Bevacizumab and platinum-based combinations for recurrent ovarian cancer: a randomised, open-label, phase 3 trial.

Abstract

BACKGROUND:

State-of-the art therapy for recurrent ovarian cancer suitable for platinum-based re-treatment includes bevacizumab-containing combinations (eg, bevacizumab combined with carboplatin-paclitaxel or carboplatin-gemcitabine) or the most active non-bevacizumab regimen: carboplatin-pegylated liposomal doxorubicin. The aim of this head-to-head trial was to compare a standard bevacizumab-containing regimen versus carboplatin-pegylated liposomal doxorubicin combined with bevacizumab.

METHODS:

This multicentre, open-label, randomised, phase 3 trial, was done in 159 academic centres in Germany, France, Australia, Austria, and the UK. Eligible patients (aged ≥18 years) had histologically confirmed epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with first disease recurrence more than 6 months after first-line platinum-based chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were stratified by platinum-free interval, residual tumour, previous antiangiogenic therapy, and study group language, and were centrally randomly assigned 1:1 using randomly permuted blocks of size two, four, or six to receive six intravenous cycles of bevacizumab (15 mg/kg, day 1) plus carboplatin (area under the concentration curve [AUC] 4, day 1) plus gemcitabine (1000 mg/m2, days 1 and 8) every 3 weeks or six cycles of bevacizumab (10 mg/kg, days 1 and 15) plus carboplatin (AUC 5, day 1) plus pegylated liposomal doxorubicin (30 mg/m2, day 1) every 4 weeks, both followed by maintenance bevacizumab (15 mg/kg every 3 weeks in both groups) until disease progression or unacceptable toxicity. There was no masking in this open-label trial. The primary endpoint was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy data were analysed in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug. This completed study is registered with ClinicalTrials.gov, NCT01837251.

FINDINGS:

Between Aug 1, 2013, and July 31, 2015, 682 eligible patients were enrolled, of whom 345 were randomly assigned to receive carboplatin-pegylated liposomal doxorubicin-bevacizumab (experimental group) and 337 were randomly assigned to receive carboplatin-gemcitabine-bevacizumab (standard group). Median follow-up for progression-free survival at data cutoff (July 10, 2018) was 12·4 months (IQR 8·3-21·7) in the experimental group and 11·3 months (8·0-18·4) in the standard group. Median progression-free survival was 13·3 months (95% CI 11·7-14·2) in the experimental group versus 11·6 months (11·0-12·7) in the standard group (hazard ratio 0·81, 95% CI 0·68-0·96; p=0·012). The most common grade 3 or 4 adverse events were hypertension (88 [27%] of 332 patients in the experimental group vs 67 [20%] of 329 patients in the standard group) and neutropenia (40 [12%] vs 73 [22%]). Serious adverse events occurred in 33 (10%) of 332 patients in the experimental group and 28 (9%) of 329 in the standard group. Treatment-related deaths occurred in one patient in the experimental group (<1%; large intestine perforation) and two patients in the standard group (1%; one case each of osmotic demyelination syndrome and intracranial haemorrhage).

INTERPRETATION:

Carboplatin-pegylated liposomal doxorubicin-bevacizumab is a new standard treatment option for platinum-eligible recurrent ovarian cancer.

FUNDING:

F Hoffmann-La Roche.

• Authors: Jacobus Pfisterer, Catherine M Shannon, Klaus Baumann, Joern Rau, Philipp Harter, Florence Joly, Jalid Sehouli, Ulrich Canzler, Barbara Schmalfeldt, Andrew P Dean, Alexander Hein, Alain G Zeimet, Lars C Hanker, Thierry Petit, Frederik Marmé, Ahmed El-Balat, Rosalind Glasspool, Nikolaus de Gregorio, Sven Mahner, Tarek M Meniawy, Tjoung-Won Park-Simon, Marie-Ange Mouret-Reynier, Cristina Costan, Werner Meier, Alexander Reinthaller, Jeffrey C Goh, Tifenn L'Haridon, Sally Baron Hay, Stefan Kommoss, Andreas du Bois, Jean-Emmanuel Kurtz, AGO-OVAR 2.21/ENGOT-ov 18 Investigators
• Journal: The Lancet. Oncology (Lancet Oncol) Vol. 21 Issue 5 Pg. 699-709 (05 2020) ISSN: 1474-5488 [Electronic] England
• PMID: 32305099 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• liposomal doxorubicin
• Bevacizumab
• Polyethylene Glycols
• Platinum
• Doxorubicin
• Carboplatin
• Paclitaxel

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Australia (epidemiology)
• Austria (epidemiology)
• Bevacizumab (administration & dosage, adverse effects)
• Carboplatin (administration & dosage, adverse effects)
• Doxorubicin (administration & dosage, analogs & derivatives)
• Fallopian Tube Neoplasms (drug therapy, pathology)
• Female
• France (epidemiology)
• Humans
• Middle Aged
• Neoplasm Recurrence, Local (drug therapy, pathology)
• Ovarian Neoplasms (drug therapy, pathology)
• Paclitaxel (administration & dosage, adverse effects)
• Platinum (administration & dosage, adverse effects)
• Polyethylene Glycols (administration & dosage)