Attacking a Moving Target: Understanding Resistance and Managing Progression in EGFR-Positive Lung Cancer Patients Treated With Tyrosine Kinase Inhibitors

Multiple randomized studies have demonstrated improved response rates, progression-free survival, and quality of life for treatment-naive, advanced-stage adenocarcinoma patients harboring sensitizing EGFR mutations when they are treated with tyrosine kinase inhibitor therapy, as compared with chemotherapy. Despite improved outcomes with these agents, the majority of patients will eventually develop resistance and subsequent clinical progression. Recently, there has been a firmer understanding of the molecular mechanisms of the resistance that develops as a consequence of treatment, most notably the identification of a second-site EGFR mutation, T790M. While this understanding can inform subsequent treatment decisions, disease progression can be heterogeneous, and there are several competing therapeutic options. Treatment decisions must consider this clinical heterogeneity, factoring in the pace of disease growth, lung cancer-related symptoms, and the potential presence of T790M mutations. Herein, we review the available literature addressing these competing strategies and attempt to clarify best treatment practices, including the emerging role of T790M-directed therapies.