Robust activity of avapritinib, potent and highly selective inhibitor of mutated KIT, in patient-derived xenograft models of gastrointestinal stromal tumors

Purpose: Gastrointestinal stromal tumors (GIST) are commonly treated with tyrosine kinase inhibitors (TKI). The majority of patients with advanced GIST ultimately become resistant to TKI due to acquisition of secondary KIT mutations, while primary resistance is mainly caused by PDGFRA p.D842V mutation. We tested the activity of avapritinib, potent and highly selective inhibitor of mutated KIT and PDGFRA, in three patient-derived xenograft (PDX) GIST models carrying different KIT mutations, with differential sensitivity to standard TKI. Experimental Design: NMRI nu/nu mice (n=93) were transplanted with human GIST xenografts with KIT exon 11+17 (UZLX-GIST9^KIT11+17), exon 11 (UZLX-GIST3^KIT11) or exon 9 (UZLX-GIST2B^KIT9) mutations, respectively. We compared avapritinib (10 and 30 mg/kg/qd) vs. vehicle, imatinib (50 mg/kg/bid) or regorafenib (30 mg/kg/qd) [UZLX-GIST9^KIT11+17]; avapritinib (10, 30, 100 mg/kg/qd) vs. vehicle or imatinib [UZLX-GIST3^KIT11]; and avapritinib (10, 30, 60 mg/kg/qd) vs. vehicle, imatinib (50, 100 mg/kg/bid) or sunitinib (40 mg/kg/qd) [UZLX-GIST2B^KIT9].Results: In all models avapritinib resulted in reduction of tumor volume, significant inhibition of proliferation and reduced KIT signaling. In two models, avapritinib led to remarkable histologic responses, increase in apoptosis and inhibition of MAPK-phosphorylation. Avapritinib showed superior (UZLX-GIST9^{KIT 11+17} and -GIST2B^KIT9) or equal (UZLX-GIST3^KIT11) anti-tumor activity to standard dose of imatinib. In UZLX-GIST9^KIT11+17, the anti-tumor effects of avapritinib were significantly better than with imatinib or regorafenib. Conclusions: Avapritinib has significant anti-tumor activity in GIST PDX models characterized by different KIT mutations and sensitivity to established TKI. These data provide strong support for ongoing clinical trials with avapritinib in patients with GIST (NCT02508532, NCT03465722).

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