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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-023-02734-5

摘要内容如下：

INTRIGUE是一项开放标签的3期研究，研究对象为患有晚期胃肠道间质瘤的成年患者，这些患者在伊马替尼治疗后出现疾病进展或对伊马替尼不耐受，并随机接受每日一次的利普替尼150mg或舒尼替尼50mg治疗。在初步分析中，利普替尼的无进展生存期（PFS）并不优于舒尼替尼。在临床和非临床研究中，基于KIT突变的外显子位置，利普替尼和舒尼替尼表现出不同的活性。因此，我们假设使用循环肿瘤DNA（ctDNA）的突变分析可能提供进一步的见解。在该探索性分析（n=362）中，通过基于74基因ctDNA下一代测序的分析来分析基线外周全血。在280/362（77%）样本中检测到ctDNA，在213/362（59%）患者中检测到KIT突变。在试剂盒ATP结合口袋（外显子13/14）和激活环（外显子17/18）中发现了伊马替尼耐药突变。突变亚组评估显示2个相互排斥的群体具有不同的治疗效果。仅有KIT外显子11+13/14突变的患者（利普替尼，n=21；舒尼替尼，n=20）与利普替尼相比，舒尼替尼的PFS更好（中位数分别为15.0个月和4.0个月）。仅有KIT外显子11+17/18突变的患者（利普替尼，n=27；舒尼替尼，n=25）与舒尼替尼相比，利普替尼的PFS更好（中位数分别为14.2个月和1.5个月）。该探索性分析的结果表明，ctDNA测序可能改善单药治疗的疗效预测，并支持进一步评估利普替尼在KIT外显子11+17/18突变患者中的疗效。ClinicalTrials.gov标识符：NCT03673501。

英文原文如下：

Abstracts

INTRIGUE was an open-label, phase 3 study in adult patients with advanced gastrointestinal stromal tumor who had disease progression on or intolerance to imatinib and who were randomized to once-daily ripretinib 150 mg or sunitinib 50 mg. In the primary analysis, progression-free survival (PFS) with ripretinib was not superior to sunitinib. In clinical and nonclinical studies, ripretinib and sunitinib have demonstrated differential activity based on the exon location of KIT mutations. Therefore, we hypothesized that mutational analysis using circulating tumor DNA (ctDNA) might provide further insight. In this exploratory analysis (N = 362), baseline peripheral whole blood was analyzed by a 74-gene ctDNA next-generation sequencing-based assay. ctDNA was detected in 280/362 (77%) samples with KIT mutations in 213/362 patients (59%). Imatinib-resistant mutations were found in the KIT ATP-binding pocket (exons 13/14) and activation loop (exons 17/18). Mutational subgroup assessment showed 2 mutually exclusive populations with differential treatment effects. Patients with only KIT exon 11 + 13/14 mutations (ripretinib, n = 21; sunitinib, n = 20) had better PFS with sunitinib versus ripretinib (median, 15.0 versus 4.0 months). Patients with only KIT exon 11 + 17/18 mutations (ripretinib, n = 27; sunitinib, n = 25) had better PFS with ripretinib versus sunitinib (median, 14.2 versus 1.5 months). The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations. ClinicalTrials.gov identifier: NCT03673501.

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