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