Discouraging OS Results With Bevacizumab in Ovarian Cancer

Bevacizumab added to chemotherapy did not result in any difference in survival, according to long-term follow-up of a phase III trial of women with newly diagnosed ovarian, fallopian tube, or primary peritoneal cancer.

“The biology of high-grade serous carcinoma encourages early dissemination through activation of pro-angiogenic pathways,” wrote study authors led by Krishnansu S. Tewari, MD, of the University of California, Irvine, Medical Center. “A key promoter of tumor angiogenesis, vascular endothelial growth factor (VEGF), has emerged as a validated target, with bevacizumab achieving single-agent responses of 20% in recurrent disease.”

The GOG-0218 trial previously reported a 28% reduction in the risk of progression with bevacizumab over chemotherapy alone; this is similar to other trials that have shown progression-free survival (PFS) benefits without substantial overall survival (OS) benefits. The new report represented the final follow-up for the GOG-0218 trial, with a median follow-up period of 102.9 months. The results were published in the Journal of Clinical Oncology.

The study included a total of 1,873 women with incompletely resected stage III to IV ovarian, fallopian tube, or peritoneal carcinoma. They were randomized to 1 of 3 treatment groups: carboplatin and paclitaxel alone (625 patients); chemotherapy plus concurrent bevacizumab (625 patients); or chemotherapy plus concurrent bevacizumab followed by maintenance bevacizumab (623 patients). Patients had a median age of 60 years in all 3 groups, more than 80% of patients were white, and more than 80% had serous histology.

The median OS in the control group was 41.1 months. In the chemotherapy and concurrent bevacizumab group, the median OS was 43.4 months, for a hazard ratio (HR) compared with chemotherapy alone of 0.96 (95% CI, 0.85–1.09; P = .53). In the group that also received maintenance bevacizumab, the median OS was 40.8 months, for an HR compared with the control group of 1.06 (95% CI, 0.94–1.20; P = .34).

An exploratory analysis that excluded patients who died as a result of causes other than ovarian cancer or cancer therapy (104 patients) did not change the results. The same was true when censoring patients who received bevacizumab at crossover before progression or after progression. The treatment groups also had similar OS outcomes when stratified by treatment stage.

The study also confirmed the importance of testing for mutations to BRCA1/2 and to homologous recombination repair (HRR) genes. The HR for death in BRCA1/2-mutated carcinomas compared with wild-type tumors was 0.62 (95% CI, 0.52–0.73). Such mutations were not predictive of bevacizumab activity, however.

“The lack of survival benefit (even when adjusting for disease-specific mortality or second-line bevacizumab) is problematic, particularly in the absence of validated predictive biomarkers,” the authors wrote.

Though this and other trials have only shown PFS benefits with bevacizumab in this setting, the US Food and Drug Administration did approve bevacizumab, in combination with chemotherapy and then as single-agent maintenance therapy, in June 2018. “This approval represents an important milestone as the first medicine, other than chemotherapy, for women with advanced ovarian cancer after their initial surgery,” said the National Ovarian Cancer Coalition’s CEO Melissa Aucoin, at the time.

Other trials are ongoing that may further affect how bevacizumab, among other agents, is used in ovarian cancer. For example, the PAOLA-1 trial is comparing olaparib and placebo in patients also treated with chemotherapy and bevacizumab, and has an expected completion date of June 2022.