Clinical consequences of resistance to ALK inhibitors in non-small cell lung cancer

Expert Rev Respir Med. 2020 Apr;14(4):385-390. doi: 10.1080/17476348.2020.1721285. Epub 2020 Jan 29.


Introduction: ALK rearrangements are present in 2-7% of non-small cell lung cancer (NSCLC) cases, where the EML4-ALK fusion is the most frequent. Rearrangement of ALK with other fusion partners occurs only in ≈5% of NSCLC ALK-positive. These patients have benefited from ALK inhibitors, and currently, there are three generations of drugs as the standard of care. The first-generation ALK inhibitor crizotinib is approved in the front-line setting for the treatment of advanced NSCLC; unfortunately, these tumors may eventually develop resistance to this molecule. The Second-generation ALK inhibitors, ceritinib, alectinib, and brigatinib, are approved for patients recently diagnosed or in relapse. The third-generation inhibitor lorlatininb is approved for patients who have developed resistance to any ALK inhibitor.Areas covered: In this review, an unstructured search in Pubmed and SCOPUS was conducted. We summarized the mechanisms of resistance to ALK inhibitors and its consequences in the treatment-decision making in advanced or metastatic NSCLC after failure to a first-line ALK inhibitor.Expert opinion: Currently, there are a growing number of options of therapeutic agents against ALK+ NSCLC (approved and in development); however, adequate selection and sequencing of agents are crucial to deal with the tumor evolution.

Keywords: ALK; Non-small cell lung cancer; tyrosine-kinase inhibitors.

Publication types

  • Review

MeSH terms

  • Anaplastic Lymphoma Kinase / antagonists & inhibitors
  • Anaplastic Lymphoma Kinase / genetics
  • Antineoplastic Agents / therapeutic use*
  • Carbazoles / therapeutic use
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / physiopathology
  • Carcinoma, Non-Small-Cell Lung / secondary
  • Crizotinib / pharmacology
  • Crizotinib / therapeutic use
  • Disease Management
  • Drug Resistance, Neoplasm*
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology
  • Lung Neoplasms / physiopathology
  • Mutation
  • Organophosphorus Compounds / therapeutic use
  • Piperidines / therapeutic use
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyrimidines / therapeutic use
  • Sulfones / therapeutic use


  • Antineoplastic Agents
  • Carbazoles
  • Organophosphorus Compounds
  • Piperidines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Sulfones
  • Crizotinib
  • Anaplastic Lymphoma Kinase
  • brigatinib
  • ceritinib
  • alectinib