67P - 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 (ES) animal models and desmoplastic small round cell tumor (DSRCT)

Background

Multiple aggressive cancers, including ES and DSRCT, involve alterations that upregulate the IGF-1R pathway, such as gene fusions and/or high IGF-1R expression, correlating with poor outcomes. Prior IGF-1R inhibitors, mainly monoclonal antibodies and small molecules, showed some tumor responses but weren't approved potentially due to suboptimal potency and escape mechanisms via redundnat signaling. LX-101, a next-generation therapy targeting IGF-1R, couples a proprietary IGF-1 variant to a cytotoxic MTX payload. Phase 1 trials in adults with pretreated cancers showed LX-101 was well-tolerated, with single-agent activity and no dose-limiting toxicity. Here we investigated the anti-tumor activity of 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.

Conclusions

LX-101 showed 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.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Lirum Therapeutics.

Disclosure

M. Hoberman: Financial Interests, Personal, Full or part-time Employment: Lirum Therapeutics; Financial Interests, Personal, Stocks/Shares: Lirum Therapeutics. D.D. Truong, R. Cardenas Zuniga, J. Ludwing: Non-Financial Interests, Personal and Institutional, Funding: Lirum Therapeutics.