Meta-analysis of overall incidence and risk of ALK inhibitors-induced liver toxicities in advanced non-small-cell lung cancer

Abstract

Aim: Activation of the anaplastic lymphoma kinase (ALK) gene has been found in several human cancers, including non-small-cell lung cancer (NSCLC). Currently, novel drugs targeting ALK gene have been extensively investigated in NSCLC. However, concerns about ALK inhibitors-induced liver toxicities have been increasing.

Materials and methods: Eligible prospective clinical studies have been searched in several databases. Primary outcomes of interest were incidence rates of liver toxicities, relative risks (RRs), and 95% confidence intervals (CIs).

Results: Data from 2418 patients (1873 in the experimental arm; 545 in the control arm) were included. The incidences of all-grade alanine transaminase (ALT) and aspartate aminotransferase (AST) elevation were 26.0% (95% CI: 17.4%-37%), and 23.2% (95% CI, 16.7%-31.4%), respectively. The incidences of high-grade ALT and AST elevation were 8.4% (95% CI, 5.1%-13.4% and 7.0% (95% CI: 5.4%-9.0%), respectively. Sub-group analysis according to the ALK inhibitors found that pooled incidence of liver toxicities associated with ceritinib was higher than that of crizotinib and alectinib. In comparison with chemotherapy, ALK inhibitors significantly increased the all-grade and high-grade ALT elevation (RR 2.37, 95% CI, 1.97-2.86; P < .001; RR 7.34, 95% CI, 3.95-13.63; P < .001) and AST elevation (RR 3.27, 95% CI, 2.47-4.34; P < .001; RR 11.54, 95% CI, 4.33-30.7; P < .001), respectively. No publication bias was detected for RR of ALT and AST.

Conclusions: The findings of the present study offer substantial evidence that ALK inhibitors treatment in advanced NSCLC significantly increases the risk of developing all-grade and high-grade liver toxicities in comparison with controls. Clinicians should recognize liver toxicities promptly as early interventions may alleviate future complications.

Figure 1

Flow chart of trial selection process in the meta-analysis.

Figure 2

Pooled incidence of all-grade ALT elevation in NSCLC patients treated with ALK inhibitors. ALK = anaplastic lymphoma kinase, ALT = alanine transaminase, NSCLC = non-small-cell lung cancer.

Figure 3

Pooled incidence of high-grade ALT elevation in NSCLC patients treated with ALK inhibitors. ALK = anaplastic lymphoma kinase, ALT = alanine transaminase, NSCLC = non-small-cell lung cancer.

Figure 4

Pooled incidence of all-grade AST elevation in NSCLC patients treated with ALK inhibitors. ALK = anaplastic lymphoma kinase, AST = aspartate aminotransferase, NSCLC = non-small-cell lung cancer.

Figure 5

Pooled incidence of high-grade AST elevation in NSCLC patients treated with ALK inhibitors. ALK = anaplastic lymphoma kinase, AST = aspartate aminotransferase, NSCLC = non-small-cell lung cancer.