TY - JOUR
T1 - Linsitinib (OSI-906) for the treatment of adult and pediatric wild-type gastrointestinal stromal tumors, a SARC phase II study
AU - Von Mehren, Margaret
AU - George, Suzanne
AU - Heinrich, Michael C.
AU - Schuetze, Scott M.
AU - Yap, Jeffrey T.
AU - Yu, Jain Q.
AU - Abbott, Amanda
AU - Litwin, Samuel
AU - Crowley, John
AU - Belinsky, Martin
AU - Janeway, Katherine A.
AU - Hornick, Jason L.
AU - Flieder, Douglas B.
AU - Chugh, Rashmi
AU - Rink, Lori
AU - Van Den Abbeele, Annick D.
N1 - Funding Information:
S. George is an employee/paid consultant for Blueprint Medicines, Deciphera Pharmaceuticals, Bayer, AstraZeneca, Eli Lilly, Exelixis, and Daiichi Sankyo. M.C. Heinrich is an employee/paid consultant for Deciphera Pharmaceuticals, Blueprint Pharmaceuticals, MolecularMD; reports receiving other commercial research support from Deciphera Pharmaceuticals and Blueprint Medicines; holds ownership interest (including patents) in MolecularMD and Novartis; and reports receiving other remuneration from Novartis. K.A. Janeway is an employee/paid consultant for Bayer. J.L. Hornick is an employee/paid consultant for Eli Lilly and Epizyme. R. Chugh reports receiving commercial research grants from Plexxikon. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
The authors thank the patients and their families for participating in this study. They acknowledge the efforts of all the investigators, the clinical trial nurses, and coordinators who participated in the conduct of this trial. In addition, the support of John Wright, MD, PhD of CTEP, and collaborators at Astella Pharmaceuticals was central to the ability to carry out this clinical research. This work was funded in part by NCI R21CA150381 (M. von Mehren and A.D. Van den Abbeele); P30 CA006927 (PRMS and use of Protocol Support Laboratory); and the GIST Cancer Research Fund. The authors also acknowledge the contribution of SARC for partial funding of this trial.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/4/15
Y1 - 2020/4/15
N2 - Purpose: Most gastrointestinal stromal tumors (GIST) have activating mutations of KIT, PDGFRA, or uncommonly BRAF. Fifteen percent of adult and 85% of pediatric GISTs 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 patients with WT GIST. Patients and Methods: A multicenter phase II trial of linsitinib was conducted. The primary endpoint was objective response rate. Secondary endpoints were clinical benefit rate: complete response, partial response, and stable disease (SD) ≥ 9 months, and quantitative 2[18F]fluoro-2-deoxy-D-glucose (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. Clinical benefit rate (CBR) at 9 months was 40%. Intense FDG uptake was observed at baseline, with partial MR of 12% and stable metabolic disease of 65% at week 8; these patients had RECIST 1.1 SD as their best response. Progression-free survival (PFS) and overall survival Kaplan-Meier estimates at 9 months were 52% and 80%, respectively. SDHA/B loss determined by IHC was seen in 35% and 88% of cases, respectively. Conclusions: Linsitinib is well tolerated in patients with WT GIST. Although the 9-month CBR was 40%, and PFS at 9 months was 52%, no objective responses were observed. Rapid accrual to this study demonstrates that clinical trials of experimental agents in selected subtypes of GIST are feasible.
AB - Purpose: Most gastrointestinal stromal tumors (GIST) have activating mutations of KIT, PDGFRA, or uncommonly BRAF. Fifteen percent of adult and 85% of pediatric GISTs 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 patients with WT GIST. Patients and Methods: A multicenter phase II trial of linsitinib was conducted. The primary endpoint was objective response rate. Secondary endpoints were clinical benefit rate: complete response, partial response, and stable disease (SD) ≥ 9 months, and quantitative 2[18F]fluoro-2-deoxy-D-glucose (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. Clinical benefit rate (CBR) at 9 months was 40%. Intense FDG uptake was observed at baseline, with partial MR of 12% and stable metabolic disease of 65% at week 8; these patients had RECIST 1.1 SD as their best response. Progression-free survival (PFS) and overall survival Kaplan-Meier estimates at 9 months were 52% and 80%, respectively. SDHA/B loss determined by IHC was seen in 35% and 88% of cases, respectively. Conclusions: Linsitinib is well tolerated in patients with WT GIST. Although the 9-month CBR was 40%, and PFS at 9 months was 52%, no objective responses were observed. Rapid accrual to this study demonstrates that clinical trials of experimental agents in selected subtypes of GIST are feasible.
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U2 - 10.1158/1078-0432.CCR-19-1069
DO - 10.1158/1078-0432.CCR-19-1069
M3 - Article
C2 - 31792037
AN - SCOPUS:85083496811
VL - 26
SP - 1837
EP - 1845
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 8
ER -