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Surrogate Endpoints for Overall Survival in Cancer Randomized Controlled Trials Marion Savina

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Surrogate Endpoints for Overall Survival in Cancer Randomized Controlled Trials Marion Savina Surrogate Endpoints for Overall Survival in Cancer Randomized Controlled Trials Marion Savina To cite this version: Marion Savina. Surrogate Endpoints for Overall Survival in Cancer Randomized Controlled Trials. Human health and pathology. Université de Bordeaux, 2017. English. NNT : 2017BORD0894. tel-01865829 HAL Id: tel-01865829 https://tel.archives-ouvertes.fr/tel-01865829 Submitted on 2 Sep 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Thèse présentée pour obtenir le grade de Docteur de l’Université de Bordeaux Ecole Doctorale Sociétés, Politique, Santé Publique Spécialité Santé Publique, option Biostatistique Par Marion SAVINA Critères de Substitution à la Survie Globale dans les Essais Cliniques Randomisés en Cancérologie Surrogate Endpoints for Overall Survival in Cancer Randomized Controlled Trials Sous la direction de Carine BELLERA Soutenue le 14 décembre 2017 devant les membres du jury : M. SALMI Rachid Pr, INSERM U1219, Bordeaux Président Mme MOLLEVI Caroline Dr, INSERM U1194, Montpellier Rapporteuse M. CHAMOREY Emmanuel Dr, Université Nice-Sophia Antipolis Rapporteur Mme MATHOULIN-PELISSIER Simone Pr, INSERM U1219, Bordeaux Examinatrice Mme MIGEOT Virginie Pr, INSERM CIC1402, Poitiers Examinatrice Mme GOURGOU Sophie MsC, Institut du Cancer de Montpellier Invitée M. PORCHER Raphaël Dr, INSERM U1153, Paris Invité Mme BELLERA Carine Dr, INSERM U1219, Bordeaux Directrice de thèse Abstract In cancer randomized controlled trials (RCT), a surrogate endpoint is intended to substitute a clinically relevant endpoint, e.g. overall survival (OS), and it is supposed to predict treatment effect. Alternative endpoints, for example progression-free survival, are increasingly being used in place of OS as primary efficacy endpoints in RCTs. In practice however, the surrogate properties of these endpoints are not systematically assessed. We performed a systematic literature review to identify surrogate endpoints validated in oncology. We next conducted MAs to evaluate surrogate endpoints in two cancer settings: advanced soft-tissue sarcoma and adjuvant breast cancer. Results could not definitely validate surrogate endpoints in these indications. OS must remain the primary efficacy endpoint in these settings, even though alternative endpoints may provide valuable input in earlier phase studies (phase II trials, futility analyses). This work provides key information for the design of cancer RCTs, in particular for the choice of primary endpoints to assess treatment efficacy. Résumé Dans les essais cliniques randomisés (ECR) en cancérologie, un critère de substitution est une mesure biologique utilisée à la place d’un critère cliniquement pertinent pour le patient, par exemple la survie globale (SG), qui doit permettre de prédire l’effet attendu du traitement. Des critères alternatifs à la SG, par exemple la survie sans progression, sont de plus en plus fréquemment utilisés en tant que critère de jugement principal dans les ECR. En pratique cependant, les capacités de substitution à la SG de ces critères ne sont pas systématiquement évaluées. Nous avons dressé un état des lieux des critères de substitution validés en cancérologie à partir d’une revue systématique de la littérature. Par la suite, nous avons évalué par une approche méta-analytique des critères de substitution dans le contexte des sarcomes des tissus mous en situation avancée et du cancer du sein en situation adjuvante. Les résultats n’ont pas permis de définitivement valider de critères de substitution à la SG dans ces indications. La SG doit donc rester le critère de jugement principal des ECR, même si certains critères alternatifs restent informatifs dans des évaluations plus précoces (phase II, analyse de futilité), sous réserve que les données de survie continuent à être recueillies. Ce travail fournit des informations clés pour le développement des ECR en cancérologie afin notamment de sélectionner au mieux les critères de jugement de l’efficacité thérapeutique. 