71P - 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

Background

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).

Conclusions

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.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Lirum Therapeutics.

Funding

Lirum Therapeutics.

Disclosure

P. McDonald, M. Hoberman: Financial Interests, Personal, Full or part-time Employment: Lirum Therapeutics; Financial Interests, Personal, Stocks/Shares: Lirum Therapeutics.