Abstract 2949: LX-101, a novel, clinical stage, payload-bearing targeted therapy directed to the insulin-like growth factor receptor (IGF-1R), demonstrates potent preclinical anti-tumor activity against multiple cancer types with elevated IGF-1R expr

Abstract Objective: LX-101 is a next-generation, targeted therapy directed to IGF-1R. LX-101 consists 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 potential room for additional dose and schedule optimization. Multiple aggressive cancers of unmet need harbor alterations affecting the IGF-1R pathway, including gene fusions and/or high IGF-1R expression, that correlate with poor outcomes, including certain subsets of cancers of the breast, head and neck, esophagus, stomach, and lung, as well as Ewing’s sarcoma, osteosarcoma, and others. Prior attempts at targeting IGF-1R with non-payload bearing naked monoclonal antibodies or small molecules produced a range of clinical outcomes including some partial and complete responses. None of these agents, however, were ultimately approved, potentially due to redundant signaling, escape pathways, and/or the lack of enrichment for select tumor types with strong ties to the IGF-1/IGF-1R pathway. Herein, we investigated the anti-tumor activity of the payload-bearing agent LX-101 against IGF-1R-expressing cancer cell lines to overcome these past shortcomings. Methods: Cell lines known to highly express IGF-1R were incubated with LX-101 (∼1.6 - 2500nM). Cell viability was assessed by CellTiter-Glo after 4 days. IC50s were calculated using GraphPad PRISM software. Results: LX-101 displayed high levels of potency against lung cancer (A549, IC50 = 29 nM; NCI-H2122, IC50 = 10 nM; NCI-H526, IC50 = 23 nM), esophageal cancer (TE-1, IC50 = 16 nM; KYSE-70, IC50 = 7 nM), and stomach cancer (MKN74, IC50 = 19 nM; NUGC-4, IC50 = 30 nM). Conclusion: These results demonstrate that LX-101 has potent preclinical anti-tumor activity against multiple cancer cell lines expressing IGF-1R. These data support further clinical development of LX-101 in IGF-1R-involved cancers. New clinical trials are planned. Citation Format: Matt Hoberman. LX-101, a novel, clinical stage, payload-bearing targeted therapy directed to the insulin-like growth factor receptor (IGF-1R), demonstrates potent preclinical anti-tumor activity against multiple cancer types with elevated IGF-1R expression [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 2949.