Cabozantinib and thromboembolism in patients with cancer: a systematic review, meta-analysis, and retrospective study

Antiangiogenic agents, including vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs), represent an important class of treatments for a range of solid tumors. However, concerns have arisen over potential associations between antiangiogenic agents and thromboembolic events. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) that compared a frequently used VEGFR TKI, cabozantinib, with placebo or usual care. The primary outcome was the risk of any thromboembolism. Secondary outcomes included the risk of venous thromboembolism (VTE), risk of arterial thromboembolism (ATE) and progression-free survival. 14 RCTs were included with a combined total of 4204 patients, of whom 212 (5%) developed thromboembolism. Cabozantinib was associated with a significantly increased risk of any thromboembolism (risk ratio [RR], 2.41; 95% confidence interval [CI], 1.72-3.39) driven by VTE (RR, 3.21; 95% CI, 1.86-5.55) but not ATE (RR, 1.31; 95% CI, 0.76-2.26). To account for between-group differences in time on treatment, progression-free survival-adjusted analyses were conducted, with cabozantinib remaining associated with a significantly increased risk of any thromboembolism (RR, 1.47; 95% CI, 1.02-2.12) and VTE (RR, 1.92; 95% CI, 1.08-3.43) but not ATE (RR, 0.76; 95% CI, 0.41-1.40). In a retrospective single health care system cohort study of 295 patients treated with cabozantinib, a thromboembolism rate of 180 per 1000 patient-years on treatment was observed, with most events occurring in the first 3 months after initiation. Together these data demonstrate that cabozantinib is associated with a significantly increased risk of VTE in patients with cancer.