Bevacizumab and platinum-based combinations for recurrent ovarian cancer: a randomised, open-label, phase 3 trial - 18/04/20

Doi : 10.1016/S1470-2045(20)30142-X

Jacobus Pfisterer, ProfMD ^a,⁎ , Catherine M Shannon, MBBS ^b, Klaus Baumann, MD ^c, Joern Rau, MSc ^d, Philipp Harter, MD ^e, Florence Joly, ProfMD ^f, Jalid Sehouli, ProfMD ^g, Ulrich Canzler, MD ^h, Barbara Schmalfeldt, ProfMD ^i,^j, Andrew P Dean, MD ^k, Alexander Hein, MD ^l, Alain G Zeimet, ProfMD ^m, Lars C Hanker, MD ⁿ, Thierry Petit, ProfMD ^o, Frederik Marmé, ProfMD ^p,^q, Ahmed El-Balat, MD ^r, Rosalind Glasspool, MD ^s, Nikolaus de Gregorio, MD ^t, Sven Mahner, ProfMD ^j,^u, Tarek M Meniawy, MD ^v, Tjoung-Won Park-Simon, ProfMD ^w, Marie-Ange Mouret-Reynier, MD ^x, Cristina Costan, MD ^y, Werner Meier, ProfMD ^z,^aa, Alexander Reinthaller, ProfMD ^ab, Jeffrey C Goh, MD ^ac, Tifenn L’Haridon, MD ^ad, Sally Baron Hay, MD ^ae, Stefan Kommoss, ProfMD ^af, Andreas du Bois, ProfMD ^e, Jean-Emmanuel Kurtz, ProfMD ^ag
for the
AGO-OVAR 2.21/ENGOT-ov 18 Investigators^{^†}
A complete list of the investigators is provided in the Supplementary Material

Sven Ackermann, Christoph Anthuber, Mustafa Aydogdu, Angelika Baldauf, Wolfgang Bauer, Dirk Behringer, Antje Belau, Alexandra Bender, Cosima Brucker, Alexander Burges, Ulrich Canzler, Trygve Daabach, Dominik Denschlag, Mustafa Deryal, Steffen Dörfel, Juliane Ebert, Ahmed El-Balat, Tanja Fehm, Susanne Maria Feidicker, Gabriele Feisel-Schwickardi, Ricardo Felberbaum, Matthias Frank, Gerhard Gebauer, Bernd Gerber, Axel Gerhardt, Andrea Grafe, Martin Griesshammer, Eva-Maria Grischke, Isolde Gröll, Martina Gropp-Meier, Dietrich Hager, Volker Hanf, Carla Verena Hannig, Peer Hantschmann, Philipp Harter, Tanja Hauzenberger, Uwe Herwig, Martin Heubner, Carsten Hielscher, Felix Hilpert, Thomas Hitschold, Manfred Hofmann, Christian Jackisch, Wolfgang Janni, Ludwig Kiesel, Yon-Dschun Ko, Hans-Joachim Koch, Petra Krabisch, Peter Krieger, Thomas Kubin, Thorsten Kühn, Björn Lampe, Peter Ledwon, Sabine Lemster, Benno Lex, Clemens Liebrich, Ralf Lorenz, Hans-Joachim Lück, Sven Mahner, Peter Mallmann, Frederik Marmé, Werner Meier, Wolfgang Meinerz, Götz Menke, Volker Möbus, Thomas Müller, Volker Müller, Tanja Neunhöffer, Angelika Ober, Gülten Oskay-Özcelik, Horst Ostertag, Tjoung-Won Park-Simon, Martin Pölcher, Beate Rautenberg, Daniel Rein, Wilhelm Reiter, Andreas Rempen, Ingo Runnebaum, Barbara Schmalfeldt, Marcus Schmidt, Sabine Schnohr, Heinz Scholz, Willibald Schröder, Jalid Sehouli, Eike Simon, Antje Sperfeld, Annette Steckkönig, Hans-Georg Strauß, Ronaldo Stuth, Jürgen Terhaag, Falk Thiel, Marc Thill, Oliver Tomé, Christoph Uleer, Susanne Vogel, Hermann Voß, Michael Weigel, Ulrich Winkler, Arthur Wischnik, Tobias Zeiser, Andreas Zorr, Ros Glasspool, Emma Hudson, Rachel Jones, Judith Lafleur, Christian Marth, Edgar Petru, Alexander Reinthaller, Yoland Antill, Mary Azer, Sally Baron-Hay, Philip Beale, Stephen Begbie, Allison Black, Karen Briscoe, Andrew Dean, Jeffrey Goh, Sandra Harvey, Chee Lee, Marco Matos, Tarek Meniawy, Inger Olesen, Catherine Shannon, Paul Vasey, Sophie Abadie-Lacourtoisie, Olivier Arsene, Sophie Barthier, Célia Becuwe-Roemer, Dominique Berton-Rigaud, Maria Cappiello-Bataller, Stéphanie Catala, Cristina Costan, Francesco Del Piano, Gaël Deplanque, Raymond Despax, Nadine Dohollou, Claire Garnier-Tixidré, Julien Grenier, Emmanuel Guardiola, Anne-Claire Hardy-Bessard, Florence Joly, Jean-Emmanuel Kurtz, Claudia Lefeuvre-Plesse, Marianne Leheurteur, Anne Lesoin, Charles-Briac Levache, Tifenn L’Haridon, Raffaele Longo, Alain Lortholary, Jérôme Meunier, Marie-Ange Mouret-Reynier, Thierry Petit, Nadia Raban, Olivier Romano, Jean-Michel Vannetzel, Alain Zannetti

