Health Research Institute-Fundación Jiménez Díaz University Hospital, Universidad Autonoma de Madrid (IIS-FJD, UAM), 28040, Madrid, Spain.
Medical Oncology Department, Fundación Jimenez Diaz University Hospital, Av. de los Reyes Católicos, 2, 28040, Madrid, Spain.
Mol Cancer. 2023 Aug 9;22(1):127. doi: 10.1186/s12943-023-01832-9.
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.
大约 15%的成人 GIST 患者的肿瘤为 KIT 和 PDGFRα 基因野生型（KP-wtGIST）。这些肿瘤通常存在 SDH 缺陷，表现出更惰性的行为，并且对伊马替尼耐药。KP-wtGIST 中的潜在致癌机制包括 HIF1α 高表达、通过 MAPK 通路的高 IGF 信号传导或 BRAF 激活突变等。由于regorafenib 抑制这些信号通路，因此假设它在晚期 KP-wtGIST 的一线治疗中可能更有效。
通过 NGS 进行中央确认的晚期 KP-wtGIST 成年患者，在接受晚期疾病的系统治疗之前，被纳入这项国际 II 期试验。符合条件的患者接受regorafenib 160mg/天，每 28 天为一个周期，连用 21 天。主要终点是根据 RECIST 1.1 标准，在 12 周时的中央影像学评估的疾病控制率（DCR）。
从 2016 年 5 月至 2020 年 10 月，通过 Sanger 测序确定了 30 名患者为 KP-wtGIST，通过中央分子筛选用 NGS 确认了 16 名患者。最终，15 名患者入组并接受了regorafenib 治疗。由于 COVID 爆发导致的入组率降低，该研究提前关闭。中央评估的 12 周 DCR 为 86.7%。有 60%的亚组患者经历了一定程度的肿瘤缩小，其中部分缓解和稳定分别观察到 13%和 87%。SDH 缺陷型 GIST 的临床结果优于其他 KP-wtGIST。
regorafenib 在 KP-wtGIST 中的活性优于其他酪氨酸激酶抑制剂，特别是在 SDH 缺陷型 GIST 亚组中，应考虑将其作为晚期 KP-wtGIST 的一线治疗。
ClinicalTrials.gov 标识符：NCT02638766。
