Molecular and clinical determinants of response to checkpoint inhibitor immunotherapy in glioblastoma.

Purpose: While checkpoint inhibitor therapy (CPI) has transformed treatment in multiple solid tumors, its efficacy in glioblastoma (GBM) remains limited. Understanding the molecular and clinical factors that influence glioblastoma's response to CPI is essential to improving outcomes.

Methods: We identified patients with recurrent GBM, who had been treated with CPI and determined the association between their molecular, clinical, and demographic characteristics and survival outcomes.

Results: We identified 35 patients with recurrent GBM treated with CPI. PIK3CA mutation was associated with a statistically significant shorter OS duration, calculated from CPI initiation (p-value = 0.014). Tumor tissue without the mutation had less PD-1 expression in CD3+/CD8 + T cells. RB1 and TERT promoter mutations were associated with shorter PFS durations (p-value = 0.009, 0.053, respectively). Length of CPI therapy of more than 6 months was associated with increased PFS and OS (p-value = 0.069, 0.088, respectively), while steroid use at baseline was associated with a shorter OS (p-value = 0.0016). Multifocal disease was associated with shorter PFS and OS durations (p-value = 0.0011, 0.0015, respectively) among all patients.

Conclusions: In glioblastoma, PIK3CA, RB1, TERT promoter mutations, steroid use prior to start of CPI, and multifocal disease may be associated with a poor response to CPI while increased length of CPI may be associated with improved response. Our results may provide the rationale for clinical trials combining PI3K inhibitors with CPI in glioblastoma. The small sample size and retrospective nature of the study carries selection bias and/or confounding effects and larger studies need to be done to validate these results.