2 Acknowledgments A mon président de jury, le Pr Louis-Rachid Salmi, Merci de m’avoir fait l’honneur d’accepter de présider mon jury de thèse. Au Pr Emmanuel Chamorey, Au Pr Virginie Migeot, Au Dr Raphaël Porcher, Pour avoir accepté de faire partie de mon jury de thèse. Au Dr Caroline Mollevi, A Mme Sophie Gourgou, Pour avoir accepté de faire partie de mon jury, mais également pour m’avoir donné l’opportunité de découvrir la recherche clinique et l’envie de continuer. Je vous remercie pour votre gentillesse, votre bienveillance et vos encouragements. Au Pr Simone Mathoulin-Pélissier, Pour m’avoir fait confiance et donné l’occasion de faire cette thèse. Je vous remercie de tout le soutien que vous m’avez apporté, vous compter parmi mon jury est un honneur. A ma directrice de thèse, le Dr Carine Bellera, Pour m’avoir donné l’occasion de faire cette thèse avec toi. Je te remercie de la confiance et du soutien que tu m’as apporté, dans le travail de thèse en lui-même mais également dans mes questionnements plus personnels. Je suis très fière d’être ta première thésarde. Au Pr Virginie Rondeau, Pour avoir accepté de faire partie de mon comité de suivi. Merci pour tes encouragements, ta disponibilité et ton aide méthodologique très précieuse durant ces trois années. To Dr Saskia Litière, For your amazing availability and support. It was a real pleasure to work with you. To Dr Tomasz Burzykowski, For agreeing to be part of my steering committee. Thank you for your availability and kindness, it was a great pleasure to work with you. 3 A toute l’unité de recherche clinique de l’Institut Bergonié, Merci à Marina, Sandrine, Stéphanie, Antoine, Véronique, Derek et Maïté pour leur soutien, leur bonne humeur et les fous rires partagés. A mes collègues de bureau et amis, Merci à Lucile, Clément, Louis, et Hélène pour votre soutien et votre bonne humeur, nécessaires pour tenir jusqu’au bout. A Angéline, Merci pour… tellement de choses ! D’avoir atterri dans mon bureau tout d’abord, même si tu n’y étais pas pour grand-chose, et d’avoir su briser la glace si facilement. Merci pour ces 3 années de galères, de stress, de coups durs, de débats féministes et politiques, de sport (un peu), de repas (un peu plus), d’apéros (beaucoup), de création et de fous rires. Je n’aurais vraiment pas pu rêver meilleure partenaire de thèse (et autres) ! A mes amis, A Julianne, toujours présente, toujours souriante malgré les moments difficiles. J’admirerai toujours ta force et ton courage. Je souhaite que ta nouvelle vie t’apporte tout ce que tu mérites. A mes amis de M2, Mathilde, Anne et Yassine, même si on ne se voit pas aussi souvent que je le souhaiterais vous êtes toujours très importants pour moi. A Charlotte, mon amie de toujours et pour toujours, je te remercie d’être là pour moi. Nos vies peuvent nous éloigner quelques temps, mais jamais très longtemps. A Alexis, merci pour ton soutien indéfectible même dans les moments les plus difficiles. Je souhaite de tout mon cœur que tu réussisses à croire en toi autant que tu crois en moi. A Justine, Emilie, Séverine, Antoine, Pierre et Vincent, à Dorian, et à mes équipiers de voile Didier, Fabrice et Stéphane, merci pour tous ces moments d’évasion. Mon cerveau de blonde n’aurait certainement pas tenu sans ! A Paulin, Merci d’être qui tu es. Merci de ne pas t’être arrêté, perdu au milieu du supermarché, et d’être venu quand je t’ai invité à te réfugier dans ma cabane. Merci de croire et de me faire croire que tout est possible. Tu m’aides tous les jours à me rapprocher de la personne que je souhaite devenir. 4 A ma famille, enfin, qui m’a toujours encouragée et soutenue dans mes choix, A ma mère, merci pour ta bienveillance, ta gentillesse et ton amour. Tu es notre force. A Laurent, mon père. Merci de ta pudeur, de ta présence à mes côtés, discrète, sans jamais s’imposer. A Claire, ma sœur, mon modèle de force et de persévérance. Je t’aime. A Benjamin, mon Benjamin… J’aurais tellement de choses à te dire mais tu les connais déjà. Suis tes envies, quoiqu’il arrive, quoique les gens te disent. Tu y arriveras, j’ai entièrement confiance en toi. 5 Scientific valorization Thesis-related communications Publications in peer-reviewed journals i. Savina M, Le Cesne A, Blay J-Y, Ray-Coquard I, Mir O, Toulmonde M, Cousin S, Terrier P, Ranchere-Vince P, Meeus P, Stoeckle E, Honoré C, Sargos P, Sunyach M- P, Le Péchoux C, Giraud A, Bellera C, Le Loarer F, Italiano A. Patterns of care and outcomes of patients with METAstatic soft tissue SARComa in a real-life setting: the METASARC observational study. BMC Medicine (2017) 15:78. (Impact factor: 8.005) ii. Savina M, Gourgou S, Italiano A, Dinart D, Rondeau V, Pénel N, Mathoulin-Pélissier S, Bellera C (2017). Meta-analyses evaluating surrogate endpoints for overall survival in cancer randomized trials: A critical review. In press, Critical Reviews in Oncology / Hematology. (Impact factor: 5.039) iii. Savina M, Litière S, Italiano A, Burzykowski T, Bonnetain F, Gourgou S, Rondeau V, Blay J-Y, Cousin S, Duffaud F, Gelderblom H, Gronchi A, Judson I, Le Cesne A, Lorigan P, Maurel J, van der Graaf W, Verweij J, Mathoulin-Pélissier S, Bellera C (2017). Surrogate endpoints in advanced sarcoma trials: a meta-analysis. Submitted, Journal of Clinical Oncology.
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