Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in EGFR-Mutant Lung Cancer: Distinct Natural History of Patients with Tumors Harboring the T790M Mutation

作者：Geoffrey R. Oxnard, Maria E. Arcila, Camelia S. Sima, Gregory J. Riely, Juliann Chmielecki, Mark G. Kris, William J. Pao, Marc Ladanyi, Vincent A. Miller · 发表于：Clinical Cancer Research · 年份：2010 · DOI：10.1158/1078-0432.ccr-10-2692 · 被引用次数：634 · 研究领域：Lung Cancer Treatments and Mutations、Lung Cancer Diagnosis and Treatment、Cancer Immunotherapy and Biomarkers

PURPOSE: Patients with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI) after a median of 10 to 16 months. In half of these cases, a second EGFR mutation, T790M, underlies acquired resistance. We undertook this study to examine the clinical course of patients harboring the T790M mutation following progression on TKI. EXPERIMENTAL DESIGN: EGFR-mutant lung cancer patients with acquired resistance to EGFR TKIs were identified as part of a prospective rebiopsy protocol in which postprogression tumor specimens were collected for molecular analysis. Postprogression survival and characteristics of disease progression were compared in patients with and without T790M. RESULTS: We identified T790M in the initial rebiopsy specimens from 58 of 93 patients (62%, 95% CI: 52-72). T790M was more common in biopsies of lung/pleura tissue and lymph nodes than in more distant sites (P = 0.014). Median postprogression survival was 16 months (interquartile range = 9-29 months); patients with T790M had a significantly longer postprogression survival (P = 0.036). Patients without T790M more often progressed in a previously uninvolved organ system (P = 0.014) and exhibited a poorer performance status at time of progression (P = 0.007). CONCLUSIONS: Among patients with acquired resistance to EGFR TKIs, the presence of T790M defines a clinical subset with a relatively favorable prognosis and more indolent progression...