumor or host biologic factors predictive of efficacy and adverse events with the ultimate goal of decreasing morbidity and mortality from this disease."
Earlier data from both studies have been previously reported by Medscape Medical News: Data from ICON7 were reported from the American Society of Clinical Oncology 2011 Annual Meeting and at the 35th European Society for Medical Oncology Congress, and data from GOG0128 were reported from the American Society of Clinical Oncology 2010 Annual Meeting.
Differences in the 2 Studies
The ICON7 trial differed from the GOG trial in a number of ways.
The ICON7 study enrolled patients with advanced-stage cancer (70%) who had no visible residual disease, as well as some patients with high-risk, early-stage disease (9%). In the GOG0218 study, all of the patients had advanced disease: stage 3 (incompletely resectable, and thus some residual disease) or stage 4. All of the women in GOG0218 had epithelial disease; 90% in ICON7 did so.
Also important is that in the ICON7 study, half the dose of bevacizumab was used (7.5 mg/kg vs 15 mg/kg in the GOG0218 study) for a shorter maintenance period (12 vs 16 cycles).
Notably, the prognosis for patients at high risk for progression in the ICON7 study was similar to that for all patients in the GOG study. A 3.6-month (restricted mean) improvement in PFS was observed with bevacizumab in ICON7, "similar to that seen in the GOG-0128 study," write Dr. Perren and coauthors. "The apparently greater effect of bevacizumab in patients with a poor prognosis is encouraging," they add.
Overall Survival and Adverse Events
The primary outcomes were also different in the 2 studies. In GOG0218, the primary endpoint was PFS, but the trial is also tracking survival. At the time of the new analysis (median follow-up, 17.4 months), 76.3% of the patients were still alive, with no significant differences in overall survival.
In ICON7, PFS is a secondary outcome and overall survival is the primary outcome; these data are not yet final and are due in 2013. However, in their updated analysis, the investigators report that Kaplan-Meier estimated rate of 1-year survival was 92% in the bevacizumab group and 86% in the standard therapy group (HR, 0.85; 95% CI, 0.69 - 1.04; P = .11).
Bevacizumab did not affect the delivery of chemotherapy in either trial. However, the drug did, as the ICON7 authors worded it, "expand the range of toxic effects." Most notably, bevacizumab increased hypertension and bowel perforation. For instance, in the GOG0218 study, the rate of hypertension requiring medical therapy was higher in the bevacizumab-throughout group (22.9%) than in the control chemotherapy group (7.2%). Gastrointestinal-wall disruption requiring medical intervention occurred in 1.2% and 2.6% of patients in the control group and the bevacizumab-throughout group, respectively.
Study Designs
In GOG, all patients received chemotherapy consisting of intravenous paclitaxel at a dose of 175 mg/m2 body-surface area, plus carboplatin at an area under the curve of 6, for cycles 1 through 6, plus a study treatment (either placebo or bevacizumab) for cycles 2 through 22, with each cycle having 3 weeks' duration.
The study actually had 3 groups: 1 with chemotherapy alone and 2 with differing lengths of bevacizumab.
The control treatment was chemotherapy with placebo added in cycles 2 through 22. Another group, known as "bevacizumab-initiation" treatment, was chemotherapy with bevacizumab (15 mg/kg body weight) added in cycles 2 through 6 and placebo added in cycles 7 through 22.
The third group, known as "bevacizumab-throughout" treatment was chemotherapy with bevacizumab added in cycles 2 through 22.
The bevacizumab-initiation group had less improvement in PFS than the more treatment-intensive bevacizumab-throughout group.
In ICON7, patients were randomly assigned to receive carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg/m2 body-surface area), given every 3 weeks for 6 cycles, or to receive this regimen plus bevacizumab (7.5 mg/kg body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease.
GOG0128 was supported by Roche/Genentech and the National Cancer Institute. ICON7 was supported by Roche/Genentech and the National Institute for Health Research, through the National Cancer Research Network in the United Kingdom. The lead authors of both GOG0128 and ICON7, as well as some of their coauthors, have disclosed financial relationships with the study sponsor, Roche. The lead authors also report relationships with other pharmaceutical companies.
N Engl J Med. 2011;365:2473-2496.
