In vitro activity: Avapritinib (formerly known as BlU-285) is a potent and selective small molecule inhibitor of PDGFRα D842V and KIT Exon 17 mutants with IC50 of 0.5 nM. It is being developed as a highly targeted therapy to treat SM (systemic mastocytosis), which is a disorder of the mast cells in which a KIT Exon 17 mutation is the primary driver of disease. In phase I trial for the treatment of advanced systemic mastocytosis, patients experienced rapid and durable disease control. The overall response rate was 72%, and 56% of patients experienced a complete or partial response. No patients discontinued treatment due to adverse events, most of which were mild to moderate in nature. In addition, BLU-285 may be a potential therapeutic option for KIT exon 17-mutated CBF-AMLs and t(8;21) AMLs in particular.

Kinase Assay: Avapritinib (BLU-285) has demonstrated biochemical in vitro activity on the KIT exon 17 mutant enzyme, KIT D816V (IC50=0.27 nM).

Cell Assay: Cellular activity of Avapritinib on KIT D816 mutants is measured by autophosphorylation in the human mast cell leukemia cell line HMC1.2, and the P815 mouse mastocytoma cell line with IC50=4 and 22 nM, respectively. In Kasumi-1 cells, a t(8;21)-positive AML cell line with a KIT exon 17 N822K mutation, Avapritinib potently inhibits KIT N822K mutant autophosphorylation (IC50=40 nM), downstream signaling, as well as cellular proliferation (IC50=75 nM).

(1) NMRI nu/nu mice (n = 93) were transplanted with human GIST xenografts with KIT exon 11+17 (UZLX-GIST9 ^{KIT 11+17} ), exon 11 (UZLX-GIST3 ^{KIT 11} ), or exon 9 (UZLX-GIST2B ^KIT9 ) mutations, respectively. We compared avapritinib (10 and 30 mg/kg/once daily) versus vehicle, imatinib (50 mg/kg/bid) or regorafenib (30 mg/kg/once daily; UZLX-GIST9 ^KIT11+17 ); avapritinib (10, 30, 100 mg/kg/once daily) versus vehicle or imatinib [UZLX-GIST3 ^KIT11 ]; and avapritinib (10, 30, 60 mg/kg/once daily) versus vehicle, imatinib (50, 100 mg/kg/twice daily), or sunitinib (40 mg/kg/once daily; UZLX-GIST2B ^KIT9 ). [1]

(2) Avapritinib (BLU-285) is well tolerated and has demonstrated dose dependent antitumor efficacy. Complete tumor growth inhibition and ≥75% KIT kinase inhibition is observed with 10 mg/kg once daily, oral dosing of Avapritinib in the aggressive KIT exon 17 mutant driven P815 mastocytoma model grown as a solid tumor allograft as well as in a disseminated model of disease. Disease burden, measured by whole body luciferase imaging (photons/second/mm2), increases 86-fold in the vehicle control animals over the 24 day dosing period with widespread disease detectable in both femurs, the pelvis and circulating in peripheral blood. Disease in the Cytarabine-treated animals advanced more slowly with a 15-fold increase in luciferase values over the course of the experiment. Strikingly, Avapritinib at both doses (10 or 30 mg/kg orally, once daily) results in a marked reduction of disease burden throughout the study as compared to both vehicle controls and animals receiving Cytarabine. Avapritinib at either 10 or 30 mg/kg results in tumor regression in all animals with disease abrogation indistinguishable from background signal measurements in several animals by the end of study. Avapritinib is also well tolerated in this in vivo model and has no adverse effects on body weight at either dose. [2]

[1] Clin Cancer Res. 2019 Jan 15;25(2):609-618.

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