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

Roelof van Ewijk , Morgane Cleirec (1) , Nikolas Herold , Marie Cécile Cécile Le Deley (2, 3) , Natasha K.A. van Eijkelenburg , Pascaline Boudou-Rouquette (4, 5, 6) , Séverine Risbourg (2) , Sandra J. Strauss , Emanuela Palmerini , Kjetil Boye , L. H. Kager , Stefanie Hecker-Nolting , Antonin Marchais (7, 8) , Nathalie Gaspar (7, 8)

1 CHU Nantes - Centre Hospitalier Universitaire de Nantes
2 UNICANCER/Lille - Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille]
3 U1018 (Équipe 2) - Oncostat
4 IC UM3 (UMR 8104 / U1016) - Institut Cochin
5 Hôpital Cochin [AP-HP]
6 Cancer Research and Personalized Medicine - CARPEM [Paris]
7 Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy]
8 UMR 1015 - Immunologie des tumeurs et immunothérapie

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.

Mots clés: Clinical trial; Drug therapy; Osteosarcoma; Phase II; Recurrence; Systematic review

Domaines: Cancer; Rhumatologie et système ostéo-articulaire; Santé publique et épidémiologie

Roelof van Ewijk, Morgane Cleirec, Nikolas Herold, Marie Cécile Cécile Le Deley, Natasha K.A. van Eijkelenburg, et al.. A systematic review of recent phase-II trials in refractory or recurrent osteosarcoma: Can we inform future trial design?. Cancer Treatment Reviews, 2023, 120, pp.102625. ⟨10.1016/j.ctrv.2023.102625⟩. ⟨hal-04229528⟩