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

## TL;DR

New-generation ALK inhibitors cause less liver damage than crizotinib in lung cancer patients, with some showing better survival outcomes.

## Contribution

This study provides a meta-analysis comparing hepatotoxicity and efficacy of new-generation ALK inhibitors versus crizotinib.

## Key findings

- New-generation ALK inhibitors significantly reduce all-grade ALT elevation risk compared to crizotinib.
- Lorlatinib shows greater reduction in AST elevation and better progression-free survival than second-generation inhibitors.
- New-generation inhibitors improve progression-free survival but do not reduce treatment discontinuation rates.

## Abstract

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.

•Alectinib, lorlatinib, and brigatinib have lower hepatotoxicity risk than crizotinib•Envonalkib has higher risk of severe hepatotoxicity elevation than crizotinib•Lorlatinib has lower hepatotoxicity risk and better PFS than 2nd-generation ALK inhibitors•New ALK inhibitors have better PFS than crizotinib, but similar discontinuation rates

Alectinib, lorlatinib, and brigatinib have lower hepatotoxicity risk than crizotinib

Envonalkib has higher risk of severe hepatotoxicity elevation than crizotinib

Lorlatinib has lower hepatotoxicity risk and better PFS than 2nd-generation ALK inhibitors

New ALK inhibitors have better PFS than crizotinib, but similar discontinuation rates

Health sciences; Medicine; Medical specialty; Internal medicine; Oncology