Current evidence and challenges of systematic therapies for adult recurrent glioblastoma: Results from clinical trials

Abstract

Recurrence is a major concern for adult patients with glioblastomas (GBMs), and the prognosis remains poor. Although several therapies have been assessed, most of them have not achieved satisfactory results. Therefore, there is currently no standard treatment for adult recurrent GBM (rGBM). Here, we review the results of clinical trials for the systematic therapy of rGBM. Regorafenib, rindopepimut and neoadjuvant programmed death 1 (PD-1) inhibitors are promising agents for rGBM, while regorafenib is effective in both O⁶-methylguanine DNA methyltransferase (MGMT) promoter methylated and unmethylated patients. Temozolomide rechallenge and alkylating agents combined with bevacizumab can be useful for patients with MGMT methylation, and patients with isocitrate dehydrogenase (IDH) mutations or second recurrence can benefit from vocimagene amiretrorepvec (Toca 511). Some phase I trials on targeted therapy and immunotherapy have shown positive results, and results from further studies are expected. In addition to the analysis of existing clinical trial results, forthcoming trials should be well designed, and patients are encouraged to participate in appropriate clinical trials.

Keywords: Recurrent glioblastoma; clinical trial; immunotherapy; systematic therapy; targeted therapy.

Figure 1

Current potential therapeutic targets for rGBM (from published clinical trial results). Created with BioRender.com. VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; EGFR, epidermal growth factor receptor; EGFRvIII, epidermal growth factor receptor variant III; PI3K/AKT/mTOR, phosphatidylinositol 3-kinase/mammalian target of rapamycin, epidermal growth factor receptor variant III; AKT, protein kinase B; TRK, tyrosine kinase receptor; ErbB, erythroblastic leukemia viral oncogene homolog 2; HGF, hematopoietic growth factor; MET, mesenchymal-epithelial transition factor; TGF-β2, transforming growth factor-β2; TGF-βR, transforming growth factor-β receptor; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; PARP, poly ADP-ribose polymerase; DRD2, D2 dopamine receptor; PDGF-β, platelet-derived growth factor-β; PDGFR, platelet-derived growth factor receptor.

Figure 2

Current potential immunotherapies for rGBM (from published clinical trial results). Created with BioRender.com. PD-1, programmed death 1; PD-L1, programmed death ligand 1.