AMSTERDAM – Cediranib plus chemotherapy followed by cediranib maintenance treatment stalled recurrence and death by roughly 3 months in women with platinum-sensitive, relapsed ovarian cancer in the ICON6 study.

"This is the first trial to demonstrate a significant improvement in the progression-free and overall survival with an oral VEGF tyrosine kinase inhibitor in ovarian cancer, and these results suggest that cediranib has a clinically meaningful role in the treatment of recurrent ovarian cancer," Professor Jonathan Ledermann said at the multidisciplinary European cancer congresses.

The phase III results may provide women with another treatment option and bring cediranib (Recentin) back to life. AstraZeneca ceased development of the small molecule vascular endothelial growth factor (VEGF) inhibitor in September 2011 following disappointing results in first-line metastatic colorectal cancer, as well as non-small cell lung cancer

The three-arm, double-blinded ICON6 Gynecologic Cancer Intergroup Trial enrolled 456 women with epithelial ovarian, fallopian tube, or serous primary peritoneal cancer relapsing more than 6 months after first-line chemotherapy.

Patients were randomly assigned to platinum-based chemotherapy plus placebo and placebo maintenance therapy (chemotherapy-only arm) or cediranib 20 mg/day during chemotherapy followed by placebo (concurrent arm), or cediranib 20 mg/day during chemotherapy followed by maintenance cediranib (maintenance arm).

Treatment continued for 18 months or until disease progression, but could be used longer for patients continuing to benefit. Chemotherapy was up to six cycles of carboplatin (Paraplatin)/paclitaxel (Taxol), carboplatin/gemcitabine (Gemzar), or single-agent platinum therapy.

Median progression-free survival (PFS) was 8.7 months in the chemotherapy arm and 11.1 months in the cediranib maintenance arm (hazard ratio, 0.57; P = .00001).

However, because a test for nonproportionality was positive (P = .024), a restricted means analysis was done, resulting in a 3.1 month difference favoring cediranib (9.4 months vs. 12.5 months), said Prof. Ledermann, with University College London (UCL) Cancer Institute, Cancer Research UK, and UCL Cancer Trials Centre, London.

As a secondary endpoint, an analysis was performed on the concurrent arm showing a trend in favor of cediranib, with a PFS of 10.1 months and 11.4 months using restricted means analysis.

"There is strong evidence that cediranib has an effect by itself on progression-free survival both during and after chemotherapy," Prof. Ledermann said.

Median overall survival reached 20.3 months in the chemotherapy arm and 26.3 months in the cediranib maintenance arm (HR, 0.70; P = .042). Overall survival fell to 17.6 months and 20.3 months, respectively, in a restricted means analysis, following a positive test for nonproportionality (P = .0042). No overall survival data were presented for the concurrent arm.

"These are important results for women with recurrence ovarian cancer," Prof. Cornelis van de Velde, European Cancer Organization president, commented in a statement. "Once the disease has recurred, there are few treatment options available that make a significant difference to its progression and to overall survival. The ICON6 trial shows that cediranib does make a difference and it is to be hoped that it can be made available to women as soon as is practicable."

Laura Woodin, U.S. science media director for AstraZeneca, said in an interview that the company welcomes the commitment of the ICON6 investigators and the study sponsor, Britain’s Medical Research Council, and that "We look forward to assessing the positive results from the ICON6 study in more detail, to determine the future potential for cediranib in ovarian cancer."

Invited discussant Prof. Ignace Vergote, head of gynecological oncology at University Hospitals Leuven, Belgium, questioned why overall survival was so low in ICON6, compared with a median of 35.5 months reported with the addition of the VEGF-inhibitor bevacizumab to platinum-based chemotherapy in recurrent ovarian cancer in the phase III OCEANS trial. The cediranib dose was reduced from 30 mg/day to 20 mg/day after part one of ICON6, but it is unclear whether a higher dose in the maintenance phase would be more effective because 30-45 mg are used in most trials of cediranib monotherapy. Also unknown is whether there was less treatment in ICON6 after progression than there was in OCEANS.

The 15-month difference in overall survival between the two trials, however, might explain why overall survival was significant in ICON6 and not in the OCEANS study, Prof. Vergote said.

Finally, cediranib was associated with more treatment discontinuation, diarrhea, and fatigue, but less hypertension than bevacizumab at the dose used in the study, he observed.

Prof. Ledermann said hypertension (P = .004), diarrhea (P less than .001), and nausea (P = .008) were all significantly worse when cediranib was given during chemotherapy, but when it came to the maintenance phase, "hypertension was really quite manageable by this stage and the only side effect that was significantly worse with cediranib was diarrhea [P less than .001]."

Prof. Ledermann and his coauthors reported no relevant disclosures. AstraZeneca provided the study drug. Britain’s Medical Research Council sponsored the trial.

pwendling@frontlinemedcom.com

ICON6 ovarian cancer results may resurrect cediranib