Background: Recent clinical studies have shown that initial therapy with combined cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade and granulocyte-macrophage colony-stimulating factor (GM-CSF)-based immunotherapies can enhance the antitumor efficacy of this approach. A key unanswered question is whether systemic GM-CSF enhances CTLA-4 blockade. Thus, the objective of this study was taking a meta-analysis of randomized controlled trials to compare the effect of ipilimumab plus GM-CSF versus ipilimumab alone on overall response, overall survival, and progression-free survival, as well as the risk of adverse events (AEs) in patients with cancer.
Materials and methods: Searches were made in electronic databases PubMed and Embase, and conference abstracts published by the American Society of Clinical Oncology from 2000 to 2017. Statistical analyses were carried out using either random-effects or fixed-effects models according to the heterogeneity of eligible studies.
Results: Six trials comprising of 445 patients were included in the meta-analysis. Combination group was superior to the ipilimumab alone in overall response rate, progression-free survival, and overall survival rate (combined relative risk [RR]=1.34, 95% CI: 1.24-1.45, P=0.09; combined hazard ratio [HR]=0.57, 95% CI: 0.32-1.02, P=0.06; combined HR=0.70, 95% CI: 0.60-0.82, P<0.001). Patients with combination therapies had a lower incidence of AEs including high-grade diarrhea (combined RR=0.27, 95% CI: 0.11-0.70, P=0.007), nausea (combined RR=0.25, 95% CI: 0.07-0.89, P=0.03), colitis (combined RR=0.34, 95% CI: 0.13-0.86, P=0.02), and fatigue (combined RR=0.91, 95% CI: 0.37-2.2.3, P=0.84) compared to the group having ipilimumab alone.
Conclusion: These data suggested that the combination of ipilimumab and GM-CSF was associated with a significant improvement in overall survival and lower high-grade toxicities, but there is no difference in overall response rate and progression-free survival among the cancer patients. Therefore, large-scale and well-designed studies are needed to summarize and analyze the data to draw a more convincing conclusion.
Keywords: efficacy; ipilimumab; meta-analysis; safety; sargramostim; survival.