Zotiraciclib (TG02) for newly diagnosed glioblastoma in the elderly or for recurrent glioblastoma: The EORTC 1608 STEAM trial
- Eur J Cancer. 2024 Feb:198:113475. doi: 10.1016/j.ejca.2023.113475.
- 1. 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. Electronic address: [email protected].
- 2. European Organization for Research and Treatment of Cancer, Brussels, Belgium.
- 3. Institute of Neuropathology, Medical Faculty, Heinrich Heine University and University Hospital Düsseldorf, and German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Düsseldorf, Germany.
- 4. The Brain Tumour Center at the Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
- 5. Univ. Lille, UFR3S - Laboratoire d'Histologie, Lille, France.
- 6. CHU Lyon, Neuro-Oncology, Lyon, France.
- 7. Department of Neurology, Clinical Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.
- 8. Department of Neurology - NeuroOncology and Wilhelm Sander Neuro-Oncology Unit, University Hospital Regensburg, Regensburg, Germany.
- 9. Neuro-oncology, CHU Timone, Marseille, France.
- 10. Division of Oncology, Department of Medicine 1, Medical University, Vienna, Austria.
- 11. Department of Biomedical imaging and Image-guided Therapy, Medical University of Vienna, Austria; Research Center for Medical Image Analysis and Artificial Intelligence (MIAAI), Faculty of Medicine and Dentistry, Danube Private University, 3500 Krems, Austria.
Background: 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.
Methods: 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 O6-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.
Results: 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.
Conclusions: 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.