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Ref Type Journal Article
PMID (35091442)
Authors George S, von Mehren M, Fletcher JA, Sun J, Zhang S, Pritchard JR, Hodgson JG, Kerstein D, Rivera VM, Haluska FG, Heinrich MC
Title Phase II Study of Ponatinib in Advanced Gastrointestinal Stromal Tumors: Efficacy, Safety, and Impact of Liquid Biopsy and Other Biomarkers.
Abstract Text The purpose of this study is to evaluate ponatinib for advanced gastrointestinal stromal tumors (GIST).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.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.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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
KIT N822D missense unknown KIT N822D lies within the protein kinase domain of the Kit protein ( N822D has been identified in the scientific literature (PMID: 35091442, PMID: 18294292), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Nov 2023).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT exon11 gastrointestinal stromal tumor predicted - sensitive Ponatinib Phase II Actionable In a Phase II trial, Iclusig (ponatinib) treatment in gastrointestinal stromal tumor patients with KIT exon 11 mutations who failed prior therapy versus those without KIT exon 11 mutations led to a 16-week clinical benefit rate of 36% (10/28; 1 partial response (PR), 9 stable disease (SD)) vs 20% (3/15; 3 SD), an objective response rate of 7% (2/28; 2 PR) vs 0% (0/15), and median progression-free survival of 4.0 vs 2.0 mo and overall survival of 14.7 vs 14.3 mo, respectively (PMID: 35091442; NCT01874665). 35091442
KIT exon9 gastrointestinal stromal tumor no benefit Ponatinib Phase II Actionable In a Phase II trial, Iclusig (ponatinib) treatment did not result in clinical benefit in gastrointestinal stromal tumor patients with KIT exon 9 mutations who had failed prior tyrosine kinase inhibitor treatment (PMID: 35091442; NCT01874665). 35091442