1755P - Multimodal therapy in first line treatment of very high risk Ewing sarcoma patients: Results of the French prospective multicenter COMBINAIR3 phase II trial

Background

Ewing Sarcoma (ES) are rare tumors with metastatic spread at diagnosis in one out of three patients. Extrapulmonary disseminated disease defines very high-risk patients (VHR) with a historical 36-months event-free survival (EFS) rate of 27% and overall survival (OS) of 34%.

Methods

Pediatric and adult patients from 15 French sarcoma reference centers with a diagnosis of VHR ES were prospectively included from 2017 to 2021 in the COMBINAIR3 non-randomized phase II trial. This study aimed to evaluate a strategy combining dose-dense induction chemotherapy, high-dose consolidation (HDC) and prolonged 2-years maintenance therapy. At diagnosis, all patients underwent bone marrow analysis, primary tumor imaging and baseline full body fluorine-18-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/ computed tomography (CT) (¹⁸F-FDG PET/CT) with centralized real-time imaging review. Inadequate response at mid induction led to a switch from anthracycline-alkylating agent-based regimen to temozolomide-irinotecan. Only good responders at the end of induction were eligible for HDC. The primary endpoint was EFS and was compared to a historical external reference using a one-sample design.

Results

Forty-five patients were included, with 3 cases excluded due to misdiagnosis after review. Among those 42 patients aged 6 to 47 years (male/female 2), all presented an EWS RNA binding protein 1 (EWSR1) rearranged tumor with 36/37 of the fusion transcripts being classic and one being atypical, 35 (80%) had metastases to bone and/or bone marrow. Thirty-three patients with adequate response to induction treatment received HDC. Among them, 29 started the first year of maintenance therapy. With a median follow-up of 48 months, EFS rate at 18 and 36 months were 63.4% [CI 95%: 50.3-80] and 53.7% [CI 95%: 40.4-71.3], respectively. A one sample log-rank test led to conclude that the experimental treatment is potentially effective (p < 0.001). OS rate at 36 months was 65.5% [CI 95%:52.4-81.9].

Conclusions

The COMBINAIR3 results demonstrate an effective signal in favor of the experimental strategy in the first-line treatment of selected VHR patients with ES.

Clinical trial identification

NCT03011528.

Editorial acknowledgement

Legal entity responsible for the study

Institut Curie, Paris, France.

Funding

French Society for Childhood Cancer (SFCE, Société Française Cancers de l Enfant) Princesse Margot association Wisnia private funding.

Disclosure

All authors have declared no conflicts of interest.