Recurrent and Refractory Ewing Sarcoma Phase I/II Trials: Current Perspective From the Euro-Ewing Consortium.

Area of Science:

• Oncology
• Clinical Trials Research
• Sarcoma Research

Background:

• Recurrent/refractory (R/R) Ewing sarcoma (EwS) presents significant treatment challenges.
• Limited therapeutic options exist for patients with R/R EwS.

Purpose of the Study:

• To analyze phase I/II clinical trials for R/R EwS over the past 11 years (2014-2024).
• To identify evolving therapeutic strategies and unmet needs in EwS treatment.

Main Methods:

• Systematic review of phase I/II trials for R/R EwS from major databases and publications.
• Trials categorized by therapeutic intervention: targeted therapies, immunotherapy, chemotherapy, and combined therapies.
• Data extraction and eligibility assessment by three independent reviewers.

Main Results:

• 108 trials met inclusion criteria, predominantly academic and multicenter, with international collaboration.
• Therapeutic focus shifted towards targeted therapies (tyrosine kinase, PARP, EWSR1::FLI1, cell cycle inhibitors) and immunotherapies (monoclonal antibodies, CAR-T cells).
• Average disease control rate of 44% and response rate of 8% observed; trial initiation reduced during the COVID-19 pandemic.

Conclusions:

• Therapeutic landscape for R/R EwS is evolving with increased emphasis on targeted therapies and immunotherapies.
• Novel targets like EWSR1::FLI1 oncogenic fusion and DNA repair pathways are being explored.
• Findings support future trial designs, including international, randomized phase-II trials for all age groups.