Bevacizumab in the First-Line Treatment of Ovarian Cancer: Are We There Yet?

Bevacizumab in the First-Line Treatment of Ovarian Cancer: Are We There Yet?

Bevacizumab added to chemotherapy (CT) once every 3 weeks and followed by bevacizumab maintenance reduced the risk of disease progression by 29% in the primary treatment of women with ovarian cancer, according to data from the Gynecologic Oncology Group (GOG) 218 study.1,2 When these data were first reported during the 2010 ASCO Annual Meeting Plenary Session, presenter Robert A. Burger, MD, now with the University of Pennsylvania, said, “This regimen should be considered a standard option in this population”—that is, in women with newly diagnosed, incompletely resected, stage III or any stage IV epithelial ovarian cancer.1

Dr. Robert A. Burger Photo courtesy of David DeBalko

Bevacizumab, a VEGF inhibitor, thwarts angiogenesis, the process that provides blood supply to the growing tumor. Its evaluation in the first-line treatment of advanced ovarian cancer was based on its widespread use in recurrent disease. Because patients with recurrent disease have received multiple lines of therapy, it is difficult to determine the impact of bevacizumab on long-term survival, Dr. Burger explained to the ASCO Daily News.

What can now be said about the use of bevacizumab in the first-line treatment of patients with advanced ovarian cancer? It all depends on which side of the Atlantic one resides. On the basis of data from GOG 218, with supportive evidence from the International Collaboration on Ovarian Neoplasms 7 (ICON7) trial,1-3 the European Medicines Agency (EMA) has approved bevacizumab at the dosing schedule used in GOG 218 for the first-line treatment of advanced ovarian cancer.4 As of this writing, bevacizumab is not approved for the first-line treatment of advanced ovarian cancer in the United States.

GOG 218 and ICON7

GOG 218 and ICON7, published back to back in The New England Journal of Medicine in 2011,2,3 were both randomized, phase III studies, but they had some significant differences. GOG 218 was a double-blind, placebo-controlled, three-arm study that evaluated bevacizumab added to standard CT followed by bevacizumab maintenance for a total of 22 cycles versus standard CT (six cycles)—intravenous paclitaxel 175 mg/m2 and carboplatin at an area under the curve (AUC) of 6 on day 1 of a 3-week cycle.2 Patients in the third arm of the study received bevacizumab only with standard CT for six cycles and did not have better clinical outcomes than those treated with standard CT alone.2

ICON7 was an open-label, two-arm study in women who had stage I to III debulked or any stage IV ovarian cancer. Bevacizumab was administered for six cycles with standard CT and for an additional 12 cycles as maintenance therapy.3

Progression-free survival (PFS), the primary outcome for each study, was comparable across the two studies when examined for clinical and pathological factors. In ICON7, for patients with suboptimally debulked stage III and all stage IV disease (33% of the total ICON7 cohort), the median PFS after a median follow-up time of 19.4 months was 15.9 months when bevacizumab was administered with CT compared with 10.5 months for the CT-only arm (hazard ratio [HR] 0.68, 95% CI [0.55, 0.85]).3 In GOG 218, the median PFS after a median follow-up time of 17.4 months was 14.1 months with bevacizumab compared with 10.3 months for CT alone (HR 0.717, 95% CI [0.625, 0.824]).2

Bevacizumab Use in the United States

Although GOG 218 carried the day for first-line bevacizumab in advanced ovarian cancer in Europe,4 organizations in the United States that advance drug use in the clinic had questions that prevented a ringing endorsement.

Andrew Villani, senior manager for corporate relations at Genentech, told the ASCO Daily News that final data from GOG 218,2 OCEANS (a study in platinum-sensitive ovarian cancer),5 and AURELIA (a study in platinum-resistant ovarian cancer)6—all phase III studies—were discussed with the U.S. Food and Drug Administration, which ultimately approved bevacizumab in combination with CT for the treatment of platinum-resistant ovarian cancer based on AURELIA study data.7

In addition, after the publication of GOG 218 and ICON7, the National Comprehensive Cancer Network (NCCN) panel, which formulates recommendations for drug use across cancers, provided a category 3 recommendation for the first-line use of bevacizumab in combination for women with ovarian cancer who are treatment naive.8 For any level of evidence, a category 3 recommendation is provided when there is major NCCN disagreement that the intervention is appropriate.8

“There was a strong disagreement among the panel members,” Robert J. Morgan, Jr., MD, FACP, chair of the NCCN ovarian cancer guidelines, said. “Bevacizumab is associated with substantial toxicity and cost, and it did not show survival benefit.” In a cost-effective model, an analysis of the data from GOG 218 indicated a change in incremental cost-effectiveness ratio by more than $100,000/quality-adjusted progression-free years in favor of chemotherapy over regimens containing bevacizumab when quality of life was included in the analysis over a model that did not include this information.9

