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
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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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