Phase II Study of Ponatinib in Advanced Gastrointestinal Stromal Tumors: Efficacy, Safety, and Impact of Liquid Biopsy and Other Biomarkers.

Autor:	George S; Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., von Mehren M; Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Fletcher JA; Pathology, Brigham and Women's Hospital, Boston, Massachusetts., Sun J; Clinical Research, ARIAD Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited., Zhang S; Clinical Research, ARIAD Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited., Pritchard JR; Clinical Research, ARIAD Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited., Hodgson JG; Clinical Research, ARIAD Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited., Kerstein D; Oncology Clinical Research, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited., Rivera VM; Clinical Research, ARIAD Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited., Haluska FG; Clinical Research, ARIAD Pharmaceuticals, Inc., Cambridge, Massachusetts, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited., Heinrich MC; Medical Oncology, Portland VA Health Care System and Oregon Health & Sciences University Knight Cancer Institute, Portland, Oregon.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2022 Apr 01; Vol. 28 (7), pp. 1268-1276.
DOI:	10.1158/1078-0432.CCR-21-2037
Abstrakt:	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. (©2022 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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