Nintedanib May Extend Advanced Ovarian Cancer PFS

Advanced ovarian cancer patients have slightly prolonged progression-free survival if given nintedanib with their first-line standard chemotherapy

medwireNews: The addition of nintedanib to first-line chemotherapy significantly increases progression-free survival (PFS) in advanced ovarian cancer, AGO-OVAR 12 results indicate.

Median PFS was 17.2 months for the 911 women assigned to receive the oral triple angiokinase inhibitor at a 200 mg twice-daily dose for days 2 to 21 of each 3-week cycle of carboplatin plus paclitaxel compared with 16.6 months for the 455 women assigned to receive chemotherapy plus placebo, giving a hazard ratio (HR) of 0.84.

Haematological adverse events were “frequent” in both treatment groups but nintedanib was also associated with a higher rate of gastrointestinal side effects, with 21% of patients reporting diarrhoea compared with 2% of placebo-treated patients.

Noting this rate was higher than previously reported for nintedanib, the study authors question whether debulking surgery, and in particular bowel resection, might have increased the risk of such gastrointestinal symptoms.

“Diarrhoea was the main reason for nintedanib dose reductions or treatment discontinuation”, they write, adding that “proper management of this side-effect is therefore important to optimise treatment with nintedanib.”

Preplanned subgroup analysis showed that the physician’s choice of carboplatin dose was significantly linked to median PFS. There was a significant HR of 0.83 for nintedanib versus placebo in patients given carboplatin to an area under the curve of 5 mg/mL per minute but a nonsignificant HR of 0.91 for patients treated to 6 mg/mL per minute.

PFS was also longer in patients with FIGO stage IIB to III disease who received nintedanib versus placebo (22.1 vs 18.5 months, HR=0.76). However, no such benefit was found in women with FIGO stage IV tumours.

Posthoc analysis also looked at the impact of classifying patients at high risk if they had FIGO stage IV disease, or stage IIII tumours with debulking surgery to over 1.0 cm, as used in the ICON7 ovarian cancer trial of the angiogenesis inhibitor bevacizumab, explain Andreas du Bois, from Kliniken Essen Mitte in Germany, and co-authors in The Lancet Oncology.

Using this definition, the HR for nintedanib versus placebo was a significant 0.74 for patients who were not at high risk but there was no significant difference between the treatment groups for high-risk patients.

This is the opposite result to that found in the ICON7 trial, which showed an overall survival improvement with bevacizumab for patients with high-risk tumours compared with their low-risk counterparts, the researchers observe.

The team notes that patient tumour burden is usually defined at baseline and improvements in surgical goals and standards may explain differences in trial results, with patients who would have been classified as high-risk in the ICON7 trial now classified as low-risk in the current study.

Sean Kehoe, from the University of Birmingham in the UK, agrees in an accompanying comment. “This finding shows, for the first time—some might say at last—the effect of surgical intervention on ovarian cancer chemotherapy trials.”

Acknowledging that optimal debulking of ovarian cancer with the aim of leaving no residual disease is not universally practiced, he suggests that the time has come to standardise surgery and patient selection for surgery in clinical trials.

“Consensus regarding an acceptable level of achieving no macroscopic disease after primary surgery would seem warranted”, he concludes. “Alternatively, stratification in clinical trials, based on macroscopic clearance, could be undertaken.”

du Bois A, Kristensen G, Ray-Coquard I, et al. Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol 2015; Advance online publication 15 November.

Kehoe S. Nintedanib and ovarian cancer: standardise surgery in trials? Lancet Oncol 2015; Advance online publication 15 November. DOI:

medwireNews ( ) is an independent medical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2015