Anti-tumor effects of the novel KIT mutant inhibitor M4205 in gastrointestinal stromal tumor (GIST) xenograft models

Majority of GIST are driven by constitutively activated KIT/PDGFRA kinases and susceptible to treatment with tyrosine kinase inhibitors. During treatment most 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 M4205, a novel specific KIT inhibitor* with high activity towards the most relevant KIT mutations, in GIST xenograft models. * Blum et al. Proceedings: AACR Annual Meeting 2021. NMRI nu/nu mice were transplanted with patient-derived GIST xenograft models UZLX-GIST9 (KIT:p.P577del;W557LfsX5;D820G) known to be resistant to both imatinib and sunitinib, with the dose-dependent imatinib-sensitive and sunitinib-sensitive models 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), avapritinib (5mg/kg), sunitinib (20mg/kg), or M4205 (10mg/kg, 25mg/kg). Efficacy was assessed by tumor volume evolution, histopathology and immunohistochemistry. Histologic response (HR) was graded as previously described°. Mann Whitney U and Wilcoxon Matched Pairs tests were used for statistical analysis, with p<0.05 considered as significant. Agaram et al. Clin Cancer Res. 2007. M4205 (25mg/kg) caused tumor volume shrinkage in UZLX-GIST2B, -GIST25 and GIST882 with relative decrease to 45.6%, 35.1% and 57.3% on the last day as compared to baseline. In UZLX-GIST9 tumor growth to 132.4% was observed in M4205 (25mg/kg)-treated tumors as compared to baseline. We observed antitumor activity superior to imatinib in UZLX-GIST9, -GIST2B and GIST882, and to sunitinib in -GIST25. Compared to controls, M4205 (25mg/kg) induced a significant decrease in mitosis in all models. In -GIST25 and GIST882 grade 2-4 HR with myxoid degeneration was observed in all tumors. M4205 has significant antitumor activity in patient- and cell line-derived GIST xenograft models. The novel kinase inhibitor induces volumetric responses, decreases mitotic activity, has antiproliferative effects and in models with KIT exon 13 mutation leads to characteristic myxoid degeneration.