A Systematic Review of Glioblastoma-Targeted Therapies in Phases II, III, IV Clinical Trials

Abstract

Glioblastoma (GBM), the most frequent and aggressive glial tumor, is currently treated as first line by the Stupp protocol, which combines, after surgery, radiotherapy and chemotherapy. For recurrent GBM, in absence of standard treatment or available clinical trials, various protocols including cytotoxic drugs and/or bevacizumab are currently applied. Despite these heavy treatments, the mean overall survival of patients is under 18 months. Many clinical studies are underway. Based on clinicaltrials.org and conducted up to 1 April 2020, this review lists, not only main, but all targeted therapies in phases II-IV of 257 clinical trials on adults with newly diagnosed or recurrent GBMs for the last twenty years. It does not involve targeted immunotherapies and therapies targeting tumor cell metabolism, that are well documented in other reviews. Without surprise, the most frequently reported drugs are those targeting (i) EGFR (40 clinical trials), and more generally tyrosine kinase receptors (85 clinical trials) and (ii) VEGF/VEGFR (75 clinical trials of which 53 involving bevacizumab). But many other targets and drugs are of interest. They are all listed and thoroughly described, on an one-on-one basis, in four sections related to targeting (i) GBM stem cells and stem cell pathways, (ii) the growth autonomy and migration, (iii) the cell cycle and the escape to cell death, (iv) and angiogenesis.

Keywords: biomarkers; clinical trials; glioblastoma; targeted therapies.

Figure 1

Timeline showing the principal dates of the histological and molecular classifications of gliomas. Classifying brain tumors has been the subject of many studies for several years. The first classification published in 1926 by Bailey and Cushing was based on histogenetics [51]. According to this classification, the presence of embryonic cells would be at the origin of tumor cells. The second classification proposed in 1949 by Kernohan JW, Mabon [52], includes grades of malignancy. The WHO proposed a new classification of gliomas in 1979 [53], which is internationally recognized and was revised in 1993, 2000, 2007 and 2016 [54,55,56,57]. These classifications are based on anatomopathological analysis of a representative glioma fragment (from biopsy or surgical resection) and “grading” elements. The International Society of Neuropathology was held from 1–3 May 2014 in Haarlem, the Netherlands [58]. The meeting reached consensus regarding the incorporation of non-histological data, such as molecular information, into the next WHO classification [55].

Figure 2

Flowchart.

Figure 3

Principal biomarkers and drugs in GBM targeted therapies. The color code corresponds to the four sections of the Results section. The targeting of stem cells and stem cell pathways is represented in green, the targeting of growth autonomy and migration in blue, the targeting of the cell cycle & escape to cell death in black and the targeting of angiogenesis in red. Acronyms are defined in the text.