Alectinib for the treatment of ALK-positive stage IV non-small cell lung cancer

Drugs Today (Barc). 2015 Mar;51(3):161-70. doi: 10.1358/dot.2015.51.3.2294597.


Our increased understanding of the molecular subsets of non-small cell lung cancer (NSCLC) has led to the development of highly effective targeted therapies. In particular, the outcomes of patients with advanced NSCLC driven by the EML4-ALK fusion protein, which comprise 3-5% of cases, have remarkably improved with the use of crizotinib, an oral multi-tyrosine kinase inhibitor that targets ALK. However, patients inevitably develop progression while on crizotinib due to various mechanisms of resistance. Alectinib is a novel oral small molecule that inhibits ALK with high potency and selectivity, and demonstrates promising antitumor effects in NSCLC. Preclinical studies have shown that it is also active against several mutant forms of ALK that confer resistance to crizotinib, including the gatekeeper mutation L1196M. Moreover, an objective response rate of over 90% was observed in a phase I trial. Due to the impressive results of early phase studies, alectinib was approved for the treatment of advanced ALK-positive NSCLC in Japan, while it has been granted a breakthrough therapy designation by the FDA. A phase III trial is currently ongoing. This review will describe the biology and significance of ALK rearrangements in NSCLC, ALK inhibition by crizotinib and mechanisms of resistance, as well as the preclinical and clinical evidence for the novel ALK inhibitor alectinib.

Trial registration: NCT01579994.

Keywords: ALK-rearranged NSCLC; Alectinib; Anaplastic lymphoma kinase; Fusion gene-positive NSCLC; NSCLC.

Publication types

  • Review

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use*
  • Carbazoles / administration & dosage
  • Carbazoles / adverse effects
  • Carbazoles / pharmacokinetics
  • Carbazoles / therapeutic use*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / enzymology
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Clinical Trials as Topic
  • Drug Discovery
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / pathology
  • Piperidines / administration & dosage
  • Piperidines / adverse effects
  • Piperidines / pharmacokinetics
  • Piperidines / therapeutic use*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Treatment Outcome
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Carbazoles
  • Piperidines
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases
  • alectinib

Associated data