Incidence and risk of hepatic toxicities associated with anaplastic lymphoma kinase inhibitors in the treatment of non-small-cell lung cancer: a systematic review and meta-analysis

BACKGROUND: Two anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (-TKIs) have been approved for the treatment of patients with ALK-rearranged (ALK-positive) advanced non-small cell lung cancer (NSCLC). Severe hepatotoxicity has been observed in several clinical studies. We aim to assess the incidence and risk of liver toxicity with these drugs by a systematic review and meta-analysis of clinical trials. MATERIALS AND METHODS: The databases of PubMed, Web of Science and abstracts presented at oncology conferences’ proceedings were searched for relevant studies from January 2000 to January 2017. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated by using either random effects or fixed effect models. RESULTS: A total of 1,908 patients from 10 clinical trials were included. The incidences of all-grade aspartate aminotransferase (AST) and alanine transaminase (ALT) elevation were 25.2% (95% CI 17.7–34.7%), and 26.0% (95% CI 17.8–36.3%), respectively. The incidences of high-grade (grade 3 and 4) AST and ALT elevation were 7.0% (95% CI: 5.4–9.0%), and 9.9% (95%CI: 5.6–16.7%), respectively. Sub-group analysis according to ALK-TKIs showed that the incidence of liver toxicities associated with ceritinib was higher than that of crizotinib and alectinib. In comparison with chemotherapy, ALK-TKIs significantly increased the risk of developing all-grade and high-grade AST elevation (RR, 2.30, 95%CI: 1.87–2.83, p < 0.001; RR 10.14, 95% CI: 3.9–26.39, p < 0.001) and ALT elevation (RR 2.37, 95%CI: 1.97–2.86, p < 0.001; RR 7.34, 95% CI: 3.95–13.63, p < 0.001), respectively. CONCLUSIONS: The use of ALK-TKIs significantly increases the risk of developing all-grade and high-grade liver toxicities in lung cancer patients.