105P LX-101, a novel, clinical stage, payload-bearing, IGF-1R targeted therapy, has potent preclinical anti-tumor activity against sarcomas and other IGF-related cancers

LX-101, a next-generation, targeted therapy directed to the insulin-like growth factor 1 receptor (IGF-1R), consists of a proprietary optimized 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. Maximum tolerated dose and dose limiting toxicity were not reached, allowing for additional dose escalation and schedule optimization. Several aggressive cancers of unmet need have genetic alterations affecting the IGF-1R pathway and/or high IGF-1R expression which correlates with poor outcomes, including Ewing's sarcoma (ES), rhabdomyosarcoma (RMS), and others. Prior attempts at inhibiting the IGF-1R with non-payload bearing approaches produced a range of clinical outcomes, including some partial and complete responses. None were ultimately approved in an oncology setting, potentially due to suboptimal potency that allowed for redundant signaling pathways and other escape mechanisms. Here, we investigated the anti-tumor activity of LX-101 against sarcomas and other rare IGF-related cancer cell lines in vitro. Cell lines were incubated with LX-101 (∼1.6 - 2500nM). Viability was assessed by CellTiter-Glo after 4 days. IC50s were calculated using GraphPad PRISM software. All ES cell lines tested were sensitive to LX-101, including EWSR1-FLI1+ (RD-ES, IC50 = 10 nM; A-673, IC50 = 14 nM; SK-ES-1, IC50 = 29 nM) and EWSR1-ERG+ (CADO-ES1, IC50 = 14 nM) cell lines. LX-101 was active against PAX3-FOXO1+ alveolar RMS (SJCRH30, IC50 = 23 nM) and osteosarcoma (143B, IC50 = 6 nM; HOS, IC50 = 7 nM; U2OS, IC50 = 32 nM). LX-101 was also potent against adrenocortical carcinoma cell line SW-13 (IC50 = 9 nM). These results demonstrate that LX-101 has potent preclinical anti-tumor activity against sarcoma and other rare cancer cells with well-established ties to the IGF-1R pathway, including those with different oncogenic gene fusions. These data support the clinical development of LX-101 in IGF-1R-related sarcomas and other rare cancers. Clinical trials are planned.