TY - JOUR
T1 - Effect of Weekly Paclitaxel with or without Bevacizumab on Progression-Free Rate among Patients with Relapsed Ovarian Sex Cord-Stromal Tumors
T2 - The ALIENOR/ENGOT-ov7 Randomized Clinical Trial
AU - Ray-Coquard, Isabelle
AU - Harter, Philipp
AU - Lorusso, Domenica
AU - Dalban, Cécile
AU - Vergote, Ignace
AU - Fujiwara, Keiichi
AU - Gladieff, Laurence
AU - Lück, Hans Joachim
AU - Floquet, Anne
AU - Chevalier-Place, Annick
AU - Schnelzer, Andreas
AU - Pignata, Sandro
AU - Selle, Frédéric
AU - Sehouli, Jalid
AU - Brocard, Fabien
AU - Mangili, Giorgia
AU - Pautier, Patricia
AU - De Giorgi, Ugo
AU - Provansal, Magali
AU - Heudel, Pierre Etienne
N1 - Funding Information:
Claudius Regaud, IUCT-Oncopole, Toulouse, France (Gladieff);AGOStudyGroupandGyneco-Oncological Practice, Hannover, Germany (Lück); GINECO and InstitutBergonié,Bordeaux,France(Floquet);GINECO and Centre Oscar Lambret, Lille, France (Chevalier-Place);AGOStudyGroupandFrauenklinik Technical University Munich, Munich, Germany (Schnelzer); Current, RoMed Klinikum Rosenheim, Rosenheim, Germany (Schnelzer); MITO and Department of Urology and Gynecology, Istituto NazionaleTumoriIRCCSFondazioneG.Pascale,Napoli, Italy (Pignata); GINECO and Groupe Hospitalier Diaconesses Croix Saint-Simon, Paris, France (Selle); AGO Study Group and Medical University of Berlin, Charité–CVK,Berlin,Germany(Sehouli);GINECOand CentreOncologiedeGentilly,Nancy,France(Brocard); MITOandOspedaleSanRaffaele,Milan,Italy(Mangili); GINECOandGustaveRoussy,Villejuif,France(Pautier); MITOandIstitutoScientificoRomagnoloperloStudio e la Cura dei Tumori IRST IRCCS, Meldola, Italy (De Giorgi); GINECO and Institut Paoli Calmettes, Marseille,France(Provansal);GINECOandCentreLéon Bérard, Lyon, France (Heudel). Author Contributions: Dr Ray-Coquard had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Ray-Coquard, Harter, Pignata, Selle, Heudel. Acquisition, analysis, or interpretation of data: Ray-Coquard,Harter,Lorusso,Dalban,Vergote,Fujiwara, Gladieff, Lück, Floquet, Chevalier-Place, Schnelzer, Sehouli,Brocard,Mangili,Pautier,DeGiorgi,Provansal, Heudel. Drafting of the manuscript: Ray-Coquard, Vergote, Brocard, Heudel. Critical revision of the manuscript for important intellectual content: Ray-Coquard, Harter, Lorusso, Dalban, Fujiwara, Gladieff, Lück, Floquet, Chevalier-Place, Schnelzer, Pignata, Selle, Sehouli, Mangili, Pautier, De Giorgi, Provansal, Heudel. Statistical analysis: Dalban. Obtained funding: Ray-Coquard, Harter. Administrative, technical, or material support: Harter, Floquet, Pautier. Supervision: Ray-Coquard, Lorusso, Vergote, Pignata, Sehouli, Mangili, De Giorgi. Conflict of Interest Disclosures: Dr Ray-Coquard reportedpersonalfeesfromRoche,AstraZeneca,GSK, Clovis, Genmab, Advaxis, Amgen, and PharmaMar outsidethesubmittedwork.DrHarterreportedgrants and personal fees from AstraZeneca, GSK/Tesaro, and Roche; personal fees from Immunogen, Clovis, Sotio, Stryker, ZaiLab, and MSD; and grants from Boehringer Ingelheim,Medac,andGenmaboutsidethesubmitted work. Dr Lorusso reported personal fees from AstraZeneca, Amgen, and PharmaMar and grants and personal fees from GSK, Clovis, and Merck outside the submittedwork.DrVergotereportedpersonalfeesfrom Amgen Europe, AstraZeneca, Clovis Oncology