大约有15％的成年GIST患者携带KIT和PDGFRα基因的野生型（KP-wtGIST）。这些肿瘤通常具有SDH缺陷，表现出较缓慢的行为，并对伊马替尼具有耐药性。KP-wtGIST中的潜在致癌机制包括HIF1α的过表达、通过MAPK途径或BRAF活化突变进行高IGFR信号传导等。由于regorafenib抑制了这些信号通路，因此推测它可能在晚期KP-wtGIST的先前治疗中更为活跃。本国际II期试验纳入了经NGS进行中央确认的晚期KP-wtGIST的成年患者，这些患者之前没有接受过晚期疾病的系统治疗。符合条件的患者每28天服用regorafenib 160毫克/天，连续治疗21天。主要终点是根据中央放射学评估在12周时按照RECIST 1.1评估的疾病控制率（DCR）。从2016年5月至2020年10月，通过Sanger测序确定为KP-wtGIST的患者共有30例，经NGS进行中央分子筛查确认的有16例。最终纳入和接受regorafenib治疗的有15例。该研究因COVID爆发造成纳入率低，被提前关闭。根据中央评估，12周的DCR为86.7%。60%的患者有部分肿瘤缩小，中央评估显示有13%的患者出现部分缓解，87%的患者出现稳定。与其他酪氨酸激酶抑制剂相比，SDH缺陷的GIST在KP-wtGIST中显示出更好的临床结果。regorafenib在KP-wtGIST中的活性与其他酪氨酸激酶抑制剂相比较有优势，尤其是在SDH缺陷的GIST亚群中，应被考虑为晚期KP-wtGIST的先前治疗选择。ClinicalTrials.gov识别号：NCT02638766。©2023年。BioMed Central Ltd., Springer Nature的一部分。

Approximately 15% of adult GIST patients harbor tumors that are wild-type for KIT and PDGFRα genes (KP-wtGIST). These tumors usually have SDH deficiencies, exhibit a more indolent behavior and are resistant to imatinib. Underlying oncogenic mechanisms in KP-wtGIST include overexpression of HIF1α high IGFR signaling through the MAPK pathway or BRAF activating mutation, among others. As regorafenib inhibits these signaling pathways, it was hypothesized that it could be more active as upfront therapy in advanced KP-wtGIST.Adult patients with advanced KP-wtGIST after central confirmation by NGS, naïve of systemic treatment for advanced disease, were included in this international phase II trial. Eligible patients received regorafenib 160 mg per day for 21 days every 28 days. The primary endpoint was disease control rate (DCR), according to RECIST 1.1 at 12 weeks by central radiological assessment.From May 2016 to October 2020, 30 patients were identified as KP-wtGIST by Sanger sequencing and 16 were confirmed by central molecular screening with NGS. Finally, 15 were enrolled and received regorafenib. The study was prematurely closed due to the low accrual worsened by COVID outbreak. The DCR at 12 weeks was 86.7% by central assessment. A subset of 60% experienced some tumor shrinkage, with partial responses and stabilization observed in 13% and 87% respectively, by central assessment. SDH-deficient GIST showed better clinical outcome than other KP-wtGIST.Regorafenib activity in KP-wtGIST compares favorably with other tyrosine kinase inhibitors, especially in the SDH-deficient GIST subset and it should be taken into consideration as upfront therapy of advanced KP-wtGIST.ClinicalTrials.gov Identifier: NCT02638766.© 2023. BioMed Central Ltd., part of Springer Nature.