Targeting emerging molecular alterations in the treatment of non-small cell lung cancer: current challenges and the way forward.

Introduction: Driver molecular aberrations, such as EGFR and BRAF mutations, ALK and ROS1 rearrangements, play an important role in the oncogenesis of non-small-cell lung cancer (NSCLC). Overall, these molecular targets select about 20% of advanced nonsquamous NSCLC Caucasian patients who can be treated with the corresponding tyrosine kinase inhibitors (TKIs). Many novel driver mutations are being or have been investigated in NSCLC, with varying degrees of success and failure. These emerging molecular targets are responsible for both primary involvement in cancer growth and have acquired resistance to previous TKIs, and for which potential therapeutic strategies are under investigation.Areas covered: This review will focus on the main emerging molecular targets in advanced stage of clinical development for the management of advanced NSCLC. A systematic review of bibliographic databases for peer-reviewed research literature and of key meetings was undertaken in order to discuss these topics.Expert opinion: Many emerging driver mutations are being investigated in metastatic NSCLC. Defining the most appropriate methods of detection of molecular aberrations, focusing on their role in the mechanisms of intrinsic and acquired resistance within appropriate preclinical and clinical trials, are needed in order to improve therapeutic benefit for NSCLC patients.