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.
| Original language | English |
|---|---|
| Journal | The Lancet Oncology |
| Volume | 21 |
| Issue number | 5 |
| Pages (from-to) | 699-709 |
| Number of pages | 11 |
| ISSN | 1470-2045 |
| DOIs | |
| Publication status | Published - 05.2020 |
Funding
The trial was done according to ENGOT model A. 17 The sponsor (AGO Study Group, represented by JP) was responsible for writing this Article with the support of a medical writer (funded by F Hoffmann-La Roche). The funder of the study had no role in study design, data collection, data analysis, or data interpretation. All authors had full access to the data; JP had the final responsibility to submit for publication. JP reports grants, personal fees, and non-financial support from F Hoffmann-La Roche, during the conduct of the study; grants, personal fees, and non-financial support from AstraZeneca and Tesaro outside the submitted work; personal fees and non-financial support from Amgen outside the submitted work; and personal fees from Clovis, Merck Sharp and Dohme, and PharmaMar outside the submitted work. PH reports grants and personal fees from Roche during the conduct of the study; grants and personal fees from AstraZeneca, Tesaro, and public funding bodies (American Society of Clinical Oncology, Deutschen Krebshilfe [German Cancer Aid], Deutsche Forschungsgemeinschaft) outside the submitted work; grants from GlaxoSmithKline, Boehringer Ingelheim, Medac, and Genmab outside the submitted work; and personal fees from Sotio, Stryker, Zai Lab, Merck Sharp and Dohme, Clovis, and Immunogen outside the submitted work. FJ reports personal fees and non-financial support from Roche, Tesaro, Bristol-Myers Squibb, Merck Sharp and Dohme, Janssen, Ipsen, and Pfizer; grants, personal fees, and non-financial support from AstraZeneca; and grants and personal fees from Astellas, all outside the submitted work. JS reports personal fees from Roche; grants and personal fees from Lilly; and personal fees from Johnson and Johnson, all outside the submitted work. UC reports personal fees from AstraZeneca, Roche, and Lilly, all outside the submitted work. FM reports personal fees and research funding from Roche during the conduct of the study; personal fees and research funding from AstraZeneca, Pfizer, Tesaro, and Novartis outside the submitted work; and personal fees from Amgen, PharmaMar, Genomic Health, CureVac, Eisai, and Celgene outside the submitted work. AE-B reports personal fees from Roche, AstraZeneca, Tesaro, Clovis, PharmaMar, Merck Sharp and Dohme, and Olympus outside the submitted work. RG reports personal fees and non-financial support from Roche, Clovis Oncology, Tesaro, and AstraZeneca outside the submitted work; personal fees from Immunogen and Sotio outside the submitted work; grants from Boehringer Ingelheim and Lilly/Ignyta outside the submitted work; and site principal investigator roles for clinical trials run by Tesaro, AstraZeneca, Immunogen, and Lilly outside the submitted work. NdG reports personal fees and travel expenses for advisory boards from Tesaro, AstraZeneca, and Roche and personal fees for advisory boards from PharmaMar and Clovis, all outside the submitted work. SM reports grants and personal fees from AstraZeneca, Roche, and Tesaro, and personal fees from Clovis during the conduct of the study; grants and personal fees from Medac, Merck Sharp and Dohme, PharmaMar, and Teva outside the submitted work; and personal fees from Novartis, Olympus Europa, and Sensor Kinesis outside the submitted work. TMM reports a grant from Roche during the conduct of the study. T-WP-S reports reimbursement from AGO during the conduct of the study, and personal fees for lectures from Roche, AstraZeneca, and Tesaro outside the submitted work. AR reports research grants from Roche; speaker and advisory board honoraria from Amgen, AstraZeneca, Merck Sharp and Dohme, PharmaMar, Roche, Tesaro, and Vifor Pharma; and travel expenses from Amgen, AstraZeneca, PharmaMar, Roche, and Tesaro outside the submitted work. JCG reports personal fees from AstraZeneca, Merck Sharp and Dohme, Ipsen, Tesaro, and MundiPharma; and sponsorship to attend international congresses from Bristol-Myers Squibb, Astellas, and Roche, all outside the submitted work. SK reports personal fees from Roche, Tesaro, PharmaMar, Clovis, and AstraZeneca outside the submitted work. AdB reports personal fees for advisory boards from AstraZeneca, Tesaro, Clovis, Roche, Biocad, Pfizer, and Genmab outside the submitted work. J-EK reports personal fees and travel expenses for advisory boards from Tesaro and AstraZeneca, personal fees for advisory boards from PharmaMar and Clovis, and travel expenses from Roche outside the submitted work. All other authors declare no competing interests. The study was done by the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) Study Group (JP, KB, JR, PH, AdB, JS, UC, BS, SM, AH, LCH, FM, AE-B, NdG, T-WP-S, WM, and SK), AGO Austria (AGZ, AR), the Australia New Zealand Gynaecological Oncology Group (CMS, APD, TMM, JCG, and SBH), Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (FJ, TP, M-AM-R, CC, TL'H, and J-EK), and the Scottish Gynaecological Cancer Trials Group (RG) according to ENGOT model A with financial support and drug provided by F Hoffmann-La Roche. In the UK the trial was supported by Cancer Research UK Award Reference: C8361/A17611. The authors thank all patients and their families, the study investigators ( appendix ), the staff from the participating study groups, the Coordinating Center for Clinical Trials, members of the Independent Data Monitoring Committee, F Hoffmann-La Roche for funding the trial, the Cancer Research UK Clinical Trials Unit, Glasgow, for co-ordinating the trial in the UK, and NHS Greater Glasgow and Clyde for sponsoring the trial in the UK. The authors also acknowledge Jennifer Kelly (Medi-Kelsey Ltd; Ashbourne, UK), for medical writing assistance, funded by an unrestricted grant from F Hoffmann-La Roche. The current affiliation for BS is Gynaecology Department, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; for FM is Department of Gynaecology and Obstetrics, University Hospital Mannheim, Mannheim, Germany; for SM is Department of Obstetrics and Gynaecology, University Hospital, Ludwig-Maximilian-University, Munich, Germany; and for WM is Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Düsseldorf, Germany.
Research Areas and Centers
- Research Area: Luebeck Integrated Oncology Network (LION)
- Centers: University Cancer Center Schleswig-Holstein (UCCSH)
