Department of Neurosurgery, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland; Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland; Neuro-Oncology, General and Stereotaxic Neurosurgery Service, University Hospital of Lille, Lille, France; University of Lille, Inserm, U-1192, Lille, France.
European Organization for Research and Treatment of Cancer, Brussels, Belgium.
Eur J Cancer. 2024 Feb;198:113475. doi: 10.1016/j.ejca.2023.113475. Epub 2023 Dec 18.
Zotiraciclib (TG02) is an oral multi-cyclin dependent kinase (CDK) inhibitor thought to inhibit tumor growth via CDK-9-dependent depletion of survival proteins such as c-MYC and MCL-1 which are frequently overexpressed in glioblastoma.
EORTC 1608 (NCT03224104) (STEAM) had a three parallel group (A,B,C) phase Ib, open-label, non-randomized, multicenter design in IDH wild-type newly diagnosed glioblastoma or anaplastic astrocytoma. Groups A and B explored the maximum tolerated dose (MTD) of TG02 in elderly patients, in combination with hypofractionated radiotherapy alone (group A) or temozolomide alone (group B), according to O-methylguanine DNA methyltransferase promoter methylation status determined centrally. Group C explored single agent activity of TG02 at first relapse after temozolomide chemoradiotherapy with a primary endpoint of progression-free survival at 6 months (PFS-6). Tumor expression of CDK-9, c-MYC and MCL-1 was determined by immunohistochemistry.
The MTD was 150 mg twice weekly in combination with radiotherapy alone (group A) or temozolomide alone (group B). Two dose-limiting toxicities were observed at 150 mg: one in group A (grade 3 seizure), one in group B (multiple grade 1 events). Main toxicities included neutropenia, gastrointestinal disorders and hepatotoxicity. PFS-6 in group C was 6.7%. CDK-9, c-MYC and MCL-1 were confirmed to be expressed and their expression was moderately cross-correlated. High protein levels of MCL-1 were associated with inferior survival.
TG02 exhibits overlapping toxicity with alkylating agents and low single agent clinical activity in recurrent glioblastoma. The role of CDK-9 and its down-stream effectors as prognostic factors and therapeutic targets in glioblastoma warrants further study.
Zotiraciclib（TG02）是一种口服多细胞周期蛋白依赖性激酶（CDK）抑制剂，据推测通过 CDK-9 依赖性耗尽生存蛋白（如在胶质母细胞瘤中经常过表达的 c-MYC 和 MCL-1）来抑制肿瘤生长。
EORTC 1608（NCT03224104）（STEAM）采用三平行组（A、B、C）Ib 期、开放性、非随机、多中心设计，用于 IDH 野生型新诊断的胶质母细胞瘤或间变性星形细胞瘤。组 A 和 B 根据中央确定的 O-甲基鸟嘌呤 DNA 甲基转移酶启动子甲基化状态，探索 TG02 在老年患者中的最大耐受剂量（MTD），与单独的低分割放射治疗（组 A）或单独的替莫唑胺（组 B）联合使用。组 C 在替莫唑胺放化疗后首次复发时探索 TG02 的单药活性，主要终点为 6 个月时无进展生存期（PFS-6）。通过免疫组织化学检测肿瘤中 CDK-9、c-MYC 和 MCL-1 的表达。
MTD 与单独放疗（组 A）或单独替莫唑胺（组 B）联合使用时为 150mg，每周两次。在 150mg 时观察到两种剂量限制毒性：一种在组 A（3 级癫痫），一种在组 B（多种 1 级事件）。主要毒性包括中性粒细胞减少、胃肠道疾病和肝毒性。组 C 的 PFS-6 为 6.7%。CDK-9、c-MYC 和 MCL-1 被证实表达，并呈中度交叉相关。MCL-1 蛋白水平高与生存不良相关。
TG02 在复发性胶质母细胞瘤中表现出与烷化剂重叠的毒性和低单药临床活性。CDK-9 及其下游效应物作为胶质母细胞瘤的预后因素和治疗靶点的作用值得进一步研究。
