Oral VEGF Inhibitor, Cediranib, Improves Survival in Recurrent Ovarian Cancer
Amsterdam, The Netherlands—Treatment with the oral angiogenesis inhibitor cediranib led to significant improvements in overall survival (OS) and progression-free survival (PFS) in patients with recurrent ovarian cancer, according to new data reported at the European Cancer Congress 2013.
The median PFS improved by 2.4 months, from 8.7 to 11.1 months, in patients receiving conventional chemotherapy plus cediranib followed by cediranib maintenance. OS, a secondary end point of the trial, was 6 months longer with the cediranib regimen compared with chemotherapy and placebo.
“I think the evidence is pretty strong that antiangiogenics have a very important role in ovarian cancer, and I think there are opportunities to use different antiangiogenic drugs,” said Jonathan A. Ledermann, MD, BSc, Head, Cancer Research UK and UCL (University College London) Cancer Trials Centre, United Kingdom. “I don’t think bevacizumab [Avastin] is the only one. Certainly, in the setting of recurrent ovarian cancer, there is quite a lot of space for different types of antiangiogenics other than bevacizumab.”
Dr Ledermann reported the findings from the initial efficacy of the ICON6 Gynaecologic Cancer InterGroup trial, sponsored by the British Medical Research Council. The trial was the first to examine the activity of an oral inhibitor of vascular endothelial growth factor (VEGF) in combination with platinum-based chemotherapy and as maintenance therapy in recurrent ovarian cancer.
The trial included 456 patients with relapsed, platinum-sensitive ovarian cancer, who were randomized in a 2:3:3 ratio to platinum-based chemotherapy plus placebo and placebo maintenance therapy, chemotherapy plus cediranib followed by placebo maintenance, or to chemotherapy plus cediranib and cediranib maintenance.
The primary end point was PFS, and the primary analysis compared the chemotherapy plus placebo arm and the chemotherapy plus cediranib and cediranib arm.
The difference in PFS translated into a 43% reduction in the hazard for progression in favor of the cediranib maintenance arm (P = .001). To account for nonproportional hazards between 2 treatment groups, the investigators performed a restricted means analysis, which yielded a median PFS of 9.4 months with chemotherapy alone and 12.5 months with chemotherapy and cediranib.
The uncorrected analysis of OS showed a median of 20.3 months for chemotherapy alone versus 26.3 months for the cediranib maintenance arm (P = .042). A restricted means analysis reduced the difference to 2.7 months (20.3 with cediranib maintenance and 17.6 with chemotherapy alone).
The adverse events reported with cediranib were consistent with previous trials of VEGF inhibitors (hypertension, fatigue, diarrhea, and nausea) and were controlled with dose reduction or treatment interruption. “The addition of cediranib did not compromise the delivery of chemotherapy,” said Dr Ledermann. “In the maintenance phase, most patients were able to tolerate prolonged oral therapy.”
Although seemingly modest, the improvements in PFS and OS were clinically meaningful, as well as statistically significant, said Dr Ledermann.
“We’ve made progress in cancer therapy in small increments,” he said. “This is an increment, and I think most people would accept an increment of 2 to 3 months in overall survival as a worthwhile increment to have.”
Having more than 1 effective anti-VEGF option could prove valuable in the management of patients with recurrent ovarian cancer, said Cora N. Sternberg, MD, Chief, Department of Medical Oncology, San Camillo-Forlanini Hospital, Rome, Italy.
“A patient might become resistant to bevacizumab, a monoclonal antibody, and then respond to a tyrosine kinase inhibitor that has several different mechanisms of action,” said Dr Sternberg. “I could actually see use of one tyrosine kinase inhibitor after another in different populations.”
Despite these favorable results, cediranib has an uncertain future: its manufacturer (AstraZeneca) has suspended its clinical development, according to Dr Ledermann. “It is a drug that has been tested in a number of tumor types,” he said. “All of those trials did not reach the end point that [the manufacturer] required to take forward for licensing, so the company decided to stop developing the drug.”