Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial.
Publication/Presentation Date
1-1-2016
Abstract
BACKGROUND: Angiogenesis is a target in the treatment of ovarian cancer. Nintedanib, an oral triple angiokinase inhibitor of VEGF receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, has shown activity in phase 2 trials in this setting. We investigated the combination of nintedanib with standard carboplatin and paclitaxel chemotherapy in patients with newly diagnosed advanced ovarian cancer.
METHODS: In this double-blind phase 3 trial, chemotherapy-naive patients (aged 18 years or older) with International Federation of Gynecology and Obstetrics (FIGO) IIB-IV ovarian cancer and upfront debulking surgery were stratified by postoperative resection status, FIGO stage, and planned carboplatin dose. Patients were randomly assigned (2:1) via an interactive voice or web-based response system to receive six cycles of carboplatin (AUC 5 mg/mL per min or 6 mg/mL per min) and paclitaxel (175 mg/m(2)) in addition to either 200 mg of nintedanib (nintedanib group) or placebo (placebo group) twice daily on days 2-21 of every 3-week cycle for up to 120 weeks. Patients, investigators, and independent radiological reviewers were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01015118.
FINDINGS: Between Dec 9, 2009, and July 27, 2011, 1503 patients were screened and 1366 randomly assigned by nine study groups in 22 countries: 911 to the nintedanib group and 455 to the placebo group. 486 (53%) of 911 patients in the nintedanib group experienced disease progression or death compared with 266 (58%) of 455 in the placebo group. Median progression-free survival was significantly longer in the nintedanib group than in the placebo group (17·2 months [95% CI 16·6-19·9] vs 16·6 months [13·9-19·1]; hazard ratio 0·84 [95% CI 0·72-0·98]; p=0·024). The most common adverse events were gastrointestinal (diarrhoea: nintedanib group 191 [21%] of 902 grade 3 and three [
INTERPRETATION: 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.
FUNDING: Boehringer Ingelheim.
Volume
17
Issue
1
First Page
78
Last Page
89
ISSN
1474-5488
Published In/Presented At
du Bois, A., Kristensen, G., Ray-Coquard, I., Reuss, A., Pignata, S., Colombo, N., Denison, U., Vergote, I., Del Campo, J. M., Ottevanger, P., Heubner, M., Minarik, T., Sevin, E., de Gregorio, N., Bidziński, M., Pfisterer, J., Malander, S., Hilpert, F., Mirza, M. R., Scambia, G., … AGO Study Group led Gynecologic Cancer Intergroup/European Network of Gynaecologic Oncology Trials Groups Intergroup Consortium (2016). Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial. The Lancet. Oncology, 17(1), 78–89. https://doi.org/10.1016/S1470-2045(15)00366-6
Disciplines
Medicine and Health Sciences
PubMedID
26590673
Department(s)
Department of Obstetrics and Gynecology
Document Type
Article