Efficacy and safety of targeted therapies for glioblastoma: a systematic review and network meta-analysis.

PURPOSE: Glioblastoma (GBM) is the most aggressive primary brain tumor with a poor prognosis. The current standard regimen of surgery combined with concurrent temozolomide chemoradiotherapy has limited efficacy. Multiple targeted therapies have been evaluated in randomized controlled trials (RCTs), but results are inconsistent and lack systematic comparisons. This review used network meta-analysis (NMA) to assess the relative efficacy and safety of different targeted drugs vs. standard treatment.

METHODS: A systematic search was conducted in PubMed, Embase, Cochrane Library, and Web of Science up to March 7, 2025. RCTs comparing targeted drugs (monotherapy or combination therapy) with standard treatment (surgical resection ± radiotherapy ± temozolomide) or comparing different targeted drugs were included. Primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary outcomes included grade ≥ 3 adverse events (AEs). Bayesian NMA estimates hazard ratios (HR), risk ratios (RR), and their 95% credible intervals (CrI). Surface under cumulative ranking area (SUCRA) ranked interventions. Additionally, subgroup analyses were conducted based on the methylation status (methylated/unmethylated) of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter.

RESULTS: In total, 14 RCTs (10 targeted interventions) were included. Compared with standard therapy, bevacizumab (HR for PFS = 0.57, 95% CrI 0.41-0.80) prolonged PFS but did not significantly improve OS. Compared with other targeted therapies, it still improved PFS. Some drugs (e.g., nivolumab) may even shorten survival. Regarding safety, marizomib, nivolumab, depatuxizumab mafodotin, cediranib, and nimotuzumab were associated with a high risk of AEs. In the subgroup analysis of MGMT methylation, no remarkable differences were noticed. In exploratory MGMT-stratified analysis, nivolumab was associated with less favorable OS and PFS estimates in the unmethylated subgroup.

CONCLUSION: Bevacizumab was associated with improved PFS, but not OS compared to standard therapy and other targeted therapies in newly diagnosed GBM patients. Exploratory subgroup findings suggested that nivolumab may be associated with less favorable OS and PFS estimates in MGMT-unmethylated patients. SUCRA rankings should be interpreted as exploratory because most interventions were supported by limited trial evidence. However, certain targeted drugs exhibit inadequate safety profiles, and careful risk-benefit assessment is required. Future research should further explore safer and more effective multi-targeted combination strategies to overcome GBM's survival bottleneck.