Abstract 64P
Background
LX-101 is a next-generation, targeted therapy directed to the insulin-like growth factor 1 receptor (IGF-1R) consisting of a proprietary IGF-1 variant coupled to a cytotoxic methotrexate payload. LX-101 was previously evaluated in phase I trials of adult patients with advanced, pretreated cancers, where it was well-tolerated and demonstrated single agent activity, with no DLT or MTD reached (Venepalli 2019; Alkhateeb 2020). Certain cancer types and subsets have genetic alterations affecting the IGF-1R pathway and/or high IGF-1R expression, including cancers of the breast, head and neck, Ewing’s sarcoma, osteosarcoma, and others. Past attempts to target IGF-1R with non-payload-bearing mAbs or small molecules produced a range of outcomes including some partial and complete responses. None were ultimately approved, potentially due to suboptimal potency from redundant signaling. Herein, we conducted a post hoc analysis of LX-101’s activity in patients with high tumor IGF-1R expression from prior phase I trials.
Methods
IHC staining for IGF-1R expression was performed on FFPE tumor specimens (Ventana G11, DAKO PharmDx). IGF-1R expression was analyzed both qualitatively and quantitatively by 2 board-certified pathologists, with intensity score (IS) and proportion score (PS) combined to create a Q score (range 0-7). Our retrospective, post hoc analysis considered Q scores ≥ 6 and PS ≥ 90% to constitute high IGF-1R expression.
Results
Of 19 heavily pretreated patients who received LX-101, 4 had high tumor IGF-1R expression. Of 3 evaluable patients, 67% (2/3) experienced disease control. Notably, one of these patients was treated at the highest tested dose and was the only patient in the cohort (n=7) to achieve an objective response. The other two evaluable high IGF-1R expressers were treated at lower doses and included a patient who achieved stable disease with pathologic complete response.
Conclusions
Our analysis demonstrates that patients with high IGF-1R-expressing tumors can benefit from LX-101. These data support clinical development of LX-101 in cancers with well-established ties to the IGF-1R pathway. New clinical trials, enriched for such tumor types, are planned.
Clinical trial identification
NCT02045368.
Editorial acknowledgement
Legal entity responsible for the study
Lirum Therapeutics.
Funding
Lirum Therapeutics, IGF Oncology.
Disclosure
A.Z. Dudek: Financial Interests, Personal, Advisory Role: Lirum Therapeutics. M. Hoberman: Financial Interests, Institutional, Full or part-time Employment: Lirum Therapeutics.