The investigational oral vascular endothelial growth factor (VEGF) inhibitor cediranib extended progression-free survival when given with platinum-based chemotherapy and improved overall survival when given as maintenance therapy in patients with recurrent ovarian cancer. Experts are hopeful that these encouraging results of the ICON6 trial will trigger a resurrection for development of this agent.
Cediranib plus platinum-based chemotherapy followed by maintenance cediranib prolonged progression-free survival by 3.2 months and overall survival by 2.7 months.
“These are groundbreaking data. This is the first trial to demonstrate a significant improvement in progression-free survival and overall survival with an oral VEGF tyrosine kinase inhibitor in ovarian cancer,” stated lead author Jonathan Ledermann, BSc, MD, FRCP, Professor of Medical Oncology at the UCL Cancer Institute, University College London. He presented the results at a Presidential Session during the 2013 European Cancer Congress in Amsterdam.1
At a press conference, Dr. Ledermann explained that AstraZeneca had discontinued development of cediranib after disappointing phase III results in colorectal cancer, lung cancer, and glioblastoma. The company’s cediranib team was not at the meeting, but a spokesperson for the company subsequently indicated that the results of this study would be reviewed in more detail and a decision about the possible resurrection of cediranib would be made. Thus, it remains unclear as to whether cediranib will re-enter development for U.S. Food and Drug Administration (FDA) approval in ovarian cancer.
“These results are important for women with recurrent ovarian cancer. These patients have few treatment options available that can make a significant difference to progression and overall survival,” said European CanCer Organisation (ECCO) President Cornelis van der Velde, MD, Professor of Surgical Oncology at Leiden University Medical Center, Leiden, The Netherlands, who was present at the press conference.
ICON6 is the first trial to investigate an oral VEGF receptor tyrosine kinase inhibitor combined with chemotherapy and given as maintenance in recurrent ovarian cancer. The study had a complex design. Ovarian cancer patients (N = 456) with a relapse-free interval greater than 6 months following first-line chemotherapy were randomly assigned to platinum-based chemotherapy plus placebo followed by placebo maintenance, chemotherapy plus cediranib followed by placebo maintenance, or chemotherapy plus cediranib followed by cediranib maintenance. Treatment was continued until disease progression.
Median progression-free survival was 8.7 months in the chemotherapy/placebo comparator arm (no cediranib) and 11.1 months in the cediranib-maintenance arm (P = .00001). A restricted means analysis showed a 3.2-month difference favoring cediranib (9.4 vs 12.5 months).
Dr. Ledermann clarified the rationale for a restricted means analysis of study results. “The hazard ratio is not constant over time. Although you can undertake a standard log-rank analysis, the restricted means analysis takes into account the changing proportionality of the two curves over time,” he explained.
A secondary restrictive means analysis compared the arm receiving chemotherapy/cediranib plus placebo maintenace vs the arm receiving chemotherapy/cediranib plus cediranib maintenance. This analysis showed a 1.3-month difference in progression-free survival favoring cediranib maintenance. The log-rank analysis showed a trend toward improved disease-free survival, with some benefit from adding cediranib to chemotherapy and a greater benefit from continuing cediranib as maintenance.
“The study provides strong evidence that cediranib has an effect by itself on progression-free survival both during and after chemotherapy,” Dr. Ledermann said.
Median overall survival was 20.3 months in the chemotherapy-alone arm and 26.3 months in the cediranib maintenance arm (P = .042). In a restricted means analysis, overall survival was 17.6 and 20.3 months, respectively.
Adverse events that were significantly more frequent in the maintenance arm were hypertension, diarrhea, hypothyroidism, hoarseness, hemorrhage, proteinuria, and fatigue. Most of these were manageable with dose reductions or interruptions in therapy. The addition of cediranib did not compromise the ability to undergo chemotherapy; around 80% of patients completed the full six cycles, and most patients stayed on maintenance cediranib until disease progression, Dr. Ledermann told listeners.
“These results suggest cediranib will have a role in the treatment of recurrent ovarian cancer,” Dr. Ledermann said. ■
Disclosure: Dr. Ledermann received grant support from AstraZeneca for this trial. Most of the funding was from Cancer Research UK.
1. Ledermann JA, Perren TJ, Raja FA, et al: Randomized double-blind phase III trial of cediranib (AZD 2171) in relapsed platinum-sensitive ovarian cancer: Results of the ICON6 trial. European Cancer Congress. Abstract 10. Presented September 30, 2013.
Press conference moderator Cora N. Sternberg, MD, Chief of Medical Oncology at San Camillo and Forlanini Hospitals, Rome, called the 2- to 3-month improvement in overall survival “worthwhile, and clinically meaningful.” She said this should be viewed in the context of manageable toxicity....