Immunotherapy failure in glioblastoma: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND

Immunotherapy has transformed outcomes in several solid tumors but has repeatedly failed to demonstrate benefit in glioblastoma. Early-phase signals of activity have not translated into improved survival in randomized trials, creating uncertainty regarding its true clinical value.

METHODS

A systematic review and random-effects meta-analysis of randomized controlled trials (RCTs) evaluating immunotherapy in adult glioblastoma was conducted in accordance with PRISMA 2020. PubMed, Embase, and Scopus were searched through December 2025. Overall survival (OS) was the primary outcome; progression-free survival (PFS) and objective response rate (ORR) were secondary outcomes. Hazard ratios (HRs) and odds ratios (ORs) were pooled using random-effects models. Heterogeneity, publication bias, and meta-regression were assessed.

RESULTS

Twelve RCTs were included. Immunotherapy was associated with significantly worse OS compared with control (pooled HR = 1.16, 95% CI 1.06-1.28; I² = 14.2%). No OS benefit was observed in any individual trial. PFS (11 trials) showed no consistent improvement (pooled HR = 0.93, 95% CI 0.70-1.24; I² ≈ 78%), and ORR (OR = 1.17, 95% CI 0.91-1.51) demonstrated heterogeneous, non-survival-concordant signals driven by small studies. Meta-regression identified phase III trial status as the dominant predictor of unfavorable OS effects.

CONCLUSIONS

Randomized trials demonstrate no improvement in overall survival with immunotherapy in glioblastoma, while signals in progression-free survival and objective response remain inconsistent and biased, with no survival concordance.