口服 MEK1/2 抑制剂曲美替尼联合 AKT 抑制剂 GSK2141795 治疗伴有 RAS 突变的急性髓系白血病患者：一项 II 期研究。
Oral MEK 1/2 Inhibitor Trametinib in Combination With AKT Inhibitor GSK2141795 in Patients With Acute Myeloid Leukemia With RAS Mutations: A Phase II Study.
机构信息
Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Atrium Health, Charlotte, NC.
Department of Medicine, University of Chicago Medical Center, Chicago, IL.
出版信息
Clin Lymphoma Myeloma Leuk. 2019 Jul;19(7):431-440.e13. doi: 10.1016/j.clml.2019.03.015. Epub 2019 Mar 26.
BACKGROUND
With proven single-agent activity and favorable toxicity profile of MEK-1/2 inhibition in advanced leukemia, investigation into combination strategies to overcome proposed resistance pathways is warranted. Resistance to MEK inhibition is secondary to upstream hyperactivation of RAS/RAF or activation of the PI3K/PTEN/AKT/mTOR pathway. This phase II multi-institution Cancer Therapy Evaluation Program-sponsored study was conducted to determine efficacy and safety of the combination of the ATP-competitive pan-AKT inhibitor GSK2141795, targeting the PI3K/AKT pathway, and the MEK inhibitor trametinib in RAS-mutated relapsed/refractory acute myeloid leukemia (AML).
PATIENTS AND METHODS
The primary objective was to determine the proportion of patients achieving a complete remission. Secondary objectives included assessment of toxicity profile and biologic effects of this combination. Twenty-three patients with RAS-mutated AML received the combination. Two dose levels were explored (dose level 1: 2 mg trametinib, 25 mg GSK2141795 and dose level 2: 1.5 mg trametinib, 50 mg GSK2141795).
RESULTS
Dose level 1 was identified as the recommended phase II dose. No complete remissions were identified in either cohort. Minor responses were recognized in 5 (22%) patients. The most common drug-related toxicities included rash and diarrhea, with dose-limiting toxicities of mucositis and colitis. Longitudinal correlative assessment of the modulation of MEK and AKT pathways using reverse phase protein array and phospho-flow analysis revealed significant and near significant down-modulation of pERK and pS6, respectively. Combined MEK and AKT inhibition had no clinical activity in patients with RAS-mutated AML.
CONCLUSION
Further investigation is required to explore the discrepancy between the activity of this combination on leukemia cells and the lack of clinical efficacy.
背景
MEK-1/2 抑制在晚期白血病中具有明确的单药活性和良好的毒性特征，因此有必要研究联合策略来克服预期的耐药途径。MEK 抑制的耐药性继发于 RAS/RAF 的上游过度激活或 PI3K/PTEN/AKT/mTOR 通路的激活。这项由癌症治疗评估计划（Cancer Therapy Evaluation Program）多机构赞助的 II 期研究旨在确定针对 PI3K/AKT 通路的 ATP 竞争性全 AKT 抑制剂 GSK2141795 与 MEK 抑制剂 trametinib 联合治疗 RAS 突变的复发性/难治性急性髓系白血病（AML）的疗效和安全性。
患者和方法
主要目的是确定完全缓解患者的比例。次要目标包括评估该联合用药的毒性特征和生物学效应。23 例 RAS 突变的 AML 患者接受了该联合治疗。探索了两个剂量水平（剂量水平 1：2 mg trametinib、25 mg GSK2141795；剂量水平 2：1.5 mg trametinib、50 mg GSK2141795）。
结果
剂量水平 1 被确定为推荐的 II 期剂量。两个队列均未发现完全缓解。5 例（22%）患者有轻微反应。最常见的药物相关毒性包括皮疹和腹泻，剂量限制毒性为粘膜炎和结肠炎。使用反相蛋白阵列和磷酸化流式分析对 MEK 和 AKT 通路的调节进行纵向相关评估，结果分别显示 pERK 和 pS6 的显著和接近显著下调。在 RAS 突变的 AML 患者中，联合 MEK 和 AKT 抑制没有临床活性。
结论
需要进一步研究以探索该联合用药在白血病细胞上的活性与缺乏临床疗效之间的差异。
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