Beyond EGFR and ALK inhibition: Unravelling and exploiting novel genetic alterations in advanced non small-cell lung cancer

• Novel molecular events that characterize NSCLC transformation may represent oncogenic drivers amenable to targeted therapy.
• Drivers beyond EGFR and ALK inhibition have emerged as novel molecular targets with potential therapeutic implications.
• These targets include genetic alterations in the genes KRAS, BRAF, HER2, PI3KCA, DDR2, ROS1, RET, MET, HER2 and FGFR1.
• A number of molecules that target the aforementioned genetic alterations are in early phase of clinical development.

During the last decade, thoracic oncology has witnessed an unprecedented outburst of knowledge regarding molecular biology of non small-cell lung cancer (NSCLC). The implementation of high-throughput sequencing analysis and genomic technologies has led to the identification of novel molecular events that characterize NSCLC transformation and may represent critical oncogenic drivers amenable to targeted therapy. Among these, the presence of activating mutations of the epidermal growth factor receptor (EGFR) gene and of chromosomic rearrangements in the anaplastic-lymphoma kinase (ALK) proto-oncogene, have been the first well characterized genetic alterations with corresponding targeted agents to enter the clinical arena. Nevertheless, in the recent years a number of other oncogenic drivers beyond EGFR and ALK inhibition have emerged as novel molecular targets with potential therapeutic implications, including mutations in the genes KRAS, BRAF, HER2, PI3KCA and DDR2, as well as ROS1 and RET rearrangements and MET, HER2 and FGFR1 gene amplifications. The aim of this review is to provide comprehensive information on the novel therapeutic targets identified by recent preclinical evidence and to discuss developments in molecular treatments targeting these oncogenic drivers or actionable mutations beyond EGFR and ALK in advanced NSCLC.