Oncogene-driven lung cancer remains the embodiment of personalized medicine. Since the first description of EGFR activating mutations found in patients with what was then called bronchiolalveolar carcinoma of the lung (BAC) in 2004, the topic of oncogene-driven lung cancer has grown rapidly and expanded to now encompass a number of additional mutation- and fusion-related entities. Recent updates to molecular testing guidelines, such as those of IASLC, have added several new oncogenes to the initial EGFR and ALK recommendations, including ROS1 and RET fusions, MET amplification or mutation, and HER2 mutations.1-3 Although the efficacy of tyrosine kinase inhibitors (TKI) in the treatment of some of these disease subsets is well established, the treatment decision-making process at the time of each relapse is becoming more complex as our knowledge of resistance pathways grows and more treatment options become available, with 2nd and 3rd generation drugs now in play. Subtping of progressive disease (PD) in oncogene-driven lung cancer into systemic PD versus oligo-PD or CNS-santuary PD can assist in determining the most appropriate therapeutic approach, as shown in Figure 1.4 Further, the methods by which we assess tumor at the time of initial or re-biopsy are also rapidly evolving, from single gene or multiplexed gene panels to highly sensitive and specific next generation sequencing (NGS). Lastly, we and others (4,5) have proposed algorithms for possible substitution of plasma cell free DNA by NGS platforms for tissue re-biopsy or for serial monitoring in plasma, as demonstrated in Figure 2. In this presentation we will present a step-wise approach to molecular testing and personalizing treatment for patients with oncogene-driven NSCLC, focusing on EGFR-mutated and ALK-rearranged subsets, since the treatment paradigms are most well established. We will emphasize some of the real world challenges faced by treating physicians. Decision criteria for selecting the best first-line therapy will be reviewed, the importance of re-biopsy upon disease progression to determine the most appropriate next-line therapy highlighted, and third line therapy and beyond discussed. The emerging role of liquid biopsy for assessment of plasma cell free DNA will be discussed, as well as a rationale for substituting liquid biopsy for initial or repeat tumor biopsy in some clinical settings. Algorithms designed to facilitate treatment decision-making will be presented. Two examples in EGFR-mutated lung cancer are shown below.Figure 2Algorithm for Re-Biopsy and/or Plasma cf DNA AnalysisShow full captionIn EGFR-mutated NSCLC.View Large Image Figure ViewerDownload Hi-res image Download (PPT) 1.Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J et al: Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 2013, 8(7):823-859.2.Leighl NB, Rekhtman N, Biermann WA, Huang J, Mino-Kenudson M, Ramalingam SS, West H, Whitlock S, Somerfield MR: Molecular Testing for Selection of Patients With Lung Cancer for Epidermal Growth Factor Receptor and Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Society for the Study of Lung Cancer/Association of Molecular Pathologists Guideline. Journal of Clinical Oncology 2014.3.Ettinger, D. S., Akerley, W., Borghaei, H., Chang, A. C., Cheney, R. T., Chirieac, L. R., ... & Grant, S. C. Non–small cell lung cancer, version 2.2013. Journal of the National Comprehensive Cancer Network, 2013, 11(6), 645-653.4.Gandara DR, Li T, Lara PN, Kelly K, Riess JW, Redman MW, Mack PC: Acquired resistance to targeted therapies against oncogene-driven non-small-cell lung cancer: approach to subtyping progressive disease and clinical implications. Clinical lung cancer 2014, 15(1):1-6.5.Oxnard, G. R., Thress, K. S., Alden, R. S., Lawrance, R., Paweletz, C. P., Cantarini, M., ... & Jänne, P. A. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non–small-cell lung cancer. Journal of Clinical Oncology, 2014, JCO667162.