European Trial Shows Front-Line Addition of Nintedanib to Standard Chemotherapy Improves Progression-Free Survival in Advanced Ovarian Cancer
In a European phase III trial (AGO-OVAR 12) reported in The Lancet Oncology, du Bois et al found that adding the antiangiogenic multikinase inhibitor nintedanib (Ofev) to carboplatin/paclitaxel improved progression-free survival in patients with newly diagnosed ovarian cancer. Gastrointestinal toxicity was increased with nintedanib, which inhibits vascular endothelial growth factor receptors 1, 2, and 3; fibroblast growth factor receptors; and platelet-derived growth factor receptors α and β.
Study Details
In the double-blind trial, 1,366 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIB to IV disease from 22 countries were randomly assigned 2:1 between December 2009 and July 2011 to receive five cycles of carboplatin (AUC [area under the receiver operating characteristic curve] 5 mg/mL/min or 6 mg/mL/min) and paclitaxel (175 mg/m²) in addition to either 200 mg of nintedanib (n = 911) or placebo (n = 455) twice daily on days 2 to 21 of every 3-week cycle for up to 120 weeks.
The primary endpoint was investigator-assessed progression-free survival in the intent-to-treat population.
Progression-Free Survival
After a median follow-up of 22.4 months, disease progression or death had occurred in 53% of the nintedanib group vs 58% of the control group; median progression-free survival was 17.2 months (95% confidence interval [CI] = 16.6–19.9 months) vs 16.6 months (95% CI = 13.9–19.1 months), yielding a hazard ratio (HR) of 0.84 (P = .024). A sensitivity analysis based on an independent central review involving approximately 80 fewer events showed median progression-free survival of 19.5 vs 16.8 months (HR = 0.86, P = .068).
On subgroup analyses, nintedanib was associated with a significant progression-free survival benefit among 1,034 patients with FIGO stage IIB to III disease (22.1 vs 18.5 months, HR = 0.76, 95% CI = 0.63–0.91), among 931 with a planned carboplatin dose of AUC 5 mg/mL/min (17.0 vs 14.1 months, HR = 0.83, 95% CI = 0.69–0.99). In a post hoc analysis, among 839 patients with non–high-risk disease, defined as FIGO stage III and postoperative residuals ≤ 1 cm or stage II (27.1 vs 20.8 months, HR = 0.74, 95% CI = 0.61–0.91).
Adverse Events
The most common adverse events were gastrointestinal, including grade 3 and 4 diarrhea in 21% and < 1% of the nintedanib group vs 2% and 0% of the placebo group, and hematologic, including grade 3 or 4 neutropenia in 42% vs 36%, thrombocytopenia in 18% vs 7%, and anemia in 13% vs 7%. Serious adverse events occurred in 42% vs 34%. Drug-related adverse events led to death in three patients vs one patient.
The investigators concluded: “Nintedanib in combination with carboplatin and paclitaxel is an active first-line treatment that significantly increases progression-free survival for women with advanced ovarian cancer, but is associated with more gastrointestinal adverse events. Future studies should focus on improving patient selection and optimisation of tolerability.”
Andreas du Bois, MD, of Kliniken Essen-Mitte, Germany, is the corresponding author of The Lancet Oncology article.
The study was funded by Boehringer Ingelheim.
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