84MO Phase I study of the tetravalent death receptor 5 (DR5) agonist ozekibart (INBRX-109) combined with irinotecan (I) and temozolomide (T) in adolescents and adults with Ewing sarcoma

Background: Myxoid liposarcoma (MLPS) is a highly radiosensitive (RT) sarcoma subtype.The aim of our study is to analyze pooled data from two phase II trials (DOREMY: 36 Gy/18 fractions; LIPOMYX: 25 Gy/5 fractions) to evaluate pathological response and outcomes of reduced-dose preoperative RT.Methods: 87 patients with primary MLPS received preoperative RT (36 Gy or 25 Gy) followed by limb-sparing surgery.Histopathological changes (hyalinization, fatty maturation, necrosis) were evaluated on resected specimens.Outcomes included R0 resection rate, local control, distant metastasis-free survival (DMFS), and overall survival (OS).Results: R0 resection was achieved in 94.3% with 100% local control.Nine patients (10%) developed distant metastases.The 4-year DMFS was 82.8% and the 4-year OS was 90.1%, with no significant difference between the 36 Gy and 25 Gy regimens (DMFS, p=0.27).Wound complication rates were similar (p=0.5).Pathologic analysis showed mean hyalinization 48%, fatty maturation 25%, necrosis 9.5%, and residual viable tumor 17%, with combined hyalinization+fatty maturation in 73% of cases.The 36 Gy regimen induced greater hyalinization (median 50% vs 25%, p=0.003) and combined hyalinization + fatty maturation (p=0.02),whereas 25 Gy led to higher necrosis (median 5% vs 0%, p=0.04).Histopathologic response parameters did not correlate with DMFS, except that higher necrosis showed a borderline association with worse DMFS (p=0.0502).Conclusions: Both reduced-dose regimens achieved excellent local control and high resection quality in MLPS.The histologic response was dominated by stromal changes rather than necrosis.These findings support the use of shorter, lower-dose preoperative radiotherapy as an effective approach in this radiosensitive sarcoma subtype.