Abstract 2929: LX-101, a novel, clinical stage, payload-bearing targeted therapy directed to the insulin-like growth factor receptor (IGF-1R), demonstrates potent anti-tumor activity in Ewing sarcoma animal models and desmoplastic small round cell tu

Abstract Objective: Multiple aggressive cancers of unmet need have alterations involving the insulin-like growth factor 1 receptor (IGF-1R) pathway, including gene fusions and/or high IGF-1R expression, that correlate with poor outcomes. In Ewing sarcoma (ES) and desmoplastic small round cell tumor (DSRCT), the gene fusion-produced oncogenic proteins upregulate the IGF signaling pathway. Although prior attempts at inhibiting IGF-1R with non-payload bearing naked monoclonal antibodies or small molecules produced some tumor responses, none of these agents were ultimately approved, potentially due to suboptimal potency and escape mechanisms via redundant signaling. LX-101 is a next-generation, targeted therapy directed to the IGF-1R, consisting of a proprietary IGF-1 variant coupled to a cytotoxic methotrexate payload. LX-101 was previously evaluated in Phase 1 trials of adult patients with advanced, pretreated cancers, where it was well-tolerated and demonstrated single agent activity. Neither a dose limiting toxicity nor a maximum tolerated dose was reached, leaving room for additional dose and schedule optimization. Herein, we investigated the in vitro and in vivo anti-tumor activity of the payload-bearing agent LX-101 in ES and DSRCT. Methods: ES and DSRCT cell lines were incubated with LX-101 (1 - 10, 000 nM) for 72 h. Cell viability was assessed by CellTiter-Glo; IC50s were calculated using GraphPad PRISM software. Pretreatment IGF-1R expression levels were analyzed by RNA-seq & Western blot. NOD-SCID mice bearing subcutaneous A-673 tumors were treated i.v. with vehicle or LX-101 (16 uEq/kg, twice a week, for 3 weeks). Tumor volume and body weight were measured 3 times a week. Results: LX-101 displayed anti-tumor activity against ES and DSRCT cell lines, including EWSR1::FLI1+ cell lines A-673 (IC50 = 693 nM), ES-8 (IC50 = 354 nM), and TC-71 (IC50 = 199 nM), as well as the EWSR1::WT1+ cell line BOD-DSRCT (IC50 = 453 nM). IGF-1R mRNA levels correlated with LX-101 anti-tumor activity. In mice bearing A-673 tumors, LX-101 significantly inhibited tumor volume, in vivo, following twice a week treatment for 3 weeks (55% tumor growth inhibition relative to vehicle group on Day 21, p < 0.01). No adverse effects were observed, demonstrating that LX-101 was well-tolerated. Conclusion: These results demonstrate that LX-101 has potent anti-tumor activity against ES, in vivo and in vitro, and DSRCT, in vitro, providing a differentiated approach from previous IGF-1R targeting agents. These data support further clinical development of LX-101 in ES, DSRCT, and other IGF-1R-involved cancers. Phase 2 clinical trials are expected to begin in 2025. Citation Format: Matt Hoberman, Danh Dinh Truong, Roberto Cardenas Zuniga, Joseph A. Ludwig. LX-101, a novel, clinical stage, payload-bearing targeted therapy directed to the insulin-like growth factor receptor (IGF-1R), demonstrates potent anti-tumor activity in Ewing sarcoma animal models and desmoplastic small round cell tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2929.