Survival Outcomes of Immune Checkpoint and mTOR Inhibitor Therapies for Patients With Glioblastoma
Key Clinical Takeaways:
- Key Outcomes: Immune checkpoint inhibitors did not significantly improve overall survival but showed a modest progression-free survival (PFS) benefit; pembrolizumab in the neoadjuvant setting had the most favorable signal. mTOR inhibitors were associated with worse overall survival and no PFS benefit.
- Design/Population: Systematic review and meta-analysis of 21 randomized clinical trials including 2,130 adults with newly diagnosed or recurrent glioblastoma, evaluating ICIs and mTOR inhibitors with pooled hazard ratios for OS and PFS.
- Clinical Relevance: Targeted therapies do not provide consistent survival benefit in unselected glioblastoma populations; future clinical impact will likely depend on biomarker-driven patient selection, optimized timing, and improved drug delivery strategies.
Neither immune checkpoint nor mTOR inhibitors consistently improved survival in unselected glioblastoma (GB) populations. However, tailored approaches based on molecular features or delivery methods may offer benefits, according to a recent meta-analysis.
Glioblastoma remains the most common and aggressive malignant primary brain tumor in adults, with dismal long-term survival despite maximal surgical resection followed by radiotherapy and temozolomide. In recent years, targeted systemic therapies—including immune checkpoint inhibitors (ICIs) and mammalian target of rapamycin (mTOR) inhibitors—have been investigated in an effort to improve outcomes. However, their clinical value in glioblastoma remains uncertain.
To better define the efficacy and safety of these approaches, investigators conducted a systematic review and meta-analysis of randomized clinical trials evaluating ICIs and mTOR inhibitors in adults with newly diagnosed or recurrent glioblastoma. PubMed, the Cochrane Library, and Semantic Scholar were searched through March 2025. Overall survival (OS) and progression-free survival (PFS) hazard ratios were extracted or estimated and pooled using fixed-effect models. Risk of bias was assessed using the Cochrane tool.
There were 21 trials encompassing 2,130 patients included, comprising 12 studies of ICIs and 9 studies of mTOR inhibitors. Immune checkpoint inhibition did not confer a statistically significant improvement in OS (Hazard ratio [HR] 1.10; 95% confidence interval [CI], 0.98 to 1.24; p = 0.10), although a modest but significant improvement in PFS was observed (HR 1.17; 95% CI, 1.04 to 1.33; P = 0.01). Notably, pembrolizumab administered in the neoadjuvant setting demonstrated the most favorable survival signals among ICI strategies.
In contrast, mTOR inhibitors were associated with significantly worse OS compared with control treatments (HR 1.43; 95% CI, 1.08 to 1.89; P = 0.01) and did not improve PFS (HR 1.16; 95% CI, 0.89 to 1.51). Toxicity profiles differed by drug class: ICIs were predominantly associated with immune-related adverse events, while mTOR inhibitors more frequently caused hematologic and metabolic toxicities.
Overall, neither ICIs nor mTOR inhibitors consistently improved survival in unselected glioblastoma populations. These findings underscore the biological heterogeneity of GB and suggest that indiscriminate use of targeted therapies is unlikely to yield meaningful benefit. Future progress will likely depend on refined patient selection based on molecular or immunologic biomarkers, optimized timing (such as neoadjuvant administration), and innovative delivery strategies to overcome the blood–brain barrier.
Source:
García Gómez E, Morales Morales M A, San-Juan D, et al. Efficacy and safety of immune checkpoint inhibitors and mTOR inhibitors as targeted therapy for glioblastoma: A systematic review and meta-analysis of randomized clinical trials. Neurosurgical Review. Published online January 3, 2026. https://link.springer.com/article/10.1007/s10143-025-04043-6
