Risks of cardiovascular toxicities associated with ALK tyrosine kinase inhibitors in patients with non-small-cell lung cancer: a meta-analysis of randomized control trials.

BACKGROUND: Anaplastic lymphoma kinases (ALK) tyrosine kinase inhibitors (TKIs) are targeted therapies used in advanced ALK-positive non-small cell lung cancers (NSCLC) which showed excellent efficacy and safety. However, ALK TKIs-associated cardiovascular toxicities [cardiac disorders, venous thromboembolic events (VTEs), and hypertension] have been raising more attention and remain incompletely characterized. We conducted the first meta-analysis to investigate the cardiovascular toxicities associated with ALK TKIs in patients with ALK-positive NSCLC.

RESEARCH DESIGN AND METHODS: To determine the relative risks (RRs) of cardiovascular toxicities associated with these agents, we carried out a meta-analysis comparing ALK TKIs with chemotherapy and a meta-analysis comparing crizotinib with second- and third-generation ALK TKIs. Statistical analysis was conducted to calculate the RRs and 95% confidence intervals (CIs) by using either random effects or fixed-effect models according to the heterogeneity of the included studies.

RESULTS: A total of 11 studies (2855 patients) were included in our study. Compared with chemotherapy, ALK TKIs ranked to have more severe cardiovascular toxicities (RR 5.03, 95% CI 1.97-12.84, P=0.0007), which was mainly reflected in cardiac disorders (RR 8.38, 95% CI 5.06-13.87, P<0.00001). Compared with second- and third-generation ALK TKIs, increased risks of cardiac disorders and VTEs associated with crizotinib were found (cardiac disorders RR 1.75, 95% CI 1.07-2.86, P=0.03; risk of VTEs RR 3.97, 95% CI 1.69-9.31, P=0.002; respectively).

CONCLUSION: ALK TKIs were associated with higher risks of cardiovascular toxicities. In particular, special attention should be given to the risks of cardiac disorders and VTEs related to crizotinib therapy.