Systemic therapy of bone sarcomas: current evidence and emerging strategies

Summary Bone sarcomas are rare, biologically heterogeneous malignancies in which progress in systemic therapy has historically been slow. In Ewing sarcoma, dose-dense VDC/IE (vincristine, doxorubicin, cyclophosphamide/ifosfamide, etoposide) has become the global induction standard, with EURO-EWING 2012 and AEWS0031 demonstrating survival benefits through interval compression. Contemporary international platforms, including INTER-EWING and iEuroEwing, now provide harmonized, biomarker-integrated frameworks to evaluate novel agents, radiotherapy optimization, and maintenance strategies. In relapsed disease, the rEECur trial has redefined standards by identifying high-dose ifosfamide as the most active salvage regimen, while deprioritizing less effective combinations; additional rational combinations such as ifosfamide plus lenvatinib and trabectedin plus irinotecan are under active investigation. In osteosarcoma, MAP (high-dose methotrexate, doxorubicin, cisplatin) chemotherapy remains the first-line standard, and postoperative intensification with MAPIE (MAP, ifosfamide, etoposide) has not improved outcomes. Targeted multikinase inhibitors (TKIs), including cabozantinib and regorafenib, provide meaningful but time-limited activity in refractory disease. A large ongoing National Cancer Institute (NCI) phase II/III trial is currently evaluating the addition of cabozantinib to frontline MAP in newly diagnosed patients. Antibody–drug conjugates (ADCs) targeting LRRC15 and B7-H3 represent further promising strategies. Chondrosarcoma remains largely chemoresistant, but targeted approaches are beginning to alter the therapeutic landscape. Isocitrate dehydrogenase (IDH) 1 inhibition with ivosidenib has shown durable disease control, and death receptor (DR) 5 agonism with INBRX-109 has delivered the first positive randomized systemic therapy signal in conventional chondrosarcoma. Continued international collaboration and biomarker-driven trial design are essential to translate these advances into clinical practice.