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

Suzanne George, Margaret von Mehren, Jonathan A Fletcher, Jichao Sun, Sen Zhang, Justin R Pritchard, John Graeme Hodgson, David Kerstein, Victor M Rivera, Frank G Haluska, Michael C Heinrich, Suzanne George, Margaret von Mehren, Jonathan A Fletcher, Jichao Sun, Sen Zhang, Justin R Pritchard, John Graeme Hodgson, David Kerstein, Victor M Rivera, Frank G Haluska, Michael C Heinrich

Abstract

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.

Trial registration: ClinicalTrials.gov NCT03171389.

©2022 The Authors; Published by the American Association for Cancer Research.

Figures

Figure 1.
Figure 1.
Clinical response by duration of treatment. *Patient was discontinued per FDA request.
Figure 2.
Figure 2.
Tumor response in evaluable patients (n = 36), mutation status, and prior therapies. Dotted line at −30% indicates threshold for PR. Two patients with 0% change from baseline and one patient with 0.5% change from baseline do not have visible bars. *Patients with KIT exon 11–negative tumors. NL, new lesion; WT, wild-type.
Figure 3.
Figure 3.
Number of secondary mutations detected per patient in ctDNA.* n = 37 patients. *Number of unique secondary mutations per patient observed across all samples analyzed (pre– and post–treatment initiation). Each dot represents a unique patient. †Includes exon 9 (n = 6), exon 13 (n = 1), and exon 17 (n = 1). WT, wild-type.
Figure 4.
Figure 4.
Association between changes in target lesion size and KIT-mutated ctDNA levels (n = 19). Target lesion size (sum of all target lesions) and levels of primary mutation (in ctDNA) were compared at baseline and first post-baseline visits.

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