Background: In the majority of GISTs, oncogenic signaling is driven by mutated KIT. Patients are treated with tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib or regorafenib. Resistance to TKIs is mainly caused by secondary KIT mutations in exons 13 and 17. BLU-285 was developed at Blueprint Medicines as a potent and selective inhibitor of exon 17 mutant KIT. We investigated the efficacy of BLU-285 in a TKI-resistant KIT exon 11/17 mutant GIST PDX model. Methods: NMRI nu/nu mice were bilaterally transplanted with the human GIST xenograft, UZLX-GIST9, which carries KIT:p.P577del;W557LfsX5;D820G mutations. Mice were divided into 5 groups: control (vehicle), imatinib (50 mg/kg/bid), regorafenib (30 mg/kg/qd) and two doses of BLU-285 (10 and 30 mg/kg/qd). Animals were dosed orally for 16 days. Efficacy was assessed by tumor volume measurement, histopathology, immunohistochemistry [Ki67, pHistone H3, cleaved PARP, pMAPK] and immunoblot analysis of KIT signaling. Histologic response (HR) was graded as previously described^*. Mann Whitney U test was used for statistical analysis, and a p value of < 0.05 was considered significant. Results: BLU-285 was well tolerated at all administered doses. 30 mg/kg BLU-285 resulted in significant tumor regression (27% of baseline), ≥ grade 2 HR in 60% of tumors and complete absence of proliferation. The anti-tumor effects observed with BLU-285 were significantly better than that seen with either imatinib or regorafenib. Compared to control, BLU-285 (30 mg/kg) significantly increased apoptosis (3.4-fold; p < 0.001), comparable to regorafenib. At 10 mg/kg, BLU-285 stabilized tumor volume (83% of baseline) and had significant antiproliferative effects (27-fold decrease, p < 0.001). Both doses led to a pronounced decrease of pMAPK and KIT signaling. Conclusions: BLU-285 showed dose-dependent, robust anti-tumor efficacy in a TKI- resistant KIT exon 11/17 mutant GIST PDX model through inhibition of tumor growth, proliferation, KIT signaling and induction of apoptosis. These data support the ongoing phase I clinical trial NCT02508532. * Antonescu CR, et al. Clin Cancer Res 2005; 11:4182–90