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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 (2019) In process.
Abstract
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.
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Publication Date: 2019-12-02.
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Last updated on Friday, January 03, 2020