SU11248, a multi-targeted tyrosine kinase inhibitor, can overcome imatinib (IM) resistance caused by diverse genomic mechanisms in patients (pts) with metastatic gastrointestinal stromal tumor (GIST).
SU11248, a multi-targeted tyrosine kinase inhibitor, can overcome imatinib (IM) resistance caused by diverse genomic mechanisms in patients (pts) with metastatic gastrointestinal stromal tumor (GIST).
复制标题
SU11248 是一种多靶点酪氨酸激酶抑制剂，可以克服转移性胃肠道间质瘤 (GIST) 患者 (pts) 因多种基因组机制引起的伊马替尼 (IM) 耐药性。
DOI：
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发表时间：
2004
影响因子：
45.3
通讯作者：
M. Heinrich
中科院分区：
文献类型：
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作者：
G. Demetri;Jayesh Desai;Jonathan A Fletcher;J. Morgan;C. D. Fletcher;A. Kazanovicz;A. D. Abbeele;Charles M. Baum;Robert G. Maki;M. Heinrich
3001背景：在GIST中，初始肿瘤消退和疾病控制后对甲磺酸伊马替尼（IM）的耐药性越来越被认为是未满足的医疗需求。IM耐药可能与IM难治性GIST病变中KIT或PDGFRA酪氨酸激酶继发突变的出现相关;替代信号通路的激活和新突变激酶的不同结构生物学有助于IM耐药GIST克隆的出现。
方法
SU 11248治疗进展性IM耐药GIST患者的I/II期临床试验。通过dHPLC和测序分析获得肿瘤活检以确定KIT和PDGFRA激酶的突变状态。
结果
98例进行性GIST患者已入组这项正在进行的研究; 48例患者的肿瘤缓解数据可用，41例患者的GIST基因型确定。选择的II期方案为SU 11248 50 mg口服，每日一次，持续4周，随后在每6周周期中停药2周。SU 11248治疗在26/48例（54%）既往进展患者中诱导了临床获益（定义为客观缓解或疾病稳定≥ 6个月），其中6/48例（13%）患者证实了部分缓解（PR）。KIT外显子9突变体的继发突变比外显子11 GIST少。
结论
SU 11248治疗可诱导客观缓解，并控制患有几种GIST突变变体（具有不同的IM耐药基因组机制）的患者的疾病进展。这些数据是III期试验的基础，以进一步确定SU 11248在IM耐药GIST患者中的活性。了解SU 11248在IM耐药GIST中的疗效有助于阐明PDGFRA、KIT和其他异常信号通路在GIST发病机制中的结构生物学，并可能与其他恶性肿瘤的分子靶向治疗相关。[图：见正文] [表：见正文]。
3001 Background: Resistance to Imatinib mesylate (IM) following initial tumor regression and disease control in GIST is increasingly recognized as an unmet medical need. IM resistance can be correlated with the appearance of secondary mutations in the KIT or PDGFRA tyrosine kinases in GIST lesions refractory to IM; activation of alternative signaling pathways and different structural biology of the new mutant kinases contribute to emergence of IM-resistant GIST clones.
METHODS
Phase I/II clinical trial of SU11248 in pts with progressing IM-resistant GIST. Tumor biopsies were obtained to define the mutational status of the KIT and PDGFRA kinases by dHPLC and sequencing assays.
RESULTS
98 pts with progressive GIST have been enrolled in this ongoing study; with tumor response data available in 48 pts and GIST genotype determined in 41. The phase II regimen chosen was SU11248 50 mg orally once daily for 4 weeks, followed by a 2 week period off drug in each 6 wk cycle. SU11248 therapy induced clinical benefit (defined by objective response or stable disease for ≥ 6 months) in 26/48 (54%) of these previously progressing pts, with 6/48 (13%) confirmed partial responses (PR). KIT exon 9 mutants had fewer secondary mutations than Exon 11 GIST.
CONCLUSIONS
SU11248 therapy can induce objective responses and control progressive disease in pts with several mutational variants of GIST with different genomic mechanisms of resistance to IM. These data are the basis for a phase III trial to define further the activity of SU11248 in pts with IM-resistant GIST. Understanding the efficacy of SU11248 in IM-resistant GIST should help to elucidate the structural biology of PDGFRA, KIT and other aberrant signaling pathways in the pathogenesis of GIST and may have relevance to molecularly targeted therapies for other malignancies. [Figure: see text] [Table: see text].