A systematic review of recent phase-II trials in refractory or recurrent osteosarcoma: Can we inform future trial design?

Roelof van Ewijk; Morgane Cleirec; Nikolas Herold; Marie-Cécile le Deley; Natasha van Eijkelenburg; Pascaline Boudou-Rouquette; Séverine Risbourg; Sandra J Strauss; Emanuela Palmerini; Kjetil Boye; Leo Kager; Stefanie Hecker-Nolting; Antonin Marchais; Nathalie Gaspar; FOSTER Consortium (Fight OsteoSarcoma Through European Research), work package 3 on recurrent/refractory osteosarcoma trials

doi:10.1016/j.ctrv.2023.102625

A systematic review of recent phase-II trials in refractory or recurrent osteosarcoma: Can we inform future trial design?

Cancer Treat Rev. 2023 Nov:120:102625. doi: 10.1016/j.ctrv.2023.102625. Epub 2023 Sep 15.

Authors

Roelof van Ewijk¹, Morgane Cleirec², Nikolas Herold³, Marie-Cécile le Deley⁴, Natasha van Eijkelenburg¹, Pascaline Boudou-Rouquette⁵, Séverine Risbourg⁶, Sandra J Strauss⁷, Emanuela Palmerini⁸, Kjetil Boye⁹, Leo Kager¹⁰, Stefanie Hecker-Nolting¹¹, Antonin Marchais¹², Nathalie Gaspar¹³; FOSTER Consortium (Fight OsteoSarcoma Through European Research), work package 3 on recurrent/refractory osteosarcoma trials

Affiliations

¹ Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
² Department of Pediatric Oncology, CHU Nantes, Nantes, France.
³ Paediatric Oncology, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden, and Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
⁴ Unité de Méthodologie et Biostatistiques, Centre Oscar Lambret, Lille, France; Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, U1018 ONCOSTAT, F-94085 Villejuif, France.
⁵ Department of Medical Oncology, Cochin Hospital, Cochin Institute, INSERMU1016, Paris Cancer Institute, CARPEM, AP-HP, Paris, France.
⁶ Unité de Méthodologie et Biostatistiques, Centre Oscar Lambret, Lille, France.
⁷ Department of Oncology, University College London Cancer Institute, London, UK.
⁸ Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.
⁹ Department of Oncology, Oslo University Hospital, Norway.
¹⁰ St. Anna Children's Hospital, Department of Pediatrics, Medical University Vienna, Vienna, Austria; St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.
¹¹ Klinikum Stuttgart-Olgahospital, Stuttgart, Germany.
¹² Department of Oncology for Child and Adolescents, Gustave Roussy Cancer Center, Paris-Saclay University, Villejuif, France; National Institute for Health and Medical Research (INSERM) U1015, BiiOSTeam, Gustave Roussy Institute, Villejuif, France.
¹³ Department of Oncology for Child and Adolescents, Gustave Roussy Cancer Center, Paris-Saclay University, Villejuif, France; National Institute for Health and Medical Research (INSERM) U1015, BiiOSTeam, Gustave Roussy Institute, Villejuif, France. Electronic address: nathalie.gaspar@gustaveroussy.fr.

PMID: 37738712
DOI: 10.1016/j.ctrv.2023.102625

Abstract

Background/objective: To analyze changes in recurrent/refractory osteosarcoma phase II trials over time to inform future trials in this population with poor prognosis.

Methods: A systematic review of trials registered on trial registries between 01/01/2017-14/02/2022. Comparison of 98 trials identified between 2003 and 2016. Publication search/analysis for both periods, last update on 01/12/2022.

Results: Between 2017 and 2022, 71 phase-II trials met our selection criteria (19 osteosarcoma-specific trials, 14 solid tumor trials with and 38 trials without an osteosarcoma-specific stratum). The trial number increased over time: 13.9 versus 7 trials/year (p = 0.06). Monotherapy remained the predominant treatment (62% vs. 62%, p = 1). Targeted therapies were increasingly evaluated (66% vs. 41%, P = 0.001). Heterogeneity persisted in the trial characteristics. The inclusion criteria were measurable disease (75%), evaluable disease (14%), and surgical remission (11%). 82% of the trials included pediatric or adolescent patients. Biomarker-driven trials accounted for 25% of the total trials. The survival endpoint use (rather than response) slightly increased (40% versus 31%), but the study H₁/H₀ hypotheses remained heterogeneous. Single-arm designs predominated over multiarm trials (n = 7). Available efficacy data on 1361 osteosarcoma patients in 58 trials remained disappointing, even though 21% of these trials were considered positive, predominantly those evaluating multi-targeted kinase inhibitors.

Conclusion: Despite observed changes in trial design and an increased number of trials investigating new therapies, high heterogeneity remained with respect to patient selection, study design, primary endpoints, and statistical hypotheses in recently registered phase II trials for osteosarcoma. Continued optimization of trial design informed by a deeper biological understanding should strengthen the development of new therapies.

Keywords: Clinical trial; Drug therapy; Osteosarcoma; Phase II; Recurrence; Systematic review.

Publication types

Review