1514P 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 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 M4205, a specific inhibitor* high activity towards relevant mutations, xenograft models. * Blum et al. Proceedings: AACR Annual Meeting 2021. NMRI nu/nu mice were transplanted patient-derived models UZLX-GIST9 (KIT:p.P577del;W557LfsX5;D820G) known be resistant both imatinib sunitinib, dose-dependent imatinib-sensitive sunitinib-sensitive UZLX-GIST2B (KIT:p.A502_Y503dup), UZLX-GIST25 (KIT: p.K642E) cell-line derived model GIST882 p.K642E). Mice treated daily vehicle (control), (100mg/kg), avapritinib (5mg/kg), sunitinib (20mg/kg), M4205 (10mg/kg, 25mg/kg). Efficacy was assessed tumor volume evolution, histopathology immunohistochemistry. Histologic response (HR) graded as previously described°. Mann Whitney U Wilcoxon Matched Pairs tests used statistical analysis, p<0.05 considered significant. Agaram Clin Cancer Res. 2007. (25mg/kg) caused shrinkage UZLX-GIST2B, -GIST25 relative decrease 45.6%, 35.1% 57.3% on last day compared baseline. In growth 132.4% observed (25mg/kg)-treated antitumor superior UZLX-GIST9, -GIST2B GIST882, -GIST25. Compared controls, induced significant mitosis all grade 2-4 HR myxoid degeneration tumors. has patient- cell line-derived The inhibitor induces volumetric responses, decreases mitotic activity, antiproliferative effects exon 13 mutation leads characteristic degeneration.