Abstract
IntroductionAnaplastic lymphoma kinase (ALK) inhibitors are the mainstay treatment for patients with non-small cell lung carcinoma (NSCLC) harboring a rearrangement of the ALK gene or the ROS1 oncogenes. With the recent publication of pivotal trials leading to the approval of these compounds in different indications, their toxicity profile warrants an update.Materials and MethodsA systematic literature search was performed in July 2017. Studies evaluating US FDA approved doses of one of the following ALK inhibitors: Crizotinib, Ceritinib, Alectinib or Brigatinib as monotherapy were included. Data were analyzed using random effects meta-analysis for absolute risks (AR), study heterogeneity, publication bias and differences among treatments.ResultsFifteen trials with a total of 2,005 patients with evaluable toxicity data were included in this report. There was significant heterogeneity amongst different studies. The pooled AR of death and severe adverse events were 0.5% and 34.5%, respectively. Grade 3/4 nausea, vomiting, diarrhea, and constipation were uncommon: 2.6%, 2.5%, 2.7%, 1.2%, respectively.ConclusionsALK inhibitors have an acceptable safety profile with a low risk of treatment-related deaths. Important differences in toxicity profile were detected amongst the different drugs.
Highlights
Anaplastic lymphoma kinase (ALK) inhibitors are the mainstay treatment for patients with non-small cell lung carcinoma (NSCLC) harboring a rearrangement of the ALK gene or the ROS1 oncogenes
Utilizing medicinal www.oncotarget.com chemistry and rational design, different groups have been successful in the synthesis of novel, selective and potent ALK inhibitors with acceptable and consistent pharmacokinetic and pharmacodynamics profiles displaying strong in vivo efficacy in ALK-positive NSCLC xenograft models at well-tolerated doses
The National Comprehensive Cancer Network guidelines recommend testing for ALK rearrangement and ROS1 fusion for individuals with metastatic NSCLC since ALK inhibitors are recommended for the treatment of metastatic NSCLC in the first and second lines settings
Summary
Anaplastic lymphoma kinase (ALK) inhibitors are the mainstay treatment for patients with non-small cell lung carcinoma (NSCLC) harboring a rearrangement of the ALK gene or the ROS1 oncogenes. Non-small cell lung carcinoma (NSCLC) harboring rearrangements of the anaplastic lymphoma kinase (ALK) gene and the ROS1 oncogene constitute a unique molecular subgroup of this patient population. Utilizing medicinal www.oncotarget.com chemistry and rational design, different groups have been successful in the synthesis of novel, selective and potent ALK inhibitors with acceptable and consistent pharmacokinetic and pharmacodynamics profiles displaying strong in vivo efficacy in ALK-positive NSCLC xenograft models at well-tolerated doses. This has led to further development of these drugs [6]. Differences in the chemical structures amongst the ALK inhibitors may result in different toxicity profiles and efficacy [7]
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