Non-small cell lung cancer (NSCLC) is a major cause of death worldwide, with most of the patients being diagnosed with disease in advanced stage, when treatment is only palliative1
. Chemotherapy represents the standard of care for patients with advanced disease but conventional cytotoxic agents has reached a plateau in terms of efficacy in the last few years, encouraging the investigation of new compounds which target proteins that are selectively expressed and/or that undergo genomic alterations in cancer cells2
. In the past several years an increase in the molecular understanding of lung cancer has led to a change in the treatment of the disease. This is highlighted by somatic mutations in EGFR
where treatment with an EGFR kinase inhibitor (gefitinib) in EGFR
mutant NSCLC patients leads to a superior response rate, a prolonged progression free survival and an improved quality of life compared to cytotoxic chemotherapy3
The fusion of the anaplastic lymphoma kinase (ALK) with the echinoderm microtubule-associated protein-like 4 (EML4) was identified in 2007 in Japanese non-small cell lung cancers (NSCLC) 4
. Additional studies, mostly involving East Asian patients, have reported that between 3%–13% of lung tumors harbor EML4-ALK
. By extrapolation this would suggest that approximately 5% of all NSCLC cases contain an EML4–ALK
translocation, equivalent to over 70,000 patients diagnosed annually worldwide.
Since the ALK tyrosine kinase activity is necessary for its transforming activity and oncogenicity, several ALK kinase inhibitors have been identified and are being evaluated in pre-clinical models in vitro
and in vivo
as potential clinical therapies7, 12, 13
. ALK inhibitors lead to apoptosis in vitro
and tumor shrinkage in vivo
thus demonstrating the phenomenon of “oncogene addiction” 7
. This is further confirmed by the dramatic clinical studies to date. In the phase I trial of PF-02341066, a remarkable 60% radiographic response rate has been observed specifically in EML4-ALK
. This is a remarkably short period of time from the initial identification of the EML4-ALK
translocation as oncogene to validation as a clinical target in NSCLC.
In this reiew, we highlight the clinical, biologic and molecular feature of EML4-ALK NSCLC patients and discuss the use of ALK inhibitors as therapies for this patient population.