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von Mehren M , George S , Heinrich MC , Schuetze SM , Yap JT , Yu JQ , Abbott A , Litwin S , Crowley J , Belinsky M , Janeway KA , Hornick JL , Flieder DB , Chugh R , Rink LA , Van den Abbeele AD
Linsitinib (OSI-906) for the treatment of Adult and Pediatric Wild Type Gastrointestinal Stromal Tumors, a SARC Phase II study
Clin Cancer Res. 2020 Apr 15;26(8) :1837-1845
PMID: 31792037    PMCID: PMC7856429    URL: https://www.ncbi.nlm.nih.gov/pubmed/31792037
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PURPOSE: Most GISTs have activating mutations of KIT, PDGFRA, or uncommonly BRAF. Fifteen percent of adult and 85% of pediatric GIST are wild type (WT), commonly having high expression of IGF-1R and loss of succinate dehydrogenase (SDH) complex function. We tested the efficacy of linsitinib, an oral TKI IGF-1R inhibitor in WT GIST patients. EXPERIMENTAL DESIGN: A multi-center phase II trial of linsitinib was conducted. The primary endpoint was objective response rate. Secondary endpoints were clinical benefit rate: CR, PR and SD>/=9 months, and quantitative FDG metabolic response (MR) at week 8. Serum levels for glucose, insulin, IGF-1R ligand IGF1, and binding proteins were obtained to explore correlations to patient outcomes and FDG-PET results. RESULTS: Twenty patients were accrued in a 6 month period. Grade 3-4 toxicities possibly related to linsitinib were uncommon (8.5%). No objective responses were seen. CBR at 9 months was 40%. Intense FDG uptake was observed at baseline, with partial MR of 12% and stable MD of 65% at week 8; these patients had RECIST 1.1 SD as their best response. PFS and OS Kaplan Meier estimates at 9 months were 52% and 80%, respectively. SDHA/B loss determined by immunohistochemistry was seen in 35% and 88% of cases, respectively. CONCLUSIONS: Linsitinib is well tolerated in patients with WT GIST. While the 9 month CBR was 40%, and PFS at 9 months was 52%, no objective responses were observed. Rapid accrual to this study demonstrates clinical trials of experimental agents in selected subtypes of GIST are feasible.
von Mehren, Margaret George, Suzanne Heinrich, Michael C ORCID: https://orcid.org/0000-0003-3790-0478 Schuetze, Scott M ORCID: https://orcid.org/0000-0002-7167-4163 Yap, Jeffrey T Yu, Jian Q Abbott, Amanda Litwin, Samuel Crowley, John Belinsky, Martin Janeway, Katherine A Hornick, Jason L ORCID: https://orcid.org/0000-0001-6475-8345 Flieder, Douglas B Chugh, Rashmi Rink, Lori A Van den Abbeele, Annick D Journal Article United States Clin Cancer Res. 2020 Apr 15;26(8):1837-1845. doi: 10.1158/1078-0432.CCR-19-1069. Epub 2019 Dec 2.