Abstract 2081: Robust activity of BLU 285, a potent and highly selective inhibitor of mutant KIT and PDGFRa, in patient derived xenograft (PDX) models of gastrointestinal stromal tumor (GIST)
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 PDGFRa, 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 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 Schoffski. Robust activity of BLU 285, a potent and highly selective inhibitor of mutant KIT and PDGFRa, 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