title: Treatment of ALK-Rearranged Non-Small Cell Lung Cancer: Recent Progress and Future Directions.
abstract: Rearrangements of the anaplastic lymphoma kinase (ALK) gene originally discovered nearly 20 years ago in the context of anaplastic large cell lymphoma were identified as oncogenic drivers in a subset of non-small cell lung cancers (NSCLCs) in 2007. These ALK gene rearrangements are present in 3-5 % of NSCLC patients, typically younger, never or light smokers with adenocarcinomas. Crizotinib is a first-in-class ALK tyrosine kinase inhibitor with significant activity in ALK-positive NSCLC that received accelerated US Food and Drug Administration approval for treatment of ALK-positive NSCLC in 2011, just 4 years after identification of ALK rearrangements in this setting. Subsequently, two phase III trials have shown crizotinib to have a tolerable toxicity profile and to be superior to standard chemotherapy for the first- or second-line treatment of advanced ALK-positive lung cancer and numerous countries have approved its use. Despite initial responses, acquired resistance to crizotinib invariably leads to disease progression. Mechanisms of resistance have been described to include ALK tyrosine kinase mutations, activation of bypass signalling pathways and pharmacokinetic failure of crizotinib. Several next-generation ALK inhibitors, including ceritinib and alectinib, are in clinical development and show efficacy in both the crizotinib naïve and crizotinib refractory settings. Ongoing clinical trials will identify the optimal strategy to incorporate these novel agents in the treatment of patients with ALK-positive NSCLC.
authors.affiliation: Department of Medical Oncology, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, VIC, 3002, Australia.
authors.forename: Laird
authors.initials: L
authors.lastname: Cameron
authors.forename: Benjamin
authors.initials: B
authors.lastname: Solomon
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015507:Drugs, Investigational / Q000494:pharmacology / Q000627:therapeutic use; D015321:Gene Rearrangement / Q000235:genetics; D005820:Genetic Testing; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011720:Pyrazoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D015507:Drugs, Investigational; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases