Long-Term Results From a Randomized Phase II Trial of Standard- Versus Higher-Dose Imatinib Mesylate for Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumors Expressing <i>KIT</i>

Blanke, Charles D.; Demetri, George D.; Mehren, Margaret von; Heinrich, Michael C.; Eisenberg, Burton L.; Fletcher, Jonathan A.; Corless, Christopher L.; Fletcher, Christopher D.�M.; Roberts, Peter; Heinz, Daniela; Wehre, Elisabeth; Nikolova, Zariana; Joensuu, Heikki

doi:10.1200/jco.2007.13.4403

Cited by 937 publications

(747 citation statements)

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“…The response rate (68.4%) in the present study was similar to that previously reported [8,28]. The response rate was 54% in the initial report of the B2222 study, but it increased to 66.7% with long-term follow-up.…”

Section: Discussionsupporting

confidence: 80%

Kinase Mutations and Efficacy of Imatinib in Korean Patients with Advanced Gastrointestinal Stromal Tumors

et al. 2009

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Purpose. This study analyzed the relationship between treatment outcome and kinase mutational status in Korean patients with advanced gastrointestinal stromal tumors (GISTs).Experimental Design. Clinical data were collected from 113 consecutive patients with metastatic or unresectable GISTs treated with imatinib from June 2001 through June 2005 at five institutions in Korea. KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 were examined.Results. The median patient age was 57 years (range, 31-82 years). The overall response rate was 67.2%. KIT mutations were found in exon 11 (n ‫؍‬ 92, 81.4%) and exon 9 (n ‫؍‬ 10, 8.8%). One patient had a PDGFRA exon 18 mutation. The overall mutation rate was 91.2%. Response rates were 68.4%, 50.0%, and 80.0% in patients with KIT exon 11 mutations, KIT exon 9 mutations, and no kinase mutations, respectively. With a median follow-up of 49.0 months, the median progression-free survival (PFS) time was 42.0 months and median overall survival (OS) time was not reached. PFS and OS times did not differ significantly according to KIT genotype.Conclusion. This study was unable to find an association between KIT mutational status and clinical outcome of imatinib in Korean patients with advanced GISTs. There was a trend toward better outcomes for patients with wild-type KIT or exon 11

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Section: Discussionsupporting

confidence: 80%

Kinase Mutations and Efficacy of Imatinib in Korean Patients with Advanced Gastrointestinal Stromal Tumors

et al. 2009

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“…Treatment with IM produces an objective response or stable disease in >80% of patients with metastatic and/or unresectable GIST. However, the success of IM in these patients is tempered by the reality that treatment increases the median time to tumor progression by just two years (2-4). Second and third-line therapies, sunitinib and regorafenib, provide additional disease stabilization measured in months (5,6).…”

Section: Introductionmentioning

confidence: 99%

Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor

Zook

Pathak

Belinsky

et al. 2017

Clinical Cancer Research

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Purpose Gastrointestinal stromal tumors (GIST) generally harbor activating mutations in the receptor tyrosine kinase KIT or in the related platelet derived growth factor receptor alpha (PDGFRA). GIST treated with imatinib mesylate (IM) or second-line therapies that target mutant forms of these receptors generally escape disease control and progress over time. Inhibiting additional molecular targets may provide more substantial disease control. Recent studies have implicated the PI3-kinase/AKT pathway in the survival of IM-resistant GIST cell lines and tumors. Experimental Design Here, we performed in vitro and in vivo studies evaluating the novel combination of IM with the AKT inhibitor MK-2206 in GIST. Whole-transcriptome sequencing (WTS) of xenografts was performed to explore the molecular aspects of tumor response to this novel combination and to potentially identify additional therapeutic targets in GIST. Results This drug combination demonstrated significant synergistic effects in a panel of IM-sensitive and -resistant GIST cell lines. Furthermore, combination therapy provided significantly greater efficacy, as measured by tumor response and animal survival, in IM-sensitive GIST xenografts as compared to treatment with IM or MK-2206 alone. WTS implicated two neural genes, brain expressed X-linked 1 (BEX1) and neuronal pentraxin I (NPTX1), whose expression was significantly up-regulated in combination-treated tumors compared to tumors treated with the two monotherapies. Conclusion These studies provide strong preclinical justification for combining IM with an AKT inhibitor as a front-line therapy in GIST. In addition, the WTS implicated the BCL-2/BAX/BAD apoptotic pathway as a potential mechanism for this enhanced combination effect.

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“…4 The median time to disease progression is about 18 or 20 months when treated at 400 or 800 mg dose levels. 5,6 Therefore, the best treatment regimen for patients with malignant GISTs, like doing imatinib preoperatively or postoperatively, is still under debate. [7][8][9] The guideline for the selection of patients for adjuvant therapy varies among experts, mainly due to the criteria predicting patients with a high risk of recurrence after the surgical removal of primary GISTs have yet to be established.…”

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confidence: 99%

Stage and histological grade of gastrointestinal stromal tumors based on a new approach are strongly associated with clinical behaviors

Hou

Zhou

et al. 2009

Modern Pathology

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Tumor stage and grade for gastrointestinal stromal tumors are poorly defined. To develop a better evaluation system, we assessed 12 clinical and pathological parameters in 613 patients with follow-up information. These parameters were classified into two gross spread parameters including liver metastasis and peritoneal dissemination, five microscopic spread parameters including lymph node metastasis, vascular, fat, nerve and mucosal infiltration, and five histological parameters including mitotic count Z10 per 50 high-power fields, muscularis propria infiltration, coagulative necrosis, perivascular pattern and severe nuclear atypia. The 5-year disease-free survival and overall survival of 293 patients without any of these predictive parameters of malignancy were 99% and 100%, respectively. They were regarded as nonmalignant and further evaluations on the stage and grade of these tumors were not performed. At least one and at most seven predictive parameters of malignancy were identified in 320 patients. For these patients, the 5-year disease-free survival and overall survival rates were 44% (mean 6.7 years) and 60% (mean 9.3 years), respectively. The disease-free survival showed significant difference between patients with and without gross spread (Po0.0001), with and without microscopic spread (P ¼ 0.0009). Disease-free survival and overall survival were associated with the number of predictive parameters of malignancy in patients without gross spread (Po0.0001 for both disease-free survival and overall survival), but not in patients with gross spread (P ¼ 0.882 and 0.441, respectively). Malignant gastrointestinal stromal tumors could be divided into clinical stage I and II based on the absence and presence of gross spread, respectively. The degree of malignancy of patients in clinical stage I could be graded according to the number of predictive parameters of malignancy. Patients in clinical stage II were of the highest degree of malignancy regardless of the number of parameters. We found that the clinical stage and grade were strongly associated with prognosis.

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Long-Term Results From a Randomized Phase II Trial of Standard- Versus Higher-Dose Imatinib Mesylate for Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumors Expressing KIT

Abstract: Nearly 50% of patients with advanced GIST who were treated with imatinib mesylate survived for more than 5 years, regardless of a 400 or 600 mg/d starting dose.

Cited by 937 publications

References 18 publications

Kinase Mutations and Efficacy of Imatinib in Korean Patients with Advanced Gastrointestinal Stromal Tumors

Kinase Mutations and Efficacy of Imatinib in Korean Patients with Advanced Gastrointestinal Stromal Tumors

Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor

Stage and histological grade of gastrointestinal stromal tumors based on a new approach are strongly associated with clinical behaviors

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