Division of Pediatrics, Children's of Alabama at The University of Alabama, Birmingham.
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston.
ESMO Open. 2023 Dec;8(6):101609. doi: 10.1016/j.esmoop.2023.101609. Epub 2023 Oct 23.
Combined use of inhibitors of mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF-2) receptors is a potential strategy to overcome resistance to either class of drugs when used alone.
We designed a phase 1 trial to test the drug combination of a multikinase VEGF receptor 2 inhibitor, vandetanib, and an mTOR inhibitor, everolimus, in a pediatric and young adult patient cohort with advanced cancers. Exceptional responders were probed for tumor mutational profile to explore possible molecular mechanisms of response.
Among 21 enrolled patients, clinical benefit was observed in 38% (one patient with partial response and eight patients with stable disease) with a median progression-free survival of 3.3 months. The most common treatment-related adverse event was rash (n = 13). Other treatment-related toxicities included diarrhea, fatigue, hypertension, QT prolongation, hypertriglyceridemia/hypercholesterolemia, transaminitis, thrombocytopenia, and weight loss. None of the patients experienced dose-limiting toxicities. Three exceptional responders were analyzed and were found to harbor genetic alterations including kinase insert domain receptor (KDR) Q472H mutation, EWSR1-CREB3L1, CDKN2A/B loss, and ASPL/ASPSCR1-TFE3 fusion.
The combination of vandetanib and everolimus showed early activity and tolerable toxicity profile in pediatric patients with advanced cancers.
联合使用哺乳动物雷帕霉素靶蛋白（mTOR）和血管内皮生长因子（VEGF-2）受体抑制剂是一种潜在的策略，可以克服单独使用任何一类药物时产生的耐药性。
我们设计了一项 1 期临床试验，以测试多激酶 VEGF 受体 2 抑制剂凡德他尼（vandetanib）和 mTOR 抑制剂依维莫司（everolimus）在晚期癌症的儿科和年轻成年患者中的联合用药。对异常反应者进行肿瘤突变分析，以探索可能的反应分子机制。
在 21 名入组患者中，38%（1 名部分缓解和 8 名疾病稳定）观察到临床获益，无进展生存期的中位数为 3.3 个月。最常见的与治疗相关的不良事件是皮疹（n=13）。其他与治疗相关的毒性包括腹泻、疲劳、高血压、QT 延长、高甘油三酯/高胆固醇血症、转氨基酶升高、血小板减少和体重减轻。没有患者出现剂量限制毒性。对 3 名异常反应者进行了分析，发现他们携带的遗传改变包括激酶插入结构域受体（KDR）Q472H 突变、EWSR1-CREB3L1、CDKN2A/B 缺失和 ASPL/ASPSCR1-TFE3 融合。
凡德他尼和依维莫司联合应用在晚期癌症的儿科患者中表现出早期活性和可耐受的毒性特征。
