Beyond EGFR, ALK and ROS1: Current evidence and future perspectives on newly targetable oncogenic drivers in lung adenocarcinoma

Lung cancer is the leading cause of cancer death worldwide. In the past decade EGFR, ALK and ROS1 TKIs lead to an unprecedented survival improvement of oncogene-addicted NSCLC patients, with better toxicity profile compared to chemotherapy. In recent years the implementation of high-throughput sequencing platforms led to the identification of uncommon molecular alterations in oncogenic drivers, such as BRAF, MET, RET, HER2 and NTRK. Moreover, newly developed drugs have been found to be active against hard to target drivers, such as KRAS. Specific TKIs targeting these genomic alterations are currently in clinical development and showed impressive activity and survival improvement, leading to FDA-accelerated approval for some of them. However, virtually all patients develop resistance to TKIs by on-target or off-target mechanisms. Here we review the clinicopathological features, the emerging targeted therapies and mechanisms of resistance and strategies to overcome them of KRAS, BRAF, MET, RET, HER2 and NTRK-addicted advanced NSCLCs.