Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): A randomised, double-blind, placebo-controlled phase 3 trial

Giovanni Scambia, Andreas Du Bois, Gunnar Kristensen, Isabelle Ray-Coquard, Alexander Reuss, Sandro Pignata, Nicoletta Colombo, Ursula Denison, Ignace Vergote, Jose M Del Campo, Petronella Ottevanger, Martin Heubner, Thomas Minarik, Emmanuel Sevin, Nikolaus De Gregorio, Mariusz Bidziński, Jacobus Pfisterer, Susanne Malander, Felix Hilpert, Werner MeierMaria O Nicoletto, Line Bjørge, Alain Lortholary, Martin Oliver Sailer, Michael Merger, Philipp Harter

Risultato della ricerca: Contributo in rivistaArticolo in rivista

132 Citazioni (Scopus)

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/m2) 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 [<1%] grade 4 vs placebo group nine [2%] of 450 grade 3 only) and haematological (neutropenia: nintedanib group 180 [20%] grade 3 and 200 (22%) grade 4 vs placebo group 90 [20%] grade 3 and 72 [16%] grade 4; thrombocytopenia: 105 [12%] and 55 [6%] vs 21 [5%] and eight [2%]; anaemia: 108 [12%] and 13 [1%] vs 26 [6%] and five [1%]). Serious adverse events were reported in 376 (42%) of 902 patients in the nintedanib group and 155 (34%) of 450 in the placebo group. 29 (3%) of 902 patients in the nintedanib group experienced serious adverse events associated with death compared with 16 (4%) of 450 in the placebo group, including 12 (1%) in the nintedanib group and six (1%) in the placebo group with a malignant neoplasm progression classified as an adverse event by the investigator. Drug-related adverse events leading to death occurred in three patients in the nintedanib group (one without diagnosis of cause; one due to non-drug-related sepsis associated with drug-related diarrhoea and renal failure; and one due to peritonitis) and in one patient in the placebo group (cause unknown). 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.
Lingua originaleEnglish
pagine (da-a)78-89
Numero di pagine12
RivistaLANCET ONCOLOGY
Volume17
DOI
Stato di pubblicazionePubblicato - 2016

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Anemia
  • Antineoplastic Combined Chemotherapy Protocols
  • Carboplatin
  • Carcinoma
  • Cytoreduction Surgical Procedures
  • Diarrhea
  • Disease Progression
  • Disease-Free Survival
  • Double-Blind Method
  • Fallopian Tube Neoplasms
  • Female
  • Humans
  • Indoles
  • Intention to Treat Analysis
  • Medicine (all)
  • Middle Aged
  • Neoplasm Staging
  • Neutropenia
  • Oncology
  • Ovarian Neoplasms
  • Paclitaxel
  • Peritoneal Neoplasms
  • Response Evaluation Criteria in Solid Tumors
  • Thrombocytopenia
  • Young Adult

Fingerprint Entra nei temi di ricerca di 'Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): A randomised, double-blind, placebo-controlled phase 3 trial'. Insieme formano una fingerprint unica.

Cita questo