Dr. Jonathan A. Ledermann presents Abstract 5506.
Results of the primary analysis of what was originally a three-arm, double-blind, placebo-controlled phase III trial were published in 2016.1 The three arms of the original trial design were chemotherapy plus placebo and maintenance therapy plus placebo; chemotherapy plus cediranib and maintenance therapy plus placebo; and chemotherapy plus cediranib followed by cediranib as maintenance.
The intention of the original design was to include 2,000 patients, Dr. Ledermann said. Development of cediranib was discontinued, however, in 2011, which led to a trial redesign, including a reduction in the sample size, before analysis. As a result of the redesign, the primary outcome shifted to progression-free survival (PFS), and the trial compared two treatment arms: chemotherapy plus placebo (i.e., placebo arm) versus cediranib given with chemotherapy and as maintenance (i.e., cediranib arm). The median PFS in 2013 was 8.7 months in the placebo arm and 11.1 months in the cediranib arm (HR 0.57, 95% CI [0.45, 0.74]; p = 0.00001).
The OS analyses conducted in January demonstrated a median survival of 19.9 months in the placebo arm versus 27.3 months in the cediranib arm (HR 0.85, 95% CI [0.66, 1.10]).
Dr. Ronald J. Buckanovich discusses Abstract 5506.
A comparison of post-progression treatment between the two trial arms found that the median time to the next line of treatment was 10.7 months in the placebo arm and 13.2 months in the cediranib arm. Eighty-one percent of patients in the trial had a third line of treatment, 58% had a fourth line of treatment, and 34% had five or more total lines.
“There is clear evidence that cediranib extends PFS, and the consistent trend in favor of OS benefit suggests a promising future for cediranib, particularly when you look at the time from histological diagnosis to death, where there was an 8-month increase in median survival,” Dr. Ledermann said.
He noted that the revised design meant that the trial was unavoidably underpowered for survival. “A benefit [of cediranib] is seen with chemotherapy and during maintenance, where toxicity is less,” he said. The maintenance strategy with cediranib is being explored further in the ICON9 trial.
Discussant Ronald J. Buckanovich, MD, PhD, of the University of Michigan, said that the previously published ICON6 results showed a PFS survival advantage with cediranib, but “the OS advantage didn’t quite make the cut,” in part because the trial was underpowered as a result of the unavoidable design reorganization. “There are some interesting statistics that may mean it has more of an advantage than we think,” he said. “However, the advantage comes with significant toxicity.” Nearly 40% of patients discontinued therapy because of those toxicities, which included fatigue, diarrhea, hypertension, and hypothyroidism.
Dr. Buckanovich questioned the conclusion of the trial with regard to cediranib as maintenance therapy. In a comparison of data from the three arms of the trial, he noted that the difference in months of median survival was small between arm B, with placebo as maintenance, and arm C, with cediranib as maintenance.
–Kathy Holliman, MEd