Evolution of first versus next-line targeted therapies for metastatic non-small cell lung cancer.

The expanding armamentarium of targeted therapies has revolutionized treatment for metastatic oncogene-addicted lung cancers. For multiple subsets, such as those harboring EGFR mutations and fusions in ALK or ROS1, successive generation of increasingly potent, selective, and brain-penetrating targeted therapies have shifted the treatment paradigm towards preferential first-line use of next-generation drugs. This evolution in clinical practice provides a lens through which to review the lessons learned from drug development in oncogene-addicted lung cancers, guided by translational insights into tumor biology and mechanisms of therapeutic resistance. For oncogenic drivers that are less sensitive to single-agent targeted therapies, rationally designed combination strategies will be needed to enable first-line use of targeted agents.