Inc, Carrick Therapeutics, Debiopharm International, F. Hoffmann-La Roche Ltd, Genmab, GlaxoSmithKline Pharmaceuticals, Immunogen Inc, Medical University of Vienna, Millennium Pharmaceuticals, MSD Belgium, Octimet Oncology NV, Oncoinvent, PharmaMar-Doctaforum, Sotio a.s., Tesaro, Deciphera Pharmaceuticals, and Verastem Oncology outside the submitted work; grants from Amgen; grants and personalfeesfromRoche;andaccommodations/travel expensesinthepastfromAmgen,MSD/Merck,Roche, AstraZeneca,andTesaro.DrFujiwarareportedgrantsand personalfeesfromChugai-Rocheduringtheconductof thestudy.DrGladieffreportedpersonalfeesfromRoche, Clovis,andGSK;personalfeesandnonfinancialsupport from AstraZeneca; and grants from MSD outside the submitted work. Dr Lück reported fees for consulting, lectures, and speakers’ bureaus from Roche, GSK, Lilly, Novartis,Pfizer,AstraZeneca,Clovis,Amgen,andPierre Fabre. Dr Floquet reported nonfinancial support from Roche during the conduct of the study. Dr Pignata reported grants and personal fees from Roche, AstraZeneca, MSD, and Clovis and personal fees from Tesaro/GSK during the conduct of the study. Dr Selle reported personal fees and nonfinancial support from Roche,AstraZeneca,Tesaro,PharmaMar,andMSDand personalfeesfromClovisandGlaxoSmithKlineoutside thesubmittedwork.DrSehoulireportedstudyfeesfrom ENGOT/GINECOduringtheconductofthestudy;grants andserviceontheadvisoryboardforRoche,Clovis,GSK/ Tesaro, PharmaMar, and Lilly; service on the advisory boards for AstraZeneca, NovoCure, MSD, Pfizer, and EISAI;andgrantsfromRiemserandMedacoutsidethe submittedwork.DrDeGiorgireportedpersonalfeesand nonfinancial support from Pfizer, Ipsen, BMS, and Janssen-Cilag; personal fees from Astellas, Bayer, Novartis,MSD,andPharmaMar;grantsandpersonalfees fromSanofi;grantsandnonfinancialsupportfromRoche; andgrantsfromAstraZeneca.DrHeudelreportedgrants andnonfinancialsupportfromAstraZenecaandRoche during the conduct of the study; personal fees from Myland;grantsandnonfinancialsupportfromNovartis andPfizeroutsidethesubmittedwork;andpersonalfees and nonfinancial support from Eisai outside the submitted work. No other disclosures were reported. Funding/Support: This study was funded by Roche. Role of the Funder/Sponsor: Roche had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation,review,orapprovalofthemanuscript;and decision to submit the manuscript for publication. Data Sharing Statement: See Supplement 3. Additional Contributions: We thank the trial participants and their families, the study teams at the participating sites (Supplement 2), the coordinators at Gynecologic Cancer InterGroup and European Network for Gynaecological Oncological Trial, the statisticsteam(SylvieChabaud,PhD,ClaireCropet,MSc, David Perol, MD, PhD), the independent data safety monitoringboardmembers,thestudystaff(Bénédicte Votan[Grouped'InvestigateursNationauxpourl'Étude des Cancers Ovariens et du sein], Gabriele Elser [Arbeitsgemeinschaft Gynäkologische Onkologie], Multicenter Italian Trials in Ovarian Cancer, Belgium and Luxembourg Gynaecological Oncology Group, Gynecologic Oncology Trial and Investigation Consortium), and Roche for their financial support. MedicalwritingsupportwasprovidedbyJenniferKelly, MA, Medi-Kelsey Ltd, and was funded by GINECO.
