Protein kinase inhibitors as targeted therapy for glioblastoma: a meta-analysis of randomized controlled clinical trials

Glioblastoma, or GBM, stands as the most frequently diagnosed and most aggressive primary tumor originating in the brain. The established initial treatment protocol for individuals newly diagnosed with GBM typically involves surgical removal of the tumor, if deemed feasible by medical professionals. This surgical intervention is then followed by a combination of radiotherapy and chemotherapy utilizing the drug temozolomide. In instances where the disease progresses despite this initial treatment, the monoclonal antibody bevacizumab, which targets vascular endothelial growth factor-A (VEGF-A), may be considered as a therapeutic option.

Given the limited effectiveness of current pharmacological treatments, particularly in cases of recurrent disease where the tumor reappears after initial treatment, researchers have explored various molecularly targeted interventions. Among these are small-molecule protein kinase inhibitors (PKIs). These inhibitors are designed to block the activity of tyrosine kinase growth factor receptors and the downstream signaling pathways that are implicated in the processes of angiogenesis, the formation of new blood vessels that support tumor growth, and the infiltrative behavior of GBM cells, which allows the tumor to spread into surrounding brain tissue.

To evaluate the clinical efficacy of these PKIs, a comprehensive meta-analysis was conducted. This involved a systematic search of two major scientific literature databases, PubMed and Web Of Science, to identify relevant studies. The meta-analysis ultimately included twelve randomized controlled trials (RCTs). These trials investigated the use of PKIs in patients who had either been newly diagnosed with GBM or whose GBM had recurred after initial treatment. The researchers then performed a pooled analysis of shared clinical outcomes reported across these trials, specifically focusing on progression-free survival (PFS), which is the length of time during and after the treatment of a disease that a patient lives with the disease but it does not get worse, and overall survival (OS), which is the length of time from either the date of diagnosis or the start of treatment for a disease that patients diagnosed with the disease are still alive.

The results of this pooled analysis indicated that the use of PKIs did not lead to significant improvements in either progression-free survival or overall survival for GBM patients. When specifically examining patients with newly diagnosed GBM, the analysis revealed no statistically significant differences in median overall survival [-1.02 months, with a 95 % confidence interval (CI) ranging from -2.37 to 0.32, and a p-value of 0.14] or pooled overall survival [hazard ratio (HR) = 1.13, with a 95 % CI ranging from 0.95 to 1.35, and a p-value of 0.17] when comparing the addition of PKIs to the standard chemo-radiotherapy regimen versus chemo-radiotherapy alone. Similarly, no significant differences were observed in median progression-free survival (0.34 months, 95 % CI, -0.9 to 1.58, p = 0.60) or pooled progression-free survival (HR = 0.98, 95 % CI, 0.76 to 1.27, p = 0.89) between the two treatment approaches in newly diagnosed GBM.

In the context of recurrent GBM, the researchers conducted three distinct analyses to compare the effectiveness of PKIs in different treatment scenarios. These analyses included comparing PKI treatment directly to other forms of treatment, comparing the combination of PKIs with other treatments to those other treatments administered alone, and comparing PKI treatment alone to PKI treatment combined with other therapies. Across all three of these analyses in patients with recurrent GBM, no statistically significant clinical benefits were found to be associated with the use of PKIs. For example, when comparing PKI treatment with other treatments for recurrent GBM, the median overall survival and median progression-free survival showed no significant difference (-0.78 months, 95 % CI, -2.12 to 0.55, p = 0.25; and -0.23 months, 95 % CI, -0.79 to 0.34, p = 0.43, respectively). Similar non-significant results were obtained in the pooled analyses of overall survival (HR = 0.89, 95 % CI, 0.59 to 1.32, p = 0.55) and progression-free survival (HR = 0.83, 95 % CI, 0.63 to 1.11, p = 0.21) in this patient population.

Despite these generally negative findings from the meta-analysis, the authors noted that some data indicated potentially improved clinical outcomes in a specific subset of GBM patients who were treated with particular PKIs, such as regorafenib. This observation suggests that while PKIs as a class may not provide a broad benefit to all GBM patients, certain individual PKIs might be effective in specific contexts or patient subgroups. The researchers concluded by emphasizing the need for further investigation to identify PKIs that exhibit better penetration across the blood-brain barrier, which is a protective barrier that can limit drug delivery to the brain, CC-115 and a lower propensity for the development of drug resistance, which is a major obstacle in cancer therapy. These future research efforts may ultimately lead to the identification of more effective targeted therapies for this challenging and aggressive brain tumor.