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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 19

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          Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial.

          Imatinib is approved worldwide for use in gastrointestinal stromal tumours (GIST). We aimed to assess dose dependency of response and progression-free survival with imatinib for metastatic GIST. 946 patients were randomly allocated imatinib 400 mg either once or twice a day. Those assigned the once a day regimen who had progression were offered the option of crossover. The primary endpoint was progression-free survival. Analysis was by intention to treat. At median follow-up of 760 days (IQR 644-859), 263 (56%) of 473 patients allocated imatinib once a day had progressed compared with 235 (50%) of 473 who were assigned treatment twice a day (estimated hazard ratio 0.82 [95% CI 0.69-0.98]; p=0.026). Side-effects arose in 465/470 (99%) patients allocated the once daily regimen compared with 468/472 (99%) assigned treatment twice a day. By comparison with the group treated once a day, more dose reductions (77 [16%] vs 282 [60%]) and treatment interruptions (189 [40%] vs 302 [64%]) were recorded in patients allocated the twice daily regimen, but treatment in both arms was fairly well tolerated. 52 (5%) patients achieved a complete response, 442 (47%) a partial response, and 300 (32%) stable disease, with no difference between groups. Median time to best response was 107 days (IQR 58-172). If response induction is the only aim of treatment, a daily dose of 400 mg of imatinib is sufficient; however, a dose of 400 mg twice a day achieves significantly longer progression-free survival.
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            Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays.

            A series of substituted 2-(aminopyridyl)- and 2-(aminopyrimidinyl)thiazole-5-carboxamides was identified as potent Src/Abl kinase inhibitors with excellent antiproliferative activity against hematological and solid tumor cell lines. Compound 13 was orally active in a K562 xenograft model of chronic myelogenous leukemia (CML), demonstrating complete tumor regressions and low toxicity at multiple dose levels. On the basis of its robust in vivo activity and favorable pharmacokinetic profile, 13 was selected for additional characterization for oncology indications.
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              Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033.

              To assess potential differences in progression-free or overall survival when imatinib mesylate is administered to patients with incurable gastrointestinal stromal tumors (GIST) at a standard dose (400 mg daily) versus a high dose (400 mg twice daily). Patients with metastatic or surgically unresectable GIST were eligible for this phase III open-label clinical trial. At registration, patients were randomly assigned to either standard or high-dose imatinib, with close interval follow-up. If objective progression occurred by Response Evaluation Criteria in Solid Tumors, patients on the standard-dose arm could reregister to the trial and receive the high-dose imatinib regimen. Seven hundred forty-six patients with advanced GIST from 148 centers across the United States and Canada were enrolled onto this trial in 9 months. With a median follow-up of 4.5 years, median progression-free survival was 18 months for patients on the standard-dose arm, and 20 months for those receiving high-dose imatinib. Median overall survival was 55 and 51 months, respectively. There were no statistically significant differences in objective response rates, progression-free survival, or overall survival. After progression on standard-dose imatinib, 33% of patients who crossed over to the high-dose imatinib regimen achieved either an objective response or stable disease. There were more grade 3, 4, and 5 toxicities noted on the high-dose imatinib arm. This trial confirms the effectiveness of imatinib as primary systemic therapy for patients with incurable GIST but did not show any advantage to higher dose treatment. It appears reasonable to initiate therapy with 400 mg daily and to consider dose escalation on progression of disease.
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                Author and article information

                Journal
                JAMA Oncol
                JAMA oncology
                American Medical Association (AMA)
                2374-2445
                2374-2437
                June 01 2018
                : 4
                : 6
                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
                2678963
                10.1001/jamaoncol.2018.0601
                6145709
                29710216

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