Infusion-Related Reactions from Immune Checkpoint Inhibitors in Solid Tumors: A Proportional and Network Meta-Analysis.

[BACKGROUND] Infusion-related reactions (IRRs) to immune checkpoint inhibitors (ICIs) have been reported in up to 20% of administrations, but the incidence varies among ICIs.

[OBJECTIVE] We aimed to report and compare the incidence of IRRs among each ICI therapy.

[PATIENTS AND METHODS] We searched PubMed/MEDLINE, Embase, and Web of Science to identify phase 3 randomized controlled trials (RCTs) evaluating ICIs (CTLA-4, PD-1, PD-L1, and LAG-3 inhibitors) in solid tumors. We performed a random-effects model network meta-analysis to compare the odds ratios (ORs) of IRRs by using RCTs comparing dual ICIs, ICI monotherapy, and placebo/observation. A proportional meta-analysis was also performed to pool the incidence of IRRs of ICI monotherapy and dual ICIs. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) registry (CRD42023433659).

[RESULTS] Overall, 40,872 patients from 61 phase 3 RCTs were included in the analysis. Proportional meta-analyses revealed that the pooled incidence of treatment-related IRRs was 2.31% for PD-1 inhibitors, 8.27% for PD-L1 inhibitors (avelumab: 13.53%, non-avelumab: 1.79%), 5.70% for PD-1 plus LAG-3 inhibitors, 5.55% for PD-1 plus CTLA-4 inhibitors, and 1.79% for CTLA-4 inhibitors. A network meta-analysis of treatment-related IRRs, including 12 RCTs, showed that avelumab (OR 79.26, 95% confidence interval [CI]: 4.84-1297.49) and atezolizumab (OR 43.99, 95% CI 2.65-729.89) had a significantly higher risk of treatment-related IRRs compared with placebo/observation. Network ranking revealed that avelumab, atezolizumab, and relatlimab plus nivolumab had the greatest risk of treatment-related IRRs.

[CONCLUSIONS] Avelumab has the highest risk of IRRs followed by atezolizumab and dual ICIs. This comparative study provides insight into the incidence of IRRs with ICI regimens. These results are useful in assessing which systemic therapies are responsible for IRRs, particularly when ICIs are combined with other agents.