Beyond EGFR and ALK: targeting rare mutations in advanced non-small cell lung cancer

Lung cancer remains the leading cause of cancer-related death in men and women, despite its constantly declining rates in incidence and mortality in the developed world. The past decade has witnessed an unprecedented rise in the development of molecular targeted therapies in various types of tumors. In non-small cell lung cancer (NSCLC), the greatest paradigm shift is the implementation of EGFR and ALK tyrosine kinase inhibitors in the first line and subsequent lines of therapy, with impressive results. Though less frequent than the molecular alterations in the aforementioned genes, a number of aberrations in potential oncogenic drivers has been discovered, namely mutations in the genes KRAS, BRAF, HER2, PI3KCA and DDR2, ROS1 and RET rearrangements and MET, HER2 and FGFR1 gene amplifications. A great number of clinical trials are currently underway, evaluating agents specifically designed to target these alterations, with mixed results so far. The greatest cumulative benefit offered by these trials is that, despite their success or failure in their objective goals, they have provided us with a better understanding of the complexity of the molecular intracellular processes, necessitating thus the accurate interpretation of the preclinical data in order to appropriately select the patients that may derive benefit from targeted treatment strategies.