NEW YORK (Reuters Health) - In a phase III trial, women with advanced ovarian cancer had a small improvement in progression-free survival with nintedanib, but at the expense of gastrointestinal side effects, according to European investigators.
Nintedanib is an oral inhibitor of the VEGF receptors (VEGFRs) 1-3, fibroblast growth factor receptors (FGFRs) 1-3, and platelet-derived growth factor receptors (PDGFRs) alpha and beta, with anti-angiogenic activity.
"The trial supports the concept that angiogenesis is a valuable target in ovarian cancer," wrote Dr. Andreas du Bois, in an email to Reuters Health. At this point, however, it's not clear whether the company will try to register the drug for ovarian cancer, he said. It is approved for lung cancer treatment.
In a paper online November 15 in Lancet Oncology, Dr. du Bois of Oslo University Hospital in Norway and colleagues reported on 1,366 women with International Federation of Gynecology and Obstetrics (FIGO) stage IIIB-IV ovarian cancer and upfront debulking who were randomly assigned to receive standard carboplatin and paclitaxel chemotherapy protocols with or without nintedanib.
Nine study groups in 22 countries participated.
Median progression-free survival was about two weeks longer with nintedanib vs placebo (17.2 vs 16.6 months; p=0.024).
"There will be another analysis focusing on overall survival," Dr. du Bois told Reuters Health. "It is not mature yet."
Post hoc analyses revealed that women with low postoperative tumor burden saw the largest benefit in progression-free survival. In this non-high-risk subgroup, median progression-free survival was 27.1 months with nintedanib, compared to 20.8 months with placebo.
Gastrointestinal side effects occurred in 21% in the nintedanib group vs 2% in the placebo group.
Rates of grade 3 and grade 4 neutropenia were 20% and 22%, respectively, with nintedanib and 20% and 16% with placebo.
Serious adverse events occurred in 42% of the nintedanib group and 34% of the placebo group. The rate of adverse events leading to death were 3% with nintedanib and 4% with placebo.
The high rate of adverse GI events "demands more attention and needs further optimization," Dr. du Bois said. "However, the rate of patients stopping the drug completely was not so high, indicating that dose modifications and pauses may be an appropriate way to improve tolerability."
Dr. Charles Drescher of the Fred Hutchinson Cancer Research Center at the University of Washington in Seattle, who was not involved in the research, told Reuters Health, "Similar to prior trials, it is demonstrating some activity for anti-angiogenesis effect. However, the effectiveness is pretty modest and not a huge impact."
He added: "You have to balance that against the GI toxicity and the cost of the drug."
In a comment published with the paper, Dr. Sean Kehoe from the Institute of Cancer and Genomics at the University of Birmingham, UK, points to the "intriguing" finding that "women at lower risk of progression or lower postsurgical tumor burden who were in the nintedanib group had a longer median progression-free survival."
Dr. Kehoe contrasts this with findings from the ICON7 trial of bevacizumab added to upfront therapy, in which women with larger tumor burden or stage IV disease had improved overall survival.
"Besides the different drugs used, how can this difference be explained?" Dr. Kehoe asks. He suggests, as does Dr. du Bois, that patients with stage IV cancer in ICON7 might have been reclassified in this trial as low-risk after tumor clearance.
The study was funded by Boehringer Ingelheim.
Lancet Oncol 2015.