CHICAGO – The oral tyrosine kinase inhibitor pazopanib is likely to become a new option in maintenance therapy for advanced ovarian cancer, based on phase III trial results presented at the annual meeting of the American Society of Clinical Oncology.
Among the 940 patients studied, none of whom had disease progression after completing first-line chemotherapy, pazopanib (Votrient) prolonged median progression-free survival by 5.6 months as compared with placebo, reported lead author Dr. Andreas Du Bois, a professor of gynecologic oncology at Kliniken Essen Mitte in Essen, Germany.
Pazopanib’s safety and tolerability profiles were as expected from previous experience with the drug and its known antiangiogenic activity, consisting mainly of adverse effects such as hypertension, diarrhea, and fatigue.
"Pazopanib maintenance therapy significantly extends time without recurrence and thus increases progression-free survival and delays need for further chemotherapy in ovarian cancer. So it prolongs the time the patient has control over the disease instead of disease having control over the patient," Dr. Du Bois commented in a press briefing.
"This is the first phase III maintenance study demonstrating superior outcome for a targeted therapy in ovarian cancer. Therefore, pazopanib may be a valuable option in the future" for this patient population, he added. "This study will be used for registration purposes, and hopefully we will have this drug available soon."
Dr. Du Bois acknowledged that previous trials have assessed use of bevacizumab (Avastin), another agent having antiangiogenic activity, for maintenance therapy. But bevacizumab was started together with chemotherapy and then continued. "It was not a pure maintenance setting," he said, so it is unclear which component was responsible for benefit.
Additionally, the trial populations differed in residual tumor burden, with 85% of the patients in the pazopanib trial having no evidence of residual disease at the time of enrollment.
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Dr. Carol Aghajanian
Commenting during the press briefing, Dr. Carol Aghajanian, chief of the Gynecologic Medical Oncology Service at the Memorial Sloan-Kettering Cancer Center in New York and an ASCO spokesperson, said that the jury is still out on the optimal targeted agent and the optimal timing of its use in ovarian cancer.
"There has been a lot of discussion in ovarian cancer as to whether the patient should receive these agents as part of their initial treatment, or should you save this benefit for a later time in the course of their disease, at the time of treatment for recurrence or even at the time of treatment for platinum-resistant disease," she said. "But what we do have from the trial presented here by Dr. Du Bois is confirmation that targeting angiogenesis in ovarian cancer is important and effective."
Patients were eligible for the trail, the international intergroup trial AGO-OVAR16 sponsored by GlaxoSmithKline, if they had FIGO stage II to IV ovarian, fallopian tube, or primary peritoneal cancer, had not had progression after resection and completion of at least five cycles of first-line platinum-taxane chemotherapy, and had residual tumors measuring less than 2 cm.
They were randomized evenly to receive 800 mg pazopanib or placebo daily for 24 months.
Pazopanib is a multitargeted tyrosine kinase inhibitor that acts mainly on vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and c-kit signaling. It is approved by the Food and Drug Administration for treatment of kidney cancer and soft tissue sarcoma.
Main trial results showed that after a median follow-up of 24.3 months, median progression-free survival was 17.9 months with pazopanib and 12.3 months with placebo (hazard ratio, 0.77, P = .002). The findings were similar in subgroup analyses, according to Dr. Du Bois, who disclosed that he receives honoraria and research funding from GlaxoSmithKline.
An interim analysis of overall survival showed no significant difference between groups, but only a fifth of the patients had died as of the analysis.
Relative to placebo, pazopanib was associated with a higher incidence of serious adverse events (26% vs. 11%), according to the abstract. Three patients in the pazopanib group and one patient in the placebo group had a fatal serious adverse event.
"Predicting tolerability will be subject to further research," Dr. Du Bois noted.