BY RABIYA S. TUMA, PHD
Although the addition of bevacizumab to adjuvant chemotherapy and maintenance therapy prolongs progression-free survival in ovarian cancer patients compared with use of chemotherapy alone, it has not been clear whether the benefit is the effect of the maintenance phase or the addition of the drug during the chemotherapy phase of treatment.
Now, investigators reported this week at the American Society for Clinical Oncology Annual Meeting that using pazopanib, a small molecule multikinase inhibitor, as a maintenance treatment prolongs progression-free survival, compared with placebo (Abstract LBA5503). The benefit was seen despite the fact that the drug was not added to standard chemotherapy and thus was tested as a "pure maintenance" drug.
"This drug provided six more months with the patient getting control over the disease, instead of the disease getting control over the patient," said Andreas Du Bois, MD, Professor of Gynecologic Oncology at Kliniken Essen Mitte in Essen, Germany, who presented the data.
The international trial enrolled 940 patients from 17 countries between June 2009 and August 2010. Although patients with FIGO Stages II-IV disease were eligible, 91 percent of patients had Stages III or IV disease.
To be eligible, patients had to have had at least five cycles of platinum-taxane chemotherapy; intraperitoneal, neoadjuvant, or dose-dense chemotherapy were all allowed. Researchers excluded patients who had residual bulky disease or who had an immediate need for second-line chemotherapy, or who had had prior anti-VEGF therapy.
The researchers randomly assigned patients to receive either 800 mg of pazopanib or placebo daily for up to 24 months. The median time between diagnosis and randomization was seven months. Eighty-five percent of patients had either a complete response or no evidence of disease as their best response to chemotherapy and surgery.
With a median follow-up of 24 months, median progression-free survival was 17.9 months in the pazopanib arm and 12.3 months in the placebo arm, Du Bois reported. The statistically significant difference represents a 23 percent decreased risk of progression in the active-drug arm. "Preplanned sensitivity analysis all showed essentially the same result, so this is a very robust result favoring pazopanib," he said.
He emphasized that because of the trial design, with randomization occurring after chemotherapy and surgery, that the absolute duration of progression-free survival cannot be compared with that in other trials, unless one adds in the seven months from diagnosis to randomization. (Even then, he noted, comparing between trials is difficult to do.)
He said that researchers are collecting data on overall survival but that the data are immature, with only 190 of the 551 deaths needed for the analysis. He did, however, show Kaplan-Meier curves, which currently overlap, just to reassure the audience. "There is no conclusion that you can draw other than that there is no early detrimental affect with pazopanib," he said.
Side effects associated with the drug were similar to what has been seen with this class of agents in other studies and disease sites. Hypertension was the most common Grade 3-4 adverse event, affecting 31 percent of patients in the pazopanib arm compared with six percent of patients in the placebo arm.
Other common Grade 3-4 toxicities were liver-related events (9% vs. less than 1%, respectively), neutropenia (10% vs. 2%), diarrhea (8% vs. 1%), fatigue (3% vs. 1%), thrombocytopenia (3% vs. less than 1%), hand-foot syndrome (2% vs. less than 1%), and headache (2% vs. less than 1%).
Dose reductions were common in the pazopanib arm, with 58 percent of patients requiring some dose adjustment. The mean dose overall for the drug was 607.4 mg daily, compared with the planned dose of 800 mg.
Confirmation of Value
"There has been a lot of discussion in ovarian cancer as to whether patients should receive these agents as part of their initial treatment or whether you should save this benefit for a later time in the course of their disease, at the time of recurrence or even at the time of treatment for platinum-resistant disease," commented Carol Aghajanian, MD, an ASCO ovarian cancer spokesperson and Chief of the Gynecologic Medical Oncology Service at Memorial Sloan-Kettering Cancer Center, speaking during the news conference.
"These questions do remain as to what is the right drug and what is the right time. But what we do know from the trial presented here is confirmation that targeting angiogenesis in ovarian cancer is important and effective. All of the trials have been positive, and all have had about the same magnitude of benefit."