Abstract
Background
Ewing sarcoma (ES) is a rare tumour with metastatic spread in ~25% of cases at diagnosis. Extrapulmonary disseminated disease defines very high-risk (VHR) patients, with frequent relapse and poor overall survival (OS, ~30%).
Methods
The phase II CombinaiR3 trial (NCT03011528) enroled 45 VHR ES patients across 15 French centres (2017–2021) to evaluate a strategy combining dose-dense induction chemotherapy, high-dose consolidation, and prolonged maintenance therapy. The primary endpoint was median event-free survival (EFS). Exploratory endpoints included full-body-fluorine-18-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) and circulating tumour DNA (ctDNA) detection during treatment.
Results
Among 42 analysed patients (median age 14 years, range 6–47), 29 had a primary tumour volume ≥200 ml, and 35 presented with bone ± bone marrow metastatic lesions, 18 exhibiting more than 5 bone lesions. At 48-month follow-up, 18- and 36-month EFS rates were 63.4% and 53.7%, respectively, with 3-year OS at 65.5%. Toxicity was as expected, with no treatment-related deaths or maintenance therapy discontinuations due to toxicity. PET/CT and ctDNA monitoring showed strong correlation at diagnosis and relapse.
Discussion
This study supports the proposed experimental strategy as a first-line option for selected VHR ES patients, warranting integration into international therapeutic discussions.
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Data availability
The dataset generated and analysed during the current study is available from the corresponding author on reasonable request.
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Acknowledgement
We thank Dr. Erika Vacchelli for her assistance in writing, editing, and critically reviewing the manuscript. We also acknowledge Lisa Belin for her methodologic help.
Funding
This work was supported by the French Society for Childhood Cancer (SFCE, Société Française des Cancers de l’Enfant) and the ‘Princesse Margot’ Association. The authors also thank Mr. Wisnia for his private donation. We would like to acknowledge La Ligue Contre le Cancer for supporting the project through the 2017 ‘Enfants, Adolescents et Cancer’ grant titled: Étude de l’ADN tumoral circulant, des cellules tumorales circulantes, de la biologie des tumeurs primaires et métastatiques dans les sarcomes d’Ewing à la rechute ou de mauvais pronostic (compilation des études ancillaires EuroEwing 2012, rEECur et CombinaiR3).
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Valérie Laurence: Conceptualisation, methodology, investigation, writing-original draft, writing-reviewing and editing, funding acquisition. Nina Jehanno: Methodology, investigation, writing-original draft, writing—reviewing and editing. Sylvain Dureau: Methodology, Statistical analysis, writing-original draft, writing—reviewing and editing. Lieke Mous: Methodology, investigation, writing-original draft, writing—reviewing and editing. Line Claude Conceptualisation, writing-original draft, writing-reviewing and editing. Stelly Ballet: Methodology, investigation, writing-original draft, writing—reviewing and editing. Gaëlle Pierron: Resources, writing—review and editing. Nathalie Gaspar: Resources, writing-review and editing. Mehdi Brahmi: Resources, writing—review and editing. Thibaud Valentin: Resources, writing—review and editing. Gabriel Revon Riviere: Resources, writing—review and editing. Cyril Lervat: Resources, writing—review and editing. Jamie Probert: Resources, writing—review and editing. Natacha Entz-Werle: Resources, writing—review and editing. Ludovic Mansuy: Resources, writing-review and editing. Dominique Plantaz: Resources, writing—review and editing. Maria Rios: Resources, writing—review and editing. Laure Saumet: Resources, writing—review and editing. Cécile Vérité: Resources, writing—review and editing. Marie-Pierre Castex: Resources, writing-review and editing. Estelle Thebaud: Resources, writing—review and editing. Thibaut Cassou-Mounat: Resources, writing—review and editing. Anne-Sophie Plissonnier: Project administration. Jennifer Dieppedale: Resources and data monitoring. Olivier Delattre: Resources, writing—review and editing. Marie-Emmanuelle Legrier: Resources and data monitoring. Perrine Marec-Bérard: Resources, writing—review and editing. François Gouin: Resources, writing—review and editing. Pablo Berlanga: Resources, writing—review and editing. Camille Cordero: Resources, writing-review and editing. Didier Surdez: Conceptualisation, resources, writing—reviewing and editing. Nadège Corradini: Conceptualisation, methodology, investigation, writing-original draft, writing—reviewing and editing, funding acquisition.
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PB has consulting role (institutional funding) for Recordati and Merck, drugs for trials from Bayer, participation in educational activities organised by Recordati and is Member of the Executive Committee of the SIOPEN (European neuroblastoma research cooperative group), organisation which receives royalties for the sales of dinutuximab beta.
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Laurence, V., Jehanno, N., Dureau, S. et al. Interest of a sequential multimodal approach for the treatment of newly diagnosed patients with multimetastatic Ewing sarcoma: results of the French prospective CombinaiR3 phase II trial. Br J Cancer 134, 279–288 (2026). https://doi.org/10.1038/s41416-025-03263-3
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DOI: https://doi.org/10.1038/s41416-025-03263-3
