Reference Detail

Ref Type

PMID

Authors

Michael C. Heinrich, Margaret von Mehren, George D. Demetri, Jonathan A. Fletcher, Jichao G Sun, David Kerstein, Maureen G Conlan, Suzanne George

Title

Ponatinib efficacy and safety in patients (pts) with advanced gastrointestinal stromal tumors (GIST) after tyrosine kinase inhibitor (TKI) failure: Results from a phase 2 study.

Journal	Vol	Issue	Date	Pages	Journal Short Title
J Clin Oncol			2015

URL

https://ascopubs.org/doi/10.1200/jco.2015.33.15_suppl.10535

Abstract Text

Background: The oral TKI ponatinib has potent pre-clinical activity against mutant KIT and PDGFRA, including clinically relevant mutants resistant to available TKIs. We hypothesized that ponatinib might be effective in GIST after prior TKI treatment failure. Methods: This phase 2, single-arm study (NCT01874665) evaluated efficacy and safety of ponatinib 45 mg qd in advanced GIST after TKI failure; N = 45. Cohorts were enrolled based on presence (A) or absence (B) of KIT exon 11 mutations. Primary endpoint is clinical benefit rate (CBR = CR + PR + SD) at 16 wk by modified RECIST 1.1 in Cohort A. Secondary endpoints include CBR (Cohort B and overall) and objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Due to arterial occlusive events in other ponatinib trials, enrollment criteria were revised in early 2014 to include only pts in whom all 3 TKIs approved for GIST had failed. Results: Enrollment is complete (Cohort A, 30 pts; B, 15 pts). Median age was 59 y. Most pts (76%) received ≥4 anticancer regimens; 36% received 2 and 58% received 3 approved TKIs. Median time since diagnosis was 6 y. At 10-mo median follow-up (data as of Dec 1, 2014), 9 pts were ongoing; 15 discontinued for progressive disease per RECIST, 9 for AEs, and 12 for other reasons. Cohort A CBR was 37% (10/27); ORR 7% (2/27). Best responses: PR 2; SD 16. Median PFS/OS: 4.3 mo/15.0 mo. Cohort B CBR was 14% (2/14); ORR 0%. Best response: SD 6. Median PFS/OS: 2.0 mo/13.5 mo. Treatment-emergent AEs (TEAEs) in ≥40% of pts: rash 58%; fatigue 51%; constipation 42%; headache 42%; myalgia 40%. Myocardial ischemia, cerebrovascular accident, peripheral artery stenosis, deep vein thrombosis, and pulmonary embolism occurred in 1 pt each; 4 pts had evidence of ventricular dysfunction. Serious TEAEs (other than disease progression) in ≥2 pts: abdominal pain 9%; pneumonia 7%; fatigue, nausea, small intestinal obstruction, vomiting, 4% each. Two deaths, from pneumonia and pulmonary embolism, were considered possibly ponatinib-related. Conclusions: Ponatinib has clinical activity in advanced GIST pts after TKI failure, particularly pts with KIT exon 11 mutations. Clinical trial information: NCT01874665.

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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

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References