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

Anti-angiogenic 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 regarding the potential association between anti-angiogenic agents and an increased risk of thromboembolism. We performed a systematic review and meta-analysis of randomized controlled trials that compared a frequently used VEGFR TKI, cabozantinib, with placebo or usual care. The primary outcome was risk of any thromboembolism. Secondary outcomes included risk of venous thromboembolism, risk of arterial thromboembolism and progression free survival. We included 14 RCTs with a combined total of 4,204 patients of whom 212 (5%) developed thromboembolism. Cabozantinib was associated with a significantly increased risk of any thromboembolism (RR, 2.41; 95% CI, 1.72-3.39; I2=0%) driven by venous thromboembolism (RR, 3.21; 95% CI, 1.86-5.55; I2=0%) but not arterial thromboembolism (RR, 1.31; 95% CI, 0.76-2.26; I2=0%). To account for between-group differences in time-on-treatment, we performed progression free survival-adjusted analyses with cabozantinib remaining associated with a significantly increased risk of any thromboembolism (RR, 1.47; 95% CI, 1.02-2.12; I2=0%) and venous thromboembolism (RR, 1.92; 95% CI, 1.08-3.43; I2=0%) but not arterial thromboembolism (RR, 0.76; 95% CI, 0.41-1.40; I2=0%). In a single-healthcare system-based retrospective cohort study of 295 patients treated with cabozantinib, we observed a thromboembolism rate of 180/1000 patient-years on treatment with a majority of events occurring in the first 6-months after initiation. Taken together, these data demonstrate that the cabozantinib is associated with a significantly increased risk of venous thromboembolism in patients with cancer.