Targeted therapies in patients with newly diagnosed glioblastoma - a systematic meta-analysis of randomized clinical trials

Glioblastoma (GB) is the most common malignant primary brain tumor in adults. The standard of care for newly diagnosed GB involves surgical resection followed by radiochemotherapy with temozolomide, with or without tumor-treating fields. In recent years, various efforts have been made to identify suitable molecularly targeted treatment options for malignant brain tumors. This meta-analysis provides an overview of recently published randomized controlled trials (RCTs) with and without molecular stratification, analyzing targeted agents in patients with newly diagnosed GB. The Cochrane Library, MEDLINE (Ovid), ClinicalTrials.gov, WHO's International Clinical Trials Registry Platform, and Google Scholar were searched for RCTs on targeted therapies in patients with newly diagnosed glioblastoma. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were extracted and pooled in a random-effects meta-analysis. Twelve RCTs (n=3,941 patients) involving protein kinase inhibitors, proteasome and histone deacetylase inhibitors, anti-angiogenic approaches, and poly (ADP-ribose) polymerase (PARP) inhibitors were included in the meta-analysis. None of the targeted agents achieved a significant benefit with regard to OS (HR=0.98 [95% Confidence Interval (CI) 0.86-1.11, p=0.7731]. By comparison, targeted therapy showed a benefit for PFS (HR=0.83 [95% CI 0.74-0.94, p=0.0037], especially for patients with an unmethylated O6-Methylguanin-DNA-methyltransferase (MGMT) promoter (0.75 [95% CI 0.56-0.99, p=0.0440]). Prolongation of PFS was largely driven by VEGF inhibition with bevacizumab (HR=0.70 [95% CI 0.61-0.80, p=0.0000]). VEGF inhibition with bevacizumab prolonged PFS in patients with newly diagnosed glioblastoma compared with standard care. However, no improvement in OS was observed with any of the targeted agents

Targeted agents in patients with progressive glioblastoma—A systematic meta‐analysis of randomized clinical trials

Background Glioblastoma (GB) is the most common malignant primary brain tumor in adults and is associated with a poor prognosis. Current treatment guidelines outline the standard of care for patients with newly diagnosed GB; however, there is currently no well-established consensus for the treatment of progressive GB. With this systematic meta-analysis of recently published randomized controlled trials (RCTs), we aim to establish evidence on targeted agents in the treatment of patients with progressive GB. Material and Methods We conducted searches across the Cochrane Library, Pubmed, MEDLINE (Ovid), ClinicalTrials.gov, WHO‘s International Clinical Trials Registry Platform and Google Scholar, encompassing the time span from 1954 to 2022, aiming to identify RCTs evaluating targeted therapies in patients with progressive GB. In order to perform a random-effects meta-analysis, we extracted hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS). Results We included 16 RCTs (n = 3025 patients) in the systematic meta-analysis. Formally, regorafenib (RR 0.50; 95% CI 0.33–0.75), Depatux-M + TMZ (RR 0.66; 95% CI 0.47–0.93) and rindopepimut + bevacizumab (RR 0.53; 95% CI 0.32–0.88) were associated with an improved OS compared to the control arm. The combination of bevacizumab + CCNU (RR = 0.49; 95% CI 0.35–0.69) and regorafenib (RR 0.65; 95% CI 0.44–0.95) were formally associated with improved PFS. Conclusions The aim of this systematic meta-analysis was to establish evidence for the use of targeted therapies in progressive GB. While some studies demonstrated benefits for OS and/or PFS, those results have to be interpreted with caution as most studies had major methodological weaknesses, including potential differences in sample size, trial design, or the initial distribution of prognostic factors

Targeted therapies in patients with newly diagnosed glioblastoma - a systematic meta-analysis of randomized clinical trials

Glioblastoma (GB) is the most common malignant primary brain tumor in adults. The standard of care for newly diagnosed GB involves surgical resection followed by radiochemotherapy with temozolomide, with or without tumor-treating fields. In recent years, various efforts have been made to identify suitable molecularly targeted treatment options for malignant brain tumors. This meta-analysis provides an overview of recently published randomized controlled trials (RCTs) with and without molecular stratification, analyzing targeted agents in patients with newly diagnosed GB. The Cochrane Library, MEDLINE (Ovid), ClinicalTrials.gov, WHO's International Clinical Trials Registry Platform, and Google Scholar were searched for RCTs on targeted therapies in patients with newly diagnosed glioblastoma. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were extracted and pooled in a random-effects meta-analysis. Twelve RCTs (n=3,941 patients) involving protein kinase inhibitors, proteasome and histone deacetylase inhibitors, anti-angiogenic approaches, and poly (ADP-ribose) polymerase (PARP) inhibitors were included in the meta-analysis. None of the targeted agents achieved a significant benefit with regard to OS (HR=0.98 [95% Confidence Interval (CI) 0.86-1.11, p=0.7731]. By comparison, targeted therapy showed a benefit for PFS (HR=0.83 [95% CI 0.74-0.94, p=0.0037], especially for patients with an unmethylated O6-Methylguanin-DNA-methyltransferase (MGMT) promoter (0.75 [95% CI 0.56-0.99, p=0.0440]). Prolongation of PFS was largely driven by VEGF inhibition with bevacizumab (HR=0.70 [95% CI 0.61-0.80, p=0.0000]). VEGF inhibition with bevacizumab prolonged PFS in patients with newly diagnosed glioblastoma compared with standard care. However, no improvement in OS was observed with any of the targeted agents

Targeted agents in patients with progressive glioblastoma—A systematic meta‐analysis of randomized clinical trials

Abstract Background Glioblastoma (GB) is the most common malignant primary brain tumor in adults and is associated with a poor prognosis. Current treatment guidelines outline the standard of care for patients with newly diagnosed GB; however, there is currently no well‐established consensus for the treatment of progressive GB. With this systematic meta‐analysis of recently published randomized controlled trials (RCTs), we aim to establish evidence on targeted agents in the treatment of patients with progressive GB. Material and Methods We conducted searches across the Cochrane Library, Pubmed, MEDLINE (Ovid), ClinicalTrials.gov, WHO‘s International Clinical Trials Registry Platform and Google Scholar, encompassing the time span from 1954 to 2022, aiming to identify RCTs evaluating targeted therapies in patients with progressive GB. In order to perform a random‐effects meta‐analysis, we extracted hazard ratios (HRs) of overall survival (OS) and progression‐free survival (PFS). Results We included 16 RCTs (n = 3025 patients) in the systematic meta‐analysis. Formally, regorafenib (RR 0.50; 95% CI 0.33–0.75), Depatux‐M + TMZ (RR 0.66; 95% CI 0.47–0.93) and rindopepimut + bevacizumab (RR 0.53; 95% CI 0.32–0.88) were associated with an improved OS compared to the control arm. The combination of bevacizumab + CCNU (RR = 0.49; 95% CI 0.35–0.69) and regorafenib (RR 0.65; 95% CI 0.44–0.95) were formally associated with improved PFS. Conclusions The aim of this systematic meta‐analysis was to establish evidence for the use of targeted therapies in progressive GB. While some studies demonstrated benefits for OS and/or PFS, those results have to be interpreted with caution as most studies had major methodological weaknesses, including potential differences in sample size, trial design, or the initial distribution of prognostic factors