KIT exon 17 mutants conferring ligand-independent constitutive kinase activity are known drivers of disease in both solid tumors and hematologic malignancies. KIT Exon 17 mutations have been identified in several human diseases such as systemic mastocytosis (SM), as resistance mutations in second and third line gastrointestinal stromal tumor (GIST), and certain subsets of acute myeloid leukemia (AML). We have developed BLU-285, a potent and selective exon 17 mutant KIT kinase inhibitor. BLU-285 has demonstrated biochemical in vitro activity on the KIT exon 17 mutant enzyme, KIT D816V (half-maximal inhibitory concentration [IC50] = 0.27 nM). Cellular activity of BLU-285 on KIT D816 mutants was 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 vivo BLU-285 was well tolerated and has demonstrated dose dependent antitumor efficacy. Complete tumor growth inhibition and ≥ 75% KIT kinase inhibition was observed with 10 mg/kg once daily, oral dosing of BLU-285 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.

In AML, KIT mutations represent an uncommon molecular alteration. Yet in a defined subset of AML with core binding factor genomic rearrangements characterized by either t(8;21) or inv(16)(CBF-AML), approximately 25% of patients have an additional KIT exon 17 mutation at positions such as D816 or N822. In the case of t(8;21) AMLs, the presence of a KIT exon 17 mutation places a patient in an intermediate risk category with higher recurrence rates and lower median overall survival than t(8;21) patients without a KIT exon 17 mutation. In Kasumi-1 cells, a t(8;21)-positive AML cell line with a KIT exon 17 N822K mutation, BLU-285 potently inhibits KIT N822K mutant autophosphorylation (IC50 = 40 nM), downstream signaling, as well as cellular proliferation (IC50 = 75 nM). A Kasumi-1 luc+ AML NOG SCID mouse femoral injection model was used to assess the efficacy of BLU-285 in KIT exon 17-mutated CBF-AML. Following a 21 day post injection latency period, mice were dosed with BLU-285 orally, once daily at 10 mg/kg or 30 mg/kg through day 45. Control groups were treated with vehicle or cytarabine administered 100 mg/kg i.p once weekly. Disease burden, measured by whole body luciferase imaging (photons/second/mm2), increased 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, BLU-285 at both doses (10 or 30 mg/kg orally, once daily) resulted in a marked reduction of disease burden throughout the study as compared to both vehicle controls and animals receiving cytarabine. BLU-285 at either 10 or 30 mg/kg resulted in tumor regression in all animals with disease abrogation indistinguishable from background signal measurements in several animals by the end of study. BLU-285 was also well tolerated in this in vivo model and had no adverse effects on body weight at either dose. Recently, a phase 1 clinical trial for the treatment of relapsed or refractory GIST with BLU-285 has been initiated. In addition, a clinical trial in SM, where KIT exon 17 mutations are believed to be genetic drivers of disease, is scheduled to begin in 2015. These data suggest that KIT exon 17-mutated CBF-AMLs and t(8;21) AMLs in particular, may be an additional therapeutic indication for the clinical evaluation of BLU-285.


Evans:Blueprint Medicines: Employment, Equity Ownership. Gardino:Blueprint Medicines: Employment, Equity Ownership. Hodous:Blueprint Medicines: Employment, Equity Ownership. Davis:Blueprint Medicines: Employment, Equity Ownership. Zhu:Blueprint Medicines: Employment, Equity Ownership. Kohl:Blueprint Medicines: Employment, Equity Ownership. Lengauer:Blueprint Medicines: Employment, Equity Ownership.

Author notes


Asterisk with author names denotes non-ASH members.

Sign in via your Institution