Toxicities associated with bevacizumab include gastrointestinal perforations, wound-healing issues, bleeding, hypertension, proteinuria, and arteriovenous thromboembolism. Dr. Burger said that in a follow up of the safety assessment of GOG 218, which is now published, bevacizumab use in first-line treatment of ovarian cancer was associated with a greater risk of gastrointestinal adverse events (3.4% vs. 1.7% for CT only), and the increased incidence was associated with patients at risk for bowel resection who had anastomoses or inflammatory diseases.10

Dr. Marcia Hall
With respect to overall survival (OS), analyses of data indicate OS benefits in a subset of patients. Marcia Hall, MD, from the Mount Vernon Cancer Center, Middlesex, England, said that ICON7 showed OS benefits with the addition of bevacizumab only in patients classified as high risk.3,11,12 Dr. Burger indicated that an analysis of GOG 218 presented at the 2013 Annual Meeting of the Society of Gynecologic Oncology also showed benefit in a subset of women with stage IV disease.13

“The OS in GOG 218 was confounded with approximately 40% crossover,” Dr. Hall said.12 Dr. Burger added that “the statistical effect” also confounded the OS data. “The post-progression survival time was well in excess of the time from initial therapy start to initial progression,” he said.

However, the experts interviewed all agreed that published data on bevacizumab will influence prescribing practice. Bevacizumab has been studied across many solid tumors and has collected impressive approvals over the years, including one for platinum-resistant recurrent ovarian cancer. With its widespread availability, it is likely that bevacizumab is being incorporated by clinicians in their own ovarian cancer practices, the experts said.

Bevacizumab Dosing Variations

Even with a category 3 endorsement, the NCCN guidelines state that, when used in the first-line setting, bevacizumab must be given at the dosages and schedules studied in GOG 218 and ICON7,2,3 which may pose another dilemma.

In GOG 218, bevacizumab was administered at a dose of 15 mg/kg once every 3 weeks,1,2 whereas it was given at a dose of 7.5 mg/kg every 3 weeks in ICON7.3

“Although the EMA approval is based on the GOG 218 dosage, clinicians in the United Kingdom are using it at the ICON7 dosage,” Dr. Hall said. The ICON7 dosage of bevacizumab, in addition to its lower cost compared with the GOG 218 dosage, predisposes patients to lower cumulative toxicities associated with bevacizumab than the GOG 218 dosage, she added. Dr. Hall also pointed out that, although the EMA-approved bevacizumab dose is based on the GOG 218 study, countries in the European Union will look to their regulatory authorities and reimbursement arrangements to seek guidance on its use.

The United Kingdom’s National Institute for Health and Care Excellence (NICE) indicated that bevacizumab in combination with paclitaxel and carboplatin is not recommended for first-line treatment of advanced ovarian cancer because it was not considered a cost-effective use of National Health Service resources.14 Dr. Hall explained that NICE refused to evaluate bevacizumab at the lower dose of 7.5 mg/kg, where cost-effectiveness is much closer to the acceptable United Kingdom threshold, because it “is not the recommended licensed dose for first-line treatment of advanced ovarian cancer, so its use is off label.”

Future Advances for Advanced Ovarian Cancer

Using bevacizumab in combination with chemotherapy for the first-line treatment of advanced ovarian cancer is based on the paucity of options available to women with this disease. In the United States alone, approximately 21,000 women were estimated to be newly diagnosed with ovarian cancer, and approximately 14,000 deaths were expected as a result of the disease in 2015.15

With CT as the only viable option in advanced disease, ongoing studies aim to increase treatment options or provide meaningfully better outcomes with less toxic options. Dose-dense CT options are providing a glimmer of hope for better outcomes. In the Japanese GOG (JGOG) 3016 study, with 76.8 months of follow-up time, dose-dense treatment demonstrated significantly better PFS and OS compared with standard CT.16

In dose-dense treatment, carboplatin AUC 6 is given on day 1, and paclitaxel is administered at a lower dose, 80 mg/m2, every week, on days 1, 8, and 15 of a 3-week cycle, instead of once every 3 weeks.16

In patients with stage II-IV disease enrolled in JGOG 3016, the median PFS was 28.2 months with bevacizumab compared with 17.5 months with CT alone (p = 0.0037). The median OS was 100.5 months with bevacizumab compared with 62.2 months with CT alone (p = 0.039).16

GOG 262, like JGOG, was a study of dose-dense therapy, but bevacizumab was allowed at the discretion of the investigator.17,18 With 85% of patients receiving bevacizumab, there was no difference in PFS between patients receiving dose-dense treatment and those receiving only CT. However, among patients not receiving bevacizumab, the dose-dense treatment group had a significantly better PFS: 14 months with dose-dense treatment compared with 10 months with standard CT alone (HR 0.60, 95% CI [0.37, 0.96]).17,18

In addition, the ICON investigators have enrolled women with ovarian cancer in the ICON8 and ICON8B studies.19 ICON8 is aimed at confirming data from the JGOG 3016 study, and the ICON8B study will again try to determine whether bevacizumab has a role in the first-line treatment of advanced ovarian cancer—this time, with dose-dense treatment.   

– Alexander Castellino, PhD