Thierry Berghmans, Myriam Remmelink, Ahmad Awada

Targeted therapies are nowadays a treatment option in metastatic non-small cell lung cancer, for which oncogenic drivers have been identified. The epidermal growth factor-receptor tyrosine kinase inhibitors gefitinib and erlotinib, are the standard of care for patients in whom tumors are presenting with an activating epidermal growth factor-receptor mutation, with new active agents like afatinib reaching clinics in the near future. Other genetic abnormalities have been documented in squamous and non-squamous lung cancer. The EML4-ALK gene fusion is a rare event, occurring in around 5% of lung cancer, quite exclusively in adenocarcinoma with a predominance of young non/light smokers. Detection of ALK-positive tumors is challenging, as there is no gold-standard technique. Fluorescence in situ hybridization is the method used in prospective trials assessing the activity of crizotinib and is recommended by the American FDA. Crizotinib is the first orally active inhibitor of receptor tyrosine kinases, including ALK and ROS1, in clinical practice. Impressive results came from a phase I study and are now confirmed in a large phase II study with response rate of 60%, whatever the number of previous lines of chemotherapy. Other ALK inhibitors are currently in the preclinical phase, and some are showing promising results in early phase I/II studies. This review aims to present the current knowledge on the EML4-ALK gene fusion, the pitfalls for the pathologist and the clinician in searching this abnormality, and to review the existing literature on ALK inhibitors under development, focusing their role compared to chemotherapy in non-small cell lung cancer patients.