TY - JOUR
T1 - Phase II Study of Ponatinib in Advanced Gastrointestinal Stromal Tumors
T2 - Efficacy, Safety, and Impact of Liquid Biopsy and Other Biomarkers
AU - George, Suzanne
AU - von Mehren, Margaret
AU - Fletcher, Jonathan A.
AU - Sun, Jichao
AU - Zhang, Sen
AU - Pritchard, Justin R.
AU - Hodgson, John Graeme
AU - Kerstein, David
AU - Rivera, Victor M.
AU - Haluska, Frank G.
AU - Heinrich, Michael C.
N1 - Funding Information:
S. George reports grants from ARIAD during the conduct of the study; grants from Blueprint Medicines, Deciphera, Daiichi Sankyo, Pfizer, Bayer, Merck, Eisai, and Springworks, personal fees from Blueprint Medicines, Deciphera, Immuni-cum, and Kayothera, and other support from WCG outside the submitted work. M. von Mehren reports personal fees and other support from Deciphera, Novartis, and Blueprint, and personal fees from Exelixis during the conduct of the study; grants from Novartis outside the submitted work. J.A. Fletcher reports a patent for Imatinib licensed to Novartis. S. Zhang reports other support from ARIAD and EMD Serono outside the submitted work. J.R. Pritchard reports other support from ARIAD Pharmaceuticals during the conduct of the study; grants from Theseus Pharmaceuticals, personal fees from Theseus Pharmaceuticals, Moma Therapeutics, Third Rock Ventures, and Takeda Pharmaceuticals, and other support from Theseus Pharmaceuticals and Moma Therapeutics outside the submitted work. D. Kerstein reports other support from ARIAD Pharmaceuticals during the conduct of the study and other support from Theseus Pharmaceuticals outside the submitted work. V.M. Rivera reports other support from ARIAD Pharmaceuticals and other support from Theseus Pharmaceuticals outside the submitted work. F.G. Haluska reports other support from ARIAD Pharmaceuticals during the conduct of the study. M.C. Heinrich reports grants from ARIAD during the conduct of the study; personal fees and other support from MolecularMD, personal fees from Novartis, and grants and personal fees from Blueprint Medicines and Deciphera Pharmaceuticals outside the submitted work; in addition, M.C. Heinrich has a patent for Treatment of GIST issued, licensed, and with royalties paid from Novartis. No disclosures were reported by the other authors.
Funding Information:
This study is sponsored by Takeda Development Center Americas, Inc. M.C. Heinrich received partial salary support from a Merit Review grant from the U.S. Department of Veterans Affairs (1IOBX005358-01) and a grant from the NCI (R21CA263400).
Publisher Copyright:
© 2022 The Authors.
PY - 2022/4/1
Y1 - 2022/4/1
N2 - Purpose: The purpose of this study is to evaluate ponatinib for advanced gastrointestinal stromal tumors (GIST). Patients and Methods: This single-arm phase II trial enrolled patients with metastatic and/or unresectable GIST with failure of prior tyrosine kinase inhibitor (TKI) treatment into two cohorts based on presence or absence of KIT exon 11 (ex11) primary mutations. Patients initially received ponatinib 45 mg once daily. Following a temporary clinical hold in October 2013, dose reductions were implemented to reduce risk of arterial occlusive events (AOE). Primary endpoint was 16-week clinical benefit rate (CBR) in KIT ex11–positive cohort. KIT mutations in circulating tumor DNA (ctDNA) were assessed. Results: Forty-five patients enrolled (30 KIT ex11–positive and 15 KIT ex11–negative); median follow-up was 14.7 and 13.6 months, respectively, as of August 1, 2016. Sixteen-week CBR was 36% (KIT ex11–positive; primary endpoint) and 20% (KIT ex11–negative). ctDNA analyses (n = 37) demonstrated strong concordance of primary KIT mutations between plasma and tumor. At least two secondary mutations were detected in 35% of patients overall and 54% of KIT ex11–positive patients. Changes from baseline in mutated ctDNA levels were consistent with clinical activity. Ponatinib was ineffective in patients with KIT exon 9 primary mutations. Resistance was associated with emergence of V654A. AOEs and venous thromboembolic events occurred in three and two patients, respectively. Six patients died; two deaths (pneumonia and pulmonary embolism) were considered possibly ponatinib-related. Conclusions: Ponatinib demonstrated activity in advanced GIST, particularly in KIT ex11–positive disease. ctDNA analysis confirmed heterogeneous resistance mutations in TKI-pretreated advanced GIST. Safety was consistent with previous studies.
AB - Purpose: The purpose of this study is to evaluate ponatinib for advanced gastrointestinal stromal tumors (GIST). Patients and Methods: This single-arm phase II trial enrolled patients with metastatic and/or unresectable GIST with failure of prior tyrosine kinase inhibitor (TKI) treatment into two cohorts based on presence or absence of KIT exon 11 (ex11) primary mutations. Patients initially received ponatinib 45 mg once daily. Following a temporary clinical hold in October 2013, dose reductions were implemented to reduce risk of arterial occlusive events (AOE). Primary endpoint was 16-week clinical benefit rate (CBR) in KIT ex11–positive cohort. KIT mutations in circulating tumor DNA (ctDNA) were assessed. Results: Forty-five patients enrolled (30 KIT ex11–positive and 15 KIT ex11–negative); median follow-up was 14.7 and 13.6 months, respectively, as of August 1, 2016. Sixteen-week CBR was 36% (KIT ex11–positive; primary endpoint) and 20% (KIT ex11–negative). ctDNA analyses (n = 37) demonstrated strong concordance of primary KIT mutations between plasma and tumor. At least two secondary mutations were detected in 35% of patients overall and 54% of KIT ex11–positive patients. Changes from baseline in mutated ctDNA levels were consistent with clinical activity. Ponatinib was ineffective in patients with KIT exon 9 primary mutations. Resistance was associated with emergence of V654A. AOEs and venous thromboembolic events occurred in three and two patients, respectively. Six patients died; two deaths (pneumonia and pulmonary embolism) were considered possibly ponatinib-related. Conclusions: Ponatinib demonstrated activity in advanced GIST, particularly in KIT ex11–positive disease. ctDNA analysis confirmed heterogeneous resistance mutations in TKI-pretreated advanced GIST. Safety was consistent with previous studies.
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U2 - 10.1158/1078-0432.CCR-21-2037
DO - 10.1158/1078-0432.CCR-21-2037
M3 - Article
C2 - 35091442
AN - SCOPUS:85127345255
VL - 28
SP - 1268
EP - 1276
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 7
ER -