Surrogate endpoints in advanced sarcoma trials: a meta-analysis

// Marion Savina 1, 2, 3, 4 , Saskia Litière 5 , Antoine Italiano 6 , Tomasz Burzykowski 7 , Franck Bonnetain 8 , Sophie Gourgou 9 , Virginie Rondeau 3, 10 , Jean-Yves Blay 11, 12 , Sophie Cousin 6 , Florence Duffaud 13 , Hans Gelderblom 14 , Alessandro Gronchi 15 , Ian Judson 16 , Axel Le Cesne 17 , Paul Lorigan 18 , Joan Maurel 19 , Winette van der Graaf 20, 21, 23 , Jaap Verweij 22 , Simone Mathoulin-Pélissier 1, 2, 3, 4 and Carine Bellera 1, 2, 3, 4 1 Clinical and Epidemiological Research Unit, Institut Bergonié, Comprehensive Cancer Center, Bordeaux cedex 33076, France 2 INSERM CIC-EC 14.01 (Clinical Epidemiology), Bordeaux 33000, France 3 INSERM, ISPED, Centre INSERM U1219 Bordeaux Population Health Center, Epicene Team, Bordeaux 33000, France 4 University of Bordeaux, ISPED, Centre INSER M U1219 Bordeaux Population Health, Epicene Team, Bordeaux 33000, France 5 European Organisation for Research and Treatment of Cancer (EORTC), Brussels 1200, Belgium 6 Medical Oncology Unit, Institut Bergonié, Comprehensive Cancer Center, Bordeaux cedex 33076, France 7 Interuniversity Institute for Biostatistics and Statistical Bioinformatics (I-BioStat), Hasselt University, Hasselt 3500, Belgium 8 Methodology and Quality of life in Oncology Unit, Besançon EA3181, France 9 Biometrics Unit, Institut du Cancer de Montpellier, Univ. Montpellier, Montpellier 34298, France 10 INSERM, ISPED, Centre INSERM U1219 Bordeaux Population Health Center, Biostatistic Team, Bordeaux 33000, France 11 Centre Léon Bérard, Comprehensive Cancer Center, Lyon 69008, France 12 University Claude Bernard Lyon I, Lyon 69000, France 13 Medical Oncology Unit, University Hospital La Timone and University of Aix-Marseille, Marseille 13005, France 14 Department of Medical Oncology, Leiden University Medical Center, Leiden 2300RC, The Netherlands 15 Sarcoma Service, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy 16 Institute of Cancer Research, Sutton, Surrey, United Kingdom 17 Medicine Department, Institut Gustave Roussy, Comprehensive Cancer Center, Villejuif 94800, France 18 University of Manchester and Christie NHS Foundation Trust, Manchester M20 4BX, UK 19 Department of Medical Oncology, Hospital Clinic, CIBERehd, Translational Genomics and Targeted Therapeutics in Solid Tumors (IDIBAPS), Barcelona 08036, Spain 20 The Institute of Cancer Research, Sutton, London SM2 5NG, United Kingdom 21 Radboud University Medical Centre, Department of Medical Oncology, GA Nijmegen 6525, The Netherlands 22 Department of Medical Oncology, Erasmus University Medical Center, CE Rotterdam 3015, The Netherlands 23 Royal Marsden NHS Foundation Trust, Chelsea, London, United Kingdom Correspondence to: Carine Bellera, email: C.Bellera@bordeaux.unicancer.fr Keywords: sarcoma; surrogate endpoints; meta-analysis; randomized trial; survival Received: August 20, 2018      Accepted: September 13, 2018      Published: October 02, 2018 ABSTRACT Background: Alternative endpoints to overall survival (OS) are frequently used to assess treatment efficacy in randomized controlled trials (RCT). Their properties in terms of surrogate outcomes for OS need to be assessed. We evaluated the surrogate properties of progression-free survival (PFS), time-to-progression (TTP) and time-to-treatment failure (TTF) in advanced soft tissue sarcomas (STS). Results: A total of 21 trials originally met the selection criteria and 14 RCTs ( N = 2846) were included in the analysis. Individual-level associations were moderate (highest for 12-month PFS: Spearman’s rho = 0.66; 95% CI [0.63; 0.68]). Trial-level associations were ranked as low for the three endpoints as per the IQWiG criterion. Materials and Methods: We performed a meta-analysis using individual-patient data (IPD). Phase II/III RCTs evaluating therapies for adults with advanced STS were eligible. We estimated the individual- and the trial-level associations between then candidate surrogates and OS. Statistical methods included weighted linear regression and the two-stage model introduced by Buyse and Burzykowski. The strength of the trial-level association was ranked according to the German Institute for Quality and Efficiency in Health Care (IQWiG) guidelines. Conclusions: Our results do not support strong surrogate properties of PFS, TTP and TTF for OS in advanced STS.