Antitumor Efficacy of the Novel KIT Inhibitor IDRX-42 (Formerly M4205) in Patient- and Cell Line–Derived Xenograft Models of Gastrointestinal Stromal Tumor (GIST)

Abstract

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 KIT or PDGFRA inducing drug resistance, so there is an unmet need for novel therapies. We tested the efficacy of IDRX-42, a novel selective KIT inhibitor with high activity towards the most relevant KIT mutations, in 4 GIST xenograft models. Methods: NMRI nu/nu mice were transplanted with patient-derived GIST xenograft models UZLX-GIST9 (KIT:p.P577del;W557LfsX5;D820G), UZLX-GIST2B (KIT:p.A502_Y503dup), UZLX-GIST25 (KIT:p.K642E) and the cell-line derived model GIST882 (KIT: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 KIT exon 13 mutation IDRX-42 induced characteristic myxoid degeneration.

Recent advances in the systemic treatment of gastrointestinal stromal tumors

“…In addition, there are a number of very promising agents in development. In early 2023, a small molecule imidazopyridine (IDRX-42) demonstrated excellent kinase selectivity and a relative shrinkage of tumors (up to 57.3%) in patient- and cell line–derived xenograft models 17 . The results of the clinical trial not only with IDRX-42 but also of NB003 in advanced GIST are also eagerly awaited 18 , 19 .…”