Targeted Therapies in Non-small Cell Lung Cancer

Historically, platinum-doublet chemotherapy was the mainstay of treatment for all patients with advanced non-small cell lung cancer (NSCLC). With platinum-doublet treatment, patients had a median overall survival of approximately 8 months and a 1-year survival of 33% (Schiller et al. 2002). In the last 20 years, however, there have been remarkable advances in the understanding of the pathophysiology, immunology, genetics, and heterogeneity of NSCLC, which has led to a myriad of new drug approvals based upon improvements in survival and quality of life (Ramalingam et al. 2020; Peters et al. 2017, 2020; Hirsch et al. 2017; Chen et al. 2013). Previously, we approached all patients with NSCLC as a homogenous population. We now base treatment on each patient’s histology, molecular sequencing, and biomarkers of immune response. In this chapter, we will provide an overview of the discovery and biology of driver mutations and discuss the seven mutational targets for which treatment is currently fully approved (EGFR, ALK, ROS, RET, TRK, MET, BRAF, KRAS) and others for which investigational agents are likely to be approved in the near future (Her2). In addition, we will discuss some particular areas of interest with targeted therapies including brain metastases, issues of immunotherapy, and the influence of co-mutations and potential combinations with other agents.