Comparative safety of anaplastic lymphoma kinase tyrosine kinase inhibitors in advanced anaplastic lymphoma kinase-mutated non-small cell lung cancer: Systematic review and network meta-analysis

Lung Cancer. 2023 Oct:184:107319. doi: 10.1016/j.lungcan.2023.107319. Epub 2023 Aug 7.


Objective: Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) are new treatment for advanced non-small cell lung cancer. Here, we quantified the toxicity profiles of different ALK-TKIs to guide clinical decision making.

Materials and methods: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials. Data were analyzed using random effects and consistency models under the frequency framework.

Results: Of 865 relevant studies, 13 RCTs (encompassing 3,353 patients) were finally included. A network meta-analysis of all-grade AEs, fatal AEs, and treatment discontinuation due to AEs revealed no significant differences among the six ALK-TKIs. The rates of grade 3-4 AEs were: alectinib (16.2%), crizotinib (46.4%), brigatinib (63.7%), ensartinib (75.6%), ceritinib (78.3%), and lorlatinib (91.6%). The toxicity spectra of ALK-TKIs were different. The most frequent AEs associated with crizotinib were gastrointestinal reactions, visual disorders, neutropenia, edema, fatigue, and elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels, while those in the alectinib group were anemia and constipation. Diarrhea, hepatotoxicity, and increased serum creatinine were most common with ceritinib. The most frequent AEs in the brigatinib group were gastrointestinal reactions, hypertension, cough, headache, and elevated ALT or AST levels. The most significant toxicities of ensartinib were skin disorders, including pruritus and rash. Changes in lipid levels were the most frequent AEs associated with lorlatinib; weight gain, cognitive effects, and mood effects were lorlatinib-specific AEs.

Conclusions: The toxicity spectra of ALK-TKIs differed. Alectinib might be the safest ALK-TKI drug according to the combined evidence of grades 3-4 AEs and the combined incidence.

Keywords: ALK inhibitor; Meta-analysis; Non-small-cell lung cancer; Safety; Toxicity.

Publication types

  • Meta-Analysis
  • Systematic Review
  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaplastic Lymphoma Kinase / genetics
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Crizotinib
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Network Meta-Analysis
  • Protein Kinase Inhibitors / adverse effects
  • Protein-Tyrosine Kinases
  • Tyrosine Kinase Inhibitors


  • Anaplastic Lymphoma Kinase
  • Protein-Tyrosine Kinases
  • ceritinib
  • brigatinib
  • Tyrosine Kinase Inhibitors
  • Crizotinib
  • lorlatinib
  • Protein Kinase Inhibitors