^a Gynaecologic Oncology Center, Kiel, Germany

^b Oncology Department, Mater Cancer Care Centre, Brisbane, QLD, Australia

^c Gynaecology Department, Klinikum der Stadt Ludwigshafen am Rhein, Ludwigshafen, Germany

^d Coordinating Center for Clinical Trials, Philipps-University, Marburg, Germany

^e Department of Gynecology and Gynecological Oncology, Kliniken Essen-Mitte, Essen, Germany

^f Gynaecology Department, Centre François Baclesse, Caen, France

^g Department of Gynaecology, and European Competence Center for Ovarian Cancer, Charité – Universitätsmedizin Berlin, Campus Virchow, Berlin, Germany

^h Department of Gynaecology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

ⁱ Technical University of Munich–Klinikum Rechts der Isar, Germany

^j Department of Gynaecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

^k Gynaecological Oncology Department, St John of God Hospital, Subiaco, WA, Australia

^l Gynaecology Department, Erlangen University Hospital, Erlangen, Germany

^m Department of Obstetrics and Gynaecology, Innsbruck Medical University, Innsbruck, Austria

ⁿ Gynaecology Department, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany

^o Paul Strauss Cancer Center and Gynaecology Department, University of Strasbourg, Strasbourg, France

^p Gynaecology Department, National Center for Tumor Disease, University of Heidelberg, Heidelberg, Germany

^q Department of Gynaecology and Obstetrics, University Hospital Mannheim, Mannheim, Germany

^r Department of Gynaecology and Obstetrics, University of Frankfurt/Main, Frankfurt, Germany

^s National Cancer Research Institute, Beatson West of Scotland Cancer Centre and University of Glasgow, Glasgow, UK

^t Department of Obstetrics and Gynaecology, University of Ulm, Ulm, Germany

^u Department of Obstetrics and Gynaecology, University Hospital, Ludwig-Maximilian-University, Munich, Germany

^v Department of Medical Oncology, Sir Charles Gairdner Hospital, Perth, WA, Australia

^w Department of Gynaecology and Obstetrics, Medical University Hannover, Hannover, Germany

^x Department of Medical Oncology, Centre Jean Perrin, Clermont-Ferrand, France

^y Department of Oncology, Hôpital Michallon, Grenoble, France

^z Department of Gynaecology and Obstetrics, Evangelisches Krankenhaus Düsseldorf, Germany

^aa Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Düsseldorf, Germany

^ab Department of Gynecology and Gynecologic Oncology, Comprehensive Cancer Centre, University Hospital for Gynaecology, Medical University Vienna, Vienna, Austria

^ac Royal Brisbane & Women’s Hospital, Brisbane, QLD, Australia

^ad Centre Hospitalier Départemental les Oudairies, La Roche-Sur-Yon, France

^ae Women’s Health, Royal North Shore Hospital, Sydney, NSW, Australia

^af Department of Women’s Health, Tübingen University Hospital, Tübingen, Germany

^ag Haematology–Oncology Department, Centre Hospitalier Régional et Universitaire de Strasbourg Hôpital Civil, Strasbourg, France

^* Correspondence to: Prof Jacobus Pfisterer, Gynecologic Oncology Center, 24103, Kiel, Germany Gynecologic Oncology Center Kiel 24103 Germany

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Summary

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).