Arterial and venous thromboembolic events in patients with cancer treated with targeted therapies: a population-based cohort study

Background: Emerging data suggest a substantial risk of arterial and venous thromboembolic events (ATE/VTE) associated with targeted cancer therapies. We examined the association between selected targeted therapies and ATE/VTE-risk using Danish population-based healthcare data. Methods: We identified 41,744 patients with cancer treated with selected targeted therapies between January 2004 and December 2020. We computed cumulative incidence functions and 95% confidence intervals (CIs) of ATE/VTE after therapy initiation, considering death as competing event. A multivariable Cox proportional hazards regression analysis with time-varying exposure to targeted therapy was conducted for selected cancers, calculating hazard ratios (HRs) and 95% CIs for ATE/VTE, enabling the comparison of the time periods with and without targeted therapy, adjusting for age, sex, comorbidity burden, cancer stage, and year of diagnosis. Findings: The three-year cumulative ATE-incidence was 3.7% (95% CI: 3.2-4.2) with immune checkpoint inhibitors (ICI; n = 7880), 3.4% (95% CI: 2.8-4.1) with multi-kinase inhibitors (MKI; n = 3394), 2.6% (95% CI: 1.9-3.5) with cyclin dependent kinase (CDK) 4/6-inhibitors (n = 1966), 2.5% (95% CI: 1.0-5.4) with anaplastic lymphoma kinase (ALK)-/ROS1-targeted therapies (n = 199), 2.6% (95% CI: 2.2-2.9) with epidermal growth factor receptor (EGFR)-targeted therapies (n = 8603), 2.4% (95% CI: 2.1-2.7) with vascular endothelial growth factor (VEGF)-targeted therapies (n = 12,802), and 1.4% (95% CI: 1.2-1.6) with human epidermal growth factor receptor 2 (HER2)-targeted therapies (n = 11,683). The three-year VTE-incidence was highest for EGFR- (9.3% 95% CI: 8.7-9.9), ALK/ROS- (9.2% 95% CI: 5.7-13.8), VEGF-targeted therapies (8.8% 95% CI: 8.3-9.3), and ICI (8.1% 95% CI: 7.5-8.8), followed by 7.5% (95% CI: 6.7-8.5) with MKI, 6.9% (95% CI: 5.7-8.3) with CDK4/6-inhibitors, and 3.4% (95% CI: 3.1-3.8) with HER2-targeted therapies. Among patients with selected cancer types, time-dependent exposure to certain targeted therapies was associated with an increased risk of ATE and/or VTE. Interpretation: Selected targeted therapies pose a clinically meaningful risk of ATE and VTE in patients with cancer. Funding: Department of Clinical Epidemiology, Center for Population Medicine, Aarhus University and Aarhus University Hospital, Denmark and the Independent Research Fund Denmark (3101-00102B).