Hepatotoxicity of new-generation ALK inhibitors versus crizotinib in patients with non-small cell lung cancer: A systematic review and meta-analysis

Hepatotoxicity is a known side effect of ALK inhibitors in non-small cell lung cancer. This meta-analysis assessed the hepatotoxicity risk, measured by elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), for new-generation ALK inhibitors versus crizotinib through eight randomized controlled trials with 2,114 patients. The results suggested that new-generation ALK inhibitors were associated with a significantly reduced risk of all-grade ALT elevation (RR = 0.73, 95% confidence interval [CI] [0.58, 0.92]) and a trend toward reduced risk of grades 3-5 ALT elevation (RR = 0.55, 95% CI [0.29, 1.06]). Alectinib, lorlatinib, and brigatinib are associated with lower risks of hepatotoxicity when compared with crizotinib. New-generation ALK inhibitors improved progression-free survival but not in discontinuation rates. Lorlatinib conferred a greater reduction in any grades AST than second-generation inhibitors compared to crizotinib. Our findings suggest that the selection of the ALK inhibitor should be individualized based on the specific profile of hepatotoxicity and their efficacy.