Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial.
Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial.
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Ripretinib 与舒尼替尼治疗胃肠道间质瘤：3 期 INTRIGUE 试验的 ctDNA 生物标志物分析。
DOI：
10.1038/s41591-023-02734-5
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发表时间：
2024
期刊：
影响因子：
82.9
通讯作者：
Goldstein,Davi
中科院分区：
文献类型：
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作者：
Heinrich,MichaelC;Jones,RobinL;George,Suzanne;Gelderblom,Hans;Schöffski,Patrick;vonMehren,Margaret;Zalcberg,JohnR;Kang,Yoon-Koo;Razak,AlbiruniAbdul;Trent,Jonathan;Attia,Steven;LeCesne,Axel;Siontis,BrittanyL;Goldstein,Davi
Intirigue是一项开放标签的3期研究，研究对象是患有晚期胃肠道间质瘤的成年患者，他们的病情进展或对伊马替尼不耐受，并被随机分配到每天一次的利普替尼150 mg或舒尼替尼50 mg。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，利普替尼和舒尼替尼根据KIT突变的外显子位置显示出不同的活性。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洞察力。在这项探索性分析(NCTDNA362)中，基线外周全血通过74基因 = 下一代测序分析进行分析。362例患者中有213例(59%)检测到带有KIT突变的280/362例(77%)ctDNA。在试剂盒的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。突变亚群评估显示2个互不相容的群体具有不同的处理效果。仅有KIT外显子11 + 13/14突变的患者(利普替尼，n = 21；孙尼替尼，n = 20)接受舒尼替尼治疗后的远期疗效优于利普替尼(中位数，15.0个月对4.0个月)。仅有KIT外显子11 + 17/18突变的患者(利普替尼，n = 27；孙尼替尼，n = 25)接受利普替尼治疗后的远期疗效优于苏尼替尼(中位数，14.2月对1.5个月)。这一探索性分析的结果表明，ctDNA测序可能会改善单一药物治疗的疗效预测，并支持对KIT外显子11 + 17/18突变患者进行利培尼的进一步评估。ClinicalTrials.gov标识符：NCT03673501。
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.