American Association for Cancer Research
10780432ccr181858-sup-203463_2_supp_5025746_pwxtkw.pdf (173.42 kB)

Supplementary Table S1 from Robust Activity of Avapritinib, Potent and Highly Selective Inhibitor of Mutated KIT, in Patient-derived Xenograft Models of Gastrointestinal Stromal Tumors

Download (173.42 kB)
journal contribution
posted on 2023-03-31, 21:43 authored by Yemarshet K. Gebreyohannes, Agnieszka Wozniak, Madalina-Elena Zhai, Jasmien Wellens, Jasmien Cornillie, Ulla Vanleeuw, Erica Evans, Alexandra K. Gardino, Christoph Lengauer, Maria Debiec-Rychter, Raf Sciot, Patrick Schöffski

Grading scheme for pMAPK immunostaining. Staining was graded based on the intensity of the staining and the percent of tumor area showing pMAPK positivity.



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-GIST9KIT 11+17), exon 11 (UZLX-GIST3KIT 11), or exon 9 (UZLX-GIST2BKIT9) 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-GIST9KIT11+17); avapritinib (10, 30, 100 mg/kg/once daily) versus vehicle or imatinib [UZLX-GIST3KIT11]; 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-GIST2BKIT9). 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-GIST9KIT 11+17 and -GIST2BKIT 9) or equal (UZLX-GIST3KIT 11) antitumor activity to the standard dose of imatinib. In UZLX-GIST9KIT 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).

Usage metrics

    Clinical Cancer Research



    Ref. manager