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

Adult Aged Antineoplastic Combined Chemotherapy Protocols / administration & dosage Australia / epidemiology Austria / epidemiology Bevacizumab / administration & dosage Carboplatin / administration & dosage Doxorubicin / administration & dosage Fallopian Tube Neoplasms / drug therapy Female France / epidemiology Humans Middle Aged Neoplasm Recurrence, Local / drug therapy Ovarian Neoplasms / drug therapy Paclitaxel / administration & dosage Platinum / administration & dosage Polyethylene Glycols / administration & dosage

Journal

The Lancet. Oncology

ISSN: 1474-5488

Titre abrégé: Lancet Oncol

Pays: England

ID NLM: 100957246

Informations de publication

Date de publication:
05 2020

Historique:

received: 09 01 2020

revised: 16 02 2020

accepted: 17 02 2020

pubmed: 20 4 2020

medline: 10 7 2020

entrez: 20 4 2020

Statut: ppublish

Résumé

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. 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/m 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). Carboplatin-pegylated liposomal doxorubicin-bevacizumab is a new standard treatment option for platinum-eligible recurrent ovarian cancer. F Hoffmann-La Roche.

Sections du résumé

BACKGROUND

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/m

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.

Identifiants

DOI: 10.1016/S1470-2045(20)30142-X PMID: 32305099

pubmed: 32305099

pii: S1470-2045(20)30142-X

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

pii:

doi:

Substances chimiques

liposomal doxorubicin 0

Bevacizumab 2S9ZZM9Q9V

Polyethylene Glycols 3WJQ0SDW1A

Platinum 49DFR088MY

Doxorubicin 80168379AG

Carboplatin BG3F62OND5

Paclitaxel P88XT4IS4D

Banques de données

ClinicalTrials.gov

['NCT01837251']

Types de publication

Clinical Trial, Phase III Journal Article Randomized Controlled Trial Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

699-709

Investigateurs

Sven Ackermann (S)

Christoph Anthuber (C)

Mustafa Aydogdu (M)

Angelika Baldauf (A)

Wolfgang Bauer (W)

Dirk Behringer (D)

Antje Belau (A)

Alexandra Bender (A)

Cosima Brucker (C)

Alexander Burges (A)

Ulrich Canzler (U)

Trygve Daabach (T)

Dominik Denschlag (D)

Mustafa Deryal (M)

Steffen Dörfel (S)

Juliane Ebert (J)

Ahmed El-Balat (A)

Tanja Fehm (T)

Susanne Maria Feidicker (SM)

Gabriele Feisel-Schwickardi (G)

Ricardo Felberbaum (R)

Matthias Frank (M)

Gerhard Gebauer (G)

Bernd Gerber (B)

Axel Gerhardt (A)

Andrea Grafe (A)

Martin Griesshammer (M)

Eva-Maria Grischke (EM)

Isolde Gröll (I)

Martina Gropp-Meier (M)

Dietrich Hager (D)

Volker Hanf (V)

Carla Verena Hannig (CV)

Peer Hantschmann (P)

Philipp Harter (P)

Tanja Hauzenberger (T)

Uwe Herwig (U)

Martin Heubner (M)

Carsten Hielscher (C)

Felix Hilpert (F)

Thomas Hitschold (T)

Manfred Hofmann (M)

Christian Jackisch (C)

Wolfgang Janni (W)

Ludwig Kiesel (L)

Yon-Dschun Ko (YD)

Hans-Joachim Koch (HJ)

Petra Krabisch (P)

Peter Krieger (P)

Thomas Kubin (T)

Thorsten Kühn (T)

Björn Lampe (B)

Peter Ledwon (P)

Sabine Lemster (S)

Benno Lex (B)

Clemens Liebrich (C)

Ralf Lorenz (R)

Hans-Joachim Lück (HJ)

Sven Mahner (S)

Peter Mallmann (P)

Frederik Marmé (F)

Werner Meier (W)

Wolfgang Meinerz (W)

Götz Menke (G)

Volker Möbus (V)

Thomas Müller (T)

Volker Müller (V)

Tanja Neunhöffer (T)

Angelika Ober (A)

Gülten Oskay-Özcelik (G)

Horst Ostertag (H)

Tjoung-Won Park-Simon (TW)

Martin Pölcher (M)

Beate Rautenberg (B)

Daniel Rein (D)

Wilhelm Reiter (W)

Andreas Rempen (A)

Ingo Runnebaum (I)

Barbara Schmalfeldt (B)

Marcus Schmidt (M)

Sabine Schnohr (S)

Heinz Scholz (H)

Willibald Schröder (W)

Jalid Sehouli (J)

Eike Simon (E)

Antje Sperfeld (A)

Annette Steckkönig (A)

Hans-Georg Strauß (HG)

Ronaldo Stuth (R)

Jürgen Terhaag (J)

Falk Thiel (F)

Marc Thill (M)

Oliver Tomé (O)

Christoph Uleer (C)

Susanne Vogel (S)

Hermann Voß (H)

Michael Weigel (M)

Ulrich Winkler (U)

Arthur Wischnik (A)

Tobias Zeiser (T)

Andreas Zorr (A)

Ros Glasspool (R)

Emma Hudson (E)

Rachel Jones (R)

Judith Lafleur (J)

Christian Marth (C)

Edgar Petru (E)

Alexander Reinthaller (A)

Yoland Antill (Y)

Mary Azer (M)

Sally Baron-Hay (S)

Philip Beale (P)

Stephen Begbie (S)

Allison Black (A)

Karen Briscoe (K)

Andrew Dean (A)

Jeffrey Goh (J)

Sandra Harvey (S)

Chee Lee (C)

Marco Matos (M)

Tarek Meniawy (T)

Inger Olesen (I)

Catherine Shannon (C)

Paul Vasey (P)

Sophie Abadie-Lacourtoisie (S)

Olivier Arsene (O)

Sophie Barthier (S)

Célia Becuwe-Roemer (C)

Dominique Berton-Rigaud (D)

Maria Cappiello-Bataller (M)

Stéphanie Catala (S)

Cristina Costan (C)

Francesco Del Piano (F)

Gaël Deplanque (G)

Raymond Despax (R)

Nadine Dohollou (N)

Claire Garnier-Tixidré (C)

Julien Grenier (J)

Emmanuel Guardiola (E)

Anne-Claire Hardy-Bessard (AC)

Florence Joly (F)

Jean-Emmanuel Kurtz (JE)

Claudia Lefeuvre-Plesse (C)

Marianne Leheurteur (M)

Anne Lesoin (A)

Charles-Briac Levache (CB)

Tifenn L'Haridon (T)

Raffaele Longo (R)

Alain Lortholary (A)

Jérôme Meunier (J)

Marie-Ange Mouret-Reynier (MA)

Thierry Petit (T)

Nadia Raban (N)

Olivier Romano (O)

Jean-Michel Vannetzel (JM)

Alain Zannetti (A)

Commentaires et corrections

Type : CommentIn

Type : ErratumIn