Publisher Copyright:
© 2020 American Medical Association. All rights reserved.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12
Y1 - 2020/12
N2 - Importance: To our knowledge, this is the first randomized trial in sex cord-stromal tumors, and it establishes weekly paclitaxel as standard-of-care therapy after platinum-based therapy in this setting. Objective: To determine the efficacy of weekly paclitaxel with or without bevacizumab as treatment for relapsed sex cord-stromal tumors and evaluate whether the addition of bevacizumab to weekly paclitaxel improves 6-month progression-free rate. Design, Setting, and Participants: This open-label, academic, international, randomized phase 2 trial (ALIENOR) was conducted at 28 referral centers in France, Germany, Italy, Japan, and Belgium in collaboration with the Rare Tumor committee of the Gynecologic Cancer InterGroup and used an adaptive bayesian design. It included 60 women with sex cord-stromal tumors that had relapsed after at least 1 platinum-based chemotherapy. Enrollment occurred from 2013 to 2016, and the final analysis database lock was on March 27, 2020 (median follow-up, 38.9 months). Interventions: Participants were randomized to receive either paclitaxel (80 mg/m2, days 1, 8, and 15 every 4 weeks) alone or paclitaxel with bevacizumab (10 mg/kg, every 2 weeks) for 6 cycles followed by maintenance bevacizumab (15 mg/kg, every 3 weeks) for up to 1 year or until progression or unacceptable toxicity. Crossover to bevacizumab was permitted after progression during or following paclitaxel alone. Main Outcomes and Measures: Six-month progression-free rate. Results: Sixty patients (predominantly with granulosa cell tumors) were randomized, 32 to receive single-agent paclitaxel (median [interquartile range] age at inclusion, 60 [53-64] years) and 28 to receive paclitaxel-bevacizumab (median [interquartile range] age at inclusion, 55 [47-61] years; 1 did not receive treatment). The estimated 6-month progression-free rate was 71% (95% credible interval, 55%-84%) with paclitaxel alone and 72% (95% credible interval, 55%-87%) with paclitaxel-bevacizumab. The bayesian estimate for the probability that the 6-month progression-free rate distribution was higher with the combination than with paclitaxel alone was 57%, less than the predefined superiority threshold. The objective response rate increased from 25% (95% CI, 12%-43%) to 44% (95% CI, 26%-65%) with the addition of bevacizumab. One patient discontinued combination therapy within 6 months because of toxicity. Conclusions and Relevance: Weekly paclitaxel is a new option for relapsed sex cord-stromal tumors. In this international randomized clinical trial of patients with relapsed sex cord-stromal tumors unsuitable for surgery, adding bevacizumab to weekly paclitaxel does not improve clinical benefit. Trial Registration: ClinicalTrials.gov Identifier: NCT01770301.
AB - Importance: To our knowledge, this is the first randomized trial in sex cord-stromal tumors, and it establishes weekly paclitaxel as standard-of-care therapy after platinum-based therapy in this setting. Objective: To determine the efficacy of weekly paclitaxel with or without bevacizumab as treatment for relapsed sex cord-stromal tumors and evaluate whether the addition of bevacizumab to weekly paclitaxel improves 6-month progression-free rate. Design, Setting, and Participants: This open-label, academic, international, randomized phase 2 trial (ALIENOR) was conducted at 28 referral centers in France, Germany, Italy, Japan, and Belgium in collaboration with the Rare Tumor committee of the Gynecologic Cancer InterGroup and used an adaptive bayesian design. It included 60 women with sex cord-stromal tumors that had relapsed after at least 1 platinum-based chemotherapy. Enrollment occurred from 2013 to 2016, and the final analysis database lock was on March 27, 2020 (median follow-up, 38.9 months). Interventions: Participants were randomized to receive either paclitaxel (80 mg/m2, days 1, 8, and 15 every 4 weeks) alone or paclitaxel with bevacizumab (10 mg/kg, every 2 weeks) for 6 cycles followed by maintenance bevacizumab (15 mg/kg, every 3 weeks) for up to 1 year or until progression or unacceptable toxicity. Crossover to bevacizumab was permitted after progression during or following paclitaxel alone. Main Outcomes and Measures: Six-month progression-free rate. Results: Sixty patients (predominantly with granulosa cell tumors) were randomized, 32 to receive single-agent paclitaxel (median [interquartile range] age at inclusion, 60 [53-64] years) and 28 to receive paclitaxel-bevacizumab (median [interquartile range] age at inclusion, 55 [47-61] years; 1 did not receive treatment). The estimated 6-month progression-free rate was 71% (95% credible interval, 55%-84%) with paclitaxel alone and 72% (95% credible interval, 55%-87%) with paclitaxel-bevacizumab. The bayesian estimate for the probability that the 6-month progression-free rate distribution was higher with the combination than with paclitaxel alone was 57%, less than the predefined superiority threshold. The objective response rate increased from 25% (95% CI, 12%-43%) to 44% (95% CI, 26%-65%) with the addition of bevacizumab. One patient discontinued combination therapy within 6 months because of toxicity. Conclusions and Relevance: Weekly paclitaxel is a new option for relapsed sex cord-stromal tumors. In this international randomized clinical trial of patients with relapsed sex cord-stromal tumors unsuitable for surgery, adding bevacizumab to weekly paclitaxel does not improve clinical benefit. Trial Registration: ClinicalTrials.gov Identifier: NCT01770301.
UR - http://www.scopus.com/inward/record.url?scp=85093950566&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85093950566&partnerID=8YFLogxK
U2 - 10.1001/jamaoncol.2020.4574
DO - 10.1001/jamaoncol.2020.4574
M3 - Article
C2 - 33030515
AN - SCOPUS:85093950566
VL - 6
SP - 1923
EP - 1930
JO - JAMA oncology
JF - JAMA oncology
SN - 2374-2437
IS - 12
ER -