Data from Anti-tumor efficacy of the novel <i>KIT</i> inhibitor IDRX-42 (formerly M4205) in patient- and cell line-derived xenograft models of gastrointestinal stromal tumor (GIST)

Abstract

<div>Abstract<p>Background: The majority of GIST are driven by constitutively activated KIT/PDGFRA kinases and are susceptible to treatment with tyrosine kinase inhibitors. During treatment, most of these tumors will develop secondary mutations in <i>KIT</i> or <i>PDGFRA</i> inducing drug resistance, so there is an unmet need for novel therapies. We tested the efficacy of IDRX-42, a novel selective <i>KIT</i> inhibitor with high activity towards the most relevant <i>KIT </i>mutations, in 4 GIST xenograft models. Methods: NMRI <i>nu/nu</i> mice were transplanted with patient-derived GIST xenograft models UZLX-GIST9 (<i>KIT</i>:p.P577del;W557LfsX5;D820G), UZLX-GIST2B (<i>KIT</i>:p.A502_Y503dup), UZLX-GIST25 (<i>KIT</i>:p.K642E) and the cell-line derived model GIST882 (<i>KIT</i>:p.K642E). Mice were treated daily with vehicle (control), imatinib (100mg/kg), sunitinib (20mg/kg), avapritinib (5mg/kg), or IDRX-42 (10mg/kg, 25mg/kg). Efficacy was assessed by tumor volume evolution, histopathology, grading of histological response and immunohistochemistry. The Kruskal-Wallis and Wilcoxon Matched Pairs tests were used for statistical analysis, with p<0.05 considered as significant. Results: IDRX-42 (25mg/kg) caused tumor volume shrinkage in UZLX-GIST25, GIST882 and UZLX-GIST2B, with a relative decrease to 45.6%, 57.3% and 35.1% on the last day as compared to baseline, and tumor growth delay (160.9%) compared to control in UZLX-GIST9. Compared to controls, IDRX-42 (25mg/kg) induced a significant decrease in mitosis. In UZLX-GIST25 and GIST882 grade 2-4 HR with myxoid degeneration was observed in all IDRX-42 (25mg/kg)-treated tumors. Conclusion: IDRX-42 showed significant antitumor activity in patient- and cell line-derived GIST xenograft models. The novel kinase inhibitor induced volumetric responses, decreased mitotic activity and had antiproliferative effects. In models with <i>KIT </i>exon 13 mutation IDRX-42 induced characteristic myxoid degeneration.</p></div>