The goal of this research is to assess ponatinib in patients with advanced gastrointestinal stromal tumor (GIST). Patients with metastatic or unresectable GIST, who had failed prior tyrosine kinase inhibitor (TKI) therapy, were enrolled in two groups according to whether they carried KIT exon 11 (ex11) primary mutations. Ponatinib was subsequently given at a dose of 45 mg once daily to patients. Following a clinical hold in October 2013, dosages were lowered to minimize the risk of arterial obstructive events (AOE). KIT ex11–positive cohort was tested with the primary endpoint of 16-week clinical benefit rate (CBR). KIT Mutations in circulating tumor DNA (ctDNA) were analyzed. As of August 1, 2016, forty-five patients had been enrolled (30 KIT ex11–positive and 15 KIT ex11–negative); median follow-up was 14.7 and 13.6 months, respectively, as of that date. KIT Ex11-positive: 16 weeks, 36% (KIT ex11 positive; primary endpoint) KIT Ex11 negative: 20 weeks, 20% (KIT ex11 negative; primary endpoint). The concordance of the primary KIT mutations between plasma and tumor yielded 95% (n = 37) or higher at least two secondary changes were observed in 35% of individuals overall, and 54% of KIT ex11+ patients. Changes in mutated ctDNA levels were comparable to clinical effects. In patients with KIT exon 9 primary mutations, ponatinib was ineffective. V654A appeared as a resistance marker. The incidence of adverse events and venous thromboembolism was similar, with three and two patients suffering an AOE and VTE, respectively. About 6 patients died; two deaths (pneumonia and pulmonary embolism) were considered possibly ponatinib-connected. In advanced GIST, ponatinib showed effectiveness against KIT ex11-positive tumors. With TKI therapy, GIST patients were found to have heterogeneous resistance mutations as a result of their tumor cells’ response to the drug. Researchers also found that safety was similar to the results of prior research.