Central nervous system involvement in ALK-rearranged NSCLC: promising strategies to overcome crizotinib resistance

Expert Rev Anticancer Ther. 2016 Jun;16(6):615-23. doi: 10.1080/14737140.2016.1182427. Epub 2016 May 10.


Introduction: ALK rearranged Non Small Cell Lung Cancers (NSCLCs) represent a distinct subgroup of patients with peculiar clinic-pathological features. These patients exhibit dramatic responses when treated with the ALK tyrosine kinase inhibitor Crizotinib, albeit Central Nervous System (CNS) activity is much less impressive than that observed against extracranial lesions. CNS involvement has become increasingly observed in these patients, given their prolonged survival. Several novel generation ALK inhibitors have been developing to increase CNS penetration and to provide more complete ALK inhibition..

Areas covered: The CNS activity of Crizotinib and novel generation ALK inhibitors will be summarized in this review, evaluating the strengths and weaknesses of the therapeutic strategies developed to date in this specific subgroup of NSCLCs with a look towards the future. Expert commentary: In the next few years, the results of ongoing comparative head-to-head trials will provide the definitive conclusions on the optimal treatment sequence in ALK-rearranged NSCLCs. Moreover, ongoing clinical trials with novel-generation ALK inhibitors will produce more evidences on the best approach in the growing number of ALK-positive NSCLCs with CNS involvement.

Keywords: ALK translocations; Brain metastases; NSCLC; central nervous system metastases; leptomeningeal metastases.

Publication types

  • Review

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Animals
  • Antineoplastic Agents / pharmacology
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / secondary
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Crizotinib
  • Drug Design
  • Drug Resistance, Neoplasm
  • Gene Rearrangement
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Protein Kinase Inhibitors / pharmacology
  • Pyrazoles / pharmacology
  • Pyridines / pharmacology
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / genetics


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridines
  • Crizotinib
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases