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Ref Type

Journal Article

PMID

(30274985)

Authors

Gebreyohannes YK, Wozniak A, Zhai ME, Wellens J, Cornillie J, Vanleeuw U, Evans E, Gardino AK, Lengauer C, Debiec-Rychter M, Sciot R, Schöffski P

Title

Robust Activity of Avapritinib, Potent and Highly Selective Inhibitor of Mutated KIT, in Patient-derived Xenograft Models of Gastrointestinal Stromal Tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	25	2	2019 01 15	609-618	Clin Cancer Res

URL

Abstract Text

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, whereas primary resistance is mainly caused by PDGFRA p.D842V mutation. We tested the activity of avapritinib, a 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 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 ).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 KIT 9 ) or equal (UZLX-GIST3 KIT 11 ) antitumor activity to the standard dose of imatinib. In UZLX-GIST9 KIT 11+17 , the antitumor effects of avapritinib were significantly better than with imatinib or regorafenib.Avapritinib has significant antitumor activity in GIST PDX models characterized by different KIT mutations and sensitivity to established TKI. These data provide strong support for the ongoing clinical trials with avapritinib in patients with GIST (NCT02508532, NCT03465722).

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Molecular Profile	Treatment Approach
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Avapritinib	Avapritinib	69	8

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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Avapritinib	Ayvakit	BLU-285	KIT Inhibitor 57 PDGFR-alpha Inhibitor 10	Ayvakit (avapritinib) is a selective inhibitor of PDGFRA D842V and KIT exon 17 mutants, including KIT D816V, potentially resulting in decreased tumor growth (PMID: 30274985). Ayvakit (avapritinib) is FDA approved for use in patients with unresectable or metastatic gastrointestinal stromal tumor harboring a PDGFRA exon 18 mutation, including D842V, and in patients with advanced systemic mastocytosis (FDA.gov).

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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KIT A502_Y503dup	gastrointestinal stromal tumor	sensitive	Avapritinib	Preclinical - Pdx	Actionable	In a preclinical study, a patient derived xenograft (PDX) model with a gastrointestinal stromal tumor harboring KIT A502_Y503dup was sensitive to treatment with Ayvakit (avapritinib), demonstrating a 90% stabilized tumor volume at a dose of 30mg/kg and tumor regression at a dose of 60mg/kg, and inhibition of cell proliferation (PMID: 30274985).	30274985
KIT W557Lfs*5 KIT P577del KIT D820G	gastrointestinal stromal tumor	sensitive	Avapritinib	Preclinical - Pdx	Actionable	In a preclinical study, a patient derived xenograft (PDX) model with a gastrointestinal stromal tumor harboring KIT W557Lfs*5, KIT P577del, and KIT D820G was sensitive to treatment with Ayvakit (avapritinib), demonstrating a stabilized tumor volume at a dose of 10mg/kg and 27% tumor regression at a dose of 30mg/kg, a histologic response, and apoptotic activity (PMID: 30274985).	30274985

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