Women with advanced ovarian cancer live longer without disease progression when they receive bevacizumab (Avastin) with first-line chemotherapy and then as single-agent maintenance therapy, a phase III clinical trial presented at the 2010 ASCO Annual Meeting finds. Results of the Gynecologic Oncology Group (GOG)-0218 study were presented during the Plenary Session at the meeting.¹

Progression-free survival (PFS) was nearly 4 months (or about 39%) longer in the experimental treatment arm receiving bevacizumab and standard chemotherapy, followed by bevacizumab-alone maintenance treatment. That group had a median PFS of 14.1 months vs 10.3 months in the control arm, which received only chemotherapy.

"This regimen should be considered one treatment option for advanced ovarian cancer," said lead researcher on this trial for the GOG, Robert Burger, MD, Professor in the Department of Surgical Gynecology and Director of the Women's Cancer Center, Fox Chase Cancer Center, Philadelphia. "Bevacizumab is the first molecular targeted therapy and the first antiangiogenic agent to demonstrate benefit in this population," he said.

The NCI-supported trial conducted by the GOG enrolled 1,873 women with advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer from four countries (United States, Canada, South Korea, and Japan). Two-thirds of the patients had stage III or IV disease with suboptimal tumor debulking, and the others had optimally debulked stage III disease but with macroscopic residual (unresectable) tumor at the completion of initial surgery. None of the patients had received prior chemotherapy.

Patients were randomly assigned to one of three double-blind treatment arms. The control arm (n = 625) received six cycles of standard IV chemotherapy-carboplatin at area under the curve (AUC) 6, and paclitaxel at 175 mg/m²-plus IV infusion of placebo (five cycles). This regimen was followed by placebo every 3 weeks during a maintenance phase lasting up to 10 months. Another 625 patients received standard chemotherapy plus IV bevacizumab (15 mg/kg) beginning with the second cycle, followed by placebo maintenance. The remaining 623 patients received standard chemotherapy plus concurrent and maintenance bevacizumab.

Primary Endpoint Changed

After the study began, the investigators changed the primary endpoint from overall survival (OS) to PFS. Maintaining blinding of the treatment at disease progression was unfeasible due in part to the commercial availability and common off-label use of bevacizumab in patients with recurrent ovarian cancer; in addition, a consensus by the Gynecologic Cancer Intergroup published in 2005 in the Annals of Oncology stated that PFS is perhaps a better primary endpoint in front-line phase III ovarian cancer trials. Unblinding at disease progression allowed crossover to bevacizumab treatment, Dr. Burger said.

The use of bevacizumab during chemotherapy without maintenance doses (arm 2) did not provide a statistically significant increase in PFS (median = 11.2 months). However, all analyses, including subgroup analyses, supported an improved PFS (Fig. 1) in the concurrent and maintenance bevacizumab group (arm 3), Dr. Burger reported.

Therefore, he said, the study met its primary objective. To help determine PFS, the authors used serum cancer antigen 125 (CA-125) in addition to standard NCI response evaluation criteria in solid tumors (RECIST) criteria with radiographic imaging.

At a median follow-up of 17.4 months, OS was similar in the treatment groups, but longer follow-up is needed, according to Dr. Burger. Besides OS, secondary endpoints included safety, quality of life, and translational laboratory studies.

Adverse Events Tolerable

The bevacizumab regimen was "generally well tolerated," Dr. Burger said. Adverse events were similar to those occurring occuring in previous phase III trials of this agent in non-gynecologic cancers.

Among the adverse events that occurred more frequently in the two bevacizumab arms than in the control arm were grade 2 or greater hypertension or proteinuria; grade 3 or greater pain or gastrointestinal (GI) hemorrhage, perforation, or fistula; and grade 4 neutropenia. Less than 3% of patients in either bevacizumab arm had GI complications, he said.

The proportion of patients who discontinued therapy because of adverse events was slightly greater in the groups receiving bevacizumab. Adverse events leading to discontinuation of therapy occurred mainly in the chemotherapy phase.

After a press conference about GOG-0218, moderator Jennifer Obel, MD, medical oncologist at NorthShore University HealthSystem and Assistant Clinical Professor of Medicine, University of Chicago, told The ASCO Post that a longer PFS is meaningful, because women with ovarian cancer tend to be asymptomatic when their cancer is not progressing. The downside, she said, is the need for months of maintenance chemotherapy.

"We need to tell our patients clearly what progression-free survival means. This experimental therapy improves a patient's chance of staying free of disease, but what we don't know is whether a patient will live longer overall.

Physicians and patients must have an in-depth talk about whether the extra therapy is worth the longer progression-free survival," Dr. Obel commented. ■

References

1. Burger R, Brady MF, Bookman MA, et al: Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): A Gynecologic Oncology Group study. 2010 ASCO Annual Meeting. Abstract LBA1. Presented June 6, 2010.