Objective: Patients with advanced and treatment-resistant GIST are treated with tyrosine kinase inhibitors (TKI) such as imatinib (IMA), sunitinib (SUN) or regorafenib (REG). Resistance to these TKI is mainly caused by the emergence of on-target secondary KIT mutations in exons 13 and 17. We tested the activity of BLU-285 (Blueprint Medicines), a potent and highly selective inhibitor of mutant KIT and PDGFRα, in three PDX models of primary and refractory GIST that respond differently to the approved TKI used in the treatment of GIST. Methods: NMRI nu/nu mice (n=93) were transplanted bilaterally with human xenografts UZLX-GIST3 (KIT: exon 11 p.W557_V559delinsF; IMA-sensitive), GIST2B (KIT: exon 9 p.A502_Y503dup, IMA dose-dependent sensitive) and GIST9 (KIT: exon 11 p.P577del; W557LfsX5; exon 17 D820G; IMA and SUN-resistant). We performed the following experimental comparisons: BLU-285 (10, 30 and 100 mg/kg/qd) vs. control and IMA (50 mg/kg/bid) [GIST3]; BLU-285 (10, 30 and 60 mg/kg/qd) vs. control and IMA (50 and 100 mg/kg/bid or SUN 40 mg/kg/qd) [GIST2B]; and BLU-285 (10 and 30 mg/kg/qd) vs. control, IMA (50 mg/kg/bid) or REG (30 mg/kg/qd) [GIST9]. Animals were dosed orally for 16 days. Activity was assessed by tumor volume measurement, histopathology and Western blotting of the KIT signaling pathway (WB). Mann Whitney U test was used for statistical analysis. A p value <0.05 was considered significant. Results: In all models, BLU-285 resulted in a dose dependent reduction of tumor volume, significant inhibition of proliferation (p < 0.005 compared to the control in all models, at all doses tested), and inhibition of KIT signaling as assessed by WB. In two models, BLU-285 led to a higher histologic response (graded as described previously by Antonescu et al. 2005), a significant increase of apoptosis (p < 0.005 compared to the control in both models, at all doses tested), and a pronounced decrease in MAPK phosphorylation as compared to the control. The activity of BLU-285 was similar (GIST3) or better (GIST2B and GIST9) than a standard dose of IMA. In the IMA-resistant model (GIST9), the anti-tumor effects of BLU-285 were significantly better those seen with either IMA or REG. BLU-285 was well tolerated at all administered doses. Conclusions: BLU-285, an investigational agent, has significant anti-tumor effects in GIST PDX models characterized by different KIT mutations and variable sensitivity to established TKI therapies. These data support the therapeutic rationale for the ongoing Phase I clinical trial being conducted by Blueprint Medicines (NCT02508532) and provide further evidence that BLU-285 has the potential to be an important treatment option for patients with PDGFRα or KIT-driven GIST.

Citation Format: Yemarshet K. Gebreyohannes, Agnieszka Wozniak, Madelina-Elena Zhai, Jasmien Wellens, Jasmien Cornillie, Erica Evans, Alexandra K Gardino, Christoph Lengauer, Maria Debiec-Rychter, Raf Sciot, Patrick Schöffski. Robust activity of BLU-285, a potent and highly selective inhibitor of mutant KIT and PDGFRα, in patient-derived xenograft (PDX) models of gastrointestinal stromal tumor (GIST) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2081. doi:10.1158/1538-7445.AM2017-2081