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      Association of Dasatinib With Progression-Free Survival Among Patients With Advanced Gastrointestinal Stromal Tumors Resistant to Imatinib

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          Abstract

          Gastrointestinal stromal tumors (GISTs) are life-threatening when metastatic or not amenable to surgical removal. In a few patients with advanced GISTs refractory to imatinib mesylate, treatment with sunitinib malate followed by regorafenib provides tumor control; however, additional active treatments are needed for most patients.

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          Most cited references 24

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          Nonparametric Estimation from Incomplete Observations

           E. Kaplan,  Paul Meier (1958)
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            Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial.

            No effective therapeutic options for patients with unresectable imatinib-resistant gastrointestinal stromal tumour are available. We did a randomised, double-blind, placebo-controlled, multicentre, international trial to assess tolerability and anticancer efficacy of sunitinib, a multitargeted tyrosine kinase inhibitor, in patients with advanced gastrointestinal stromal tumour who were resistant to or intolerant of previous treatment with imatinib. Blinded sunitinib or placebo was given orally once daily at a 50-mg starting dose in 6-week cycles with 4 weeks on and 2 weeks off treatment. The primary endpoint was time to tumour progression. Intention-to-treat, modified intention-to-treat, and per-protocol analyses were done. This study is registered at ClinicalTrials.gov, number NCT00075218. 312 patients were randomised in a 2:1 ratio to receive sunitinib (n=207) or placebo (n=105); the trial was unblinded early when a planned interim analysis showed significantly longer time to tumour progression with sunitinib. Median time to tumour progression was 27.3 weeks (95% CI 16.0-32.1) in patients receiving sunitinib and 6.4 weeks (4.4-10.0) in those on placebo (hazard ratio 0.33; p<0.0001). Therapy was reasonably well tolerated; the most common treatment-related adverse events were fatigue, diarrhoea, skin discolouration, and nausea. We noted significant clinical benefit, including disease control and superior survival, with sunitinib compared with placebo in patients with advanced gastrointestinal stromal tumour after failure and discontinuation of imatinab. Tolerability was acceptable.
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              Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor.

              Most gastrointestinal stromal tumors (GISTs) express constitutively activated mutant isoforms of KIT or kinase platelet-derived growth factor receptor alpha (PDGFRA) that are potential therapeutic targets for imatinib mesylate. The relationship between mutations in these kinases and clinical response to imatinib was examined in a group of patients with advanced GIST. GISTs from 127 patients enrolled onto a phase II clinical study of imatinib were examined for mutations of KIT or PDGFRA. Mutation types were correlated with clinical outcome. Activating mutations of KIT or PDGFRA were found in 112 (88.2%) and six (4.7%) GISTs, respectively. Most KIT mutations involved exon 9 (n = 23) or exon 11 (n = 85). All KIT mutant isoforms, but only a subset of PDGFRA mutant isoforms, were sensitive to imatinib, in vitro. In patients with GISTs harboring exon 11 KIT mutations, the partial response rate (PR) was 83.5%, whereas patients with tumors containing an exon 9 KIT mutation or no detectable mutation of KIT or PDGFRA had PR rates of 47.8% (P =.0006) and 0.0% (P <.0001), respectively. Patients whose tumors contained exon 11 KIT mutations had a longer event-free and overall survival than those whose tumors expressed either exon 9 KIT mutations or had no detectable kinase mutation. Activating mutations of KIT or PDGFRA are found in the vast majority of GISTs, and the mutational status of these oncoproteins is predictive of clinical response to imatinib. PDGFRA mutations can explain response and sensitivity to imatinib in some GISTs lacking KIT mutations.
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                Author and article information

                Journal
                JAMA Oncology
                JAMA Oncol
                American Medical Association (AMA)
                2374-2437
                June 01 2018
                June 01 2018
                : 4
                : 6
                : 814
                Affiliations
                [1 ]Department of Internal Medicine, University of Michigan, Ann Arbor
                [2 ]Cancer Research and Biostatistics, Seattle, Washington
                [3 ]Department of Pathology, University of Michigan, Ann Arbor
                [4 ]Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
                [5 ]Department of Sarcoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston
                [6 ]Summit Cancer Centers, Post Falls, Idaho
                [7 ]Department of Medicine, Massachusetts General Hospital, Boston
                [8 ]Georgia Cancer Specialists, Sandy Springs
                [9 ]Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia
                [10 ]Department of Medicine, Stanford Cancer Institute, Stanford, California
                [11 ]Department of Medical Oncology and Therapeutics Research, City of Hope Medical Center, Duarte, California
                [12 ]Department of Medicine, Indiana University, Indianapolis
                [13 ]Cedars-Sinai Medical Center, Los Angeles, California
                [14 ]Medstar Washington Hospital Center, Washington, DC
                [15 ]Department of Pediatrics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland
                [16 ]Department of Oncology, Mayo Clinic, Rochester, Minnesota
                [17 ]Sarcoma Alliance for Research Through Collaboration, Ann Arbor, Michigan
                Article
                10.1001/jamaoncol.2018.0601
                6145709
                29710216
                © 2018

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