Associations Between Immune-Related Venous Thromboembolism and Efficacy of Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis

Abstract

This study aims to summarize the available data and determine if the presence of venous thromboembolism (VTE) immune-related adverse event (irAE) in patients with immune checkpoint inhibitor (ICI) therapy is associated with improved treatment efficacy and clinical outcomes, which in turn was used to help optimize patient selection for anticoagulation therapy and inform rational treatment strategies for overcoming the mechanisms of ICI resistance. PubMed, Embase, Web of Science, and Cochrane Library were searched up to March 18, 2023, for studies assessing the relationship between VTE irAE development during ICI therapy and cancer outcomes. Seven primary articles with a total of 4437 patients were included in the overall survival (OS) meta-analysis. Patients with VTE had a significant increase in overall mortality compared to patients without VTE in adjusted hazard ratios (HRs 1.36, 95% confidence interval [CI] 1.06-1.75, P = .02). In the studies where immortal time bias (ITB) was accounted for, patients with VTE irAE also had poor OS than those without. HR and the corresponding 95% CI values in the non-ITB group were 2.53 (1.75-3.66, P < .00001) with low heterogeneity (P = .17, I² = 48%) and 1.21 (1.06-1.37, P = .004) in the ITB group with no heterogeneity (P = .95, I² = 0%), respectively. Despite the heterogeneity identified, the evidence does suggest that VTE irAE occurrence could be served as a prognostic indicator, with higher frequencies of occurrence associated with poorer OS. However, the fundamental role of this association with clinical consequences should be further investigated in large cohorts and clinical trials.

Keywords: disease control rate; immortal time bias; immune checkpoint inhibitors; immune-related adverse events; overall survival; progression-free survival; venous thromboembolism.

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of the study selection process.

Figure 2.

Forest plots of pooled hazard ratios of venous thromboembolism (VTE) on overall survival in cancer patients treated with immune checkpoint inhibitors. (A) Overall survival in univariate and multivariate analysis. (B) Overall survival in the univariate Cox regression analysis. (C) Overall survival with multivariable-adjusted hazard ratios (HRs). The large diamond at the bottle of the plot indicates the overall summary estimate (width of the diamond represents the 95% confidence interval [CI]); the size of the squares indicates the weight of individual studies in the pooled analysis. Abbreviations: irVTE, immune-related venous thromboembolism.

Figure 3.

Forest plots of pooled hazard ratios of venous thromboembolism (VTE) on progression-free survival in cancer patients treated with immune checkpoint inhibitors. (A) Progression-free survival in univariate and multivariate analyses. (B) Progression-free survival in the univariate Cox regression analysis. (C) Progression-free survival with multivariable-adjusted hazard ratios (HRs). The large diamond at the bottle of the plot indicates the overall summary estimate (width of the diamond represents the 95% confidence interval [CI]); the size of the squares indicates the weight of individual studies in the pooled analysis. Abbreviations: irVTE, immune-related venous thromboembolism.

Figure 4.

Forest plots of pooled odds ratios of venous thromboembolism (VTE) on disease control rate in cancer patients treated with immune checkpoint inhibitors. The large diamond at the bottle of the plot indicates the overall summary estimate (width of the diamond represents the 95% confidence interval [CI]); the size of the squares indicates the weight of individual studies in the pooled analysis. Abbreviations: irVTE, immune-related venous thromboembolism.