Personalized Medicine and Imaging Detection and Dynamic Changes of EGFR Mutations from Circulating Tumor DNA as a Predictor of Survival Outcomes in NSCLC Patients Treated with First-line Intercalated Erlotinib and Chemotherapy

Purpose: Blood-based circulating-free (cf) tumor DNAmay be an alternative to tissue-based EGFR mutation testing in NSCLC. This exploratory analysis compares matched tumor and blood samples from the FASTACT-2 study. Experimental Design: Patients were randomized to receive six cycles of gemcitabine/platinum plus sequential erlotinib or placebo.EGFRmutation testingwas performedusing the cobas tissue test and the cobas blood test (in development). Blood samples at baseline, cycle 3, and progression were assessed for blood test detection rate, sensitivity, and specificity; concordance with matched tumor analysis (n1⁄4 238), and correlation with progression-free survival (PFS) and overall survival (OS). Results:Concordance between tissue and blood tests was 88%, withblood test sensitivity of 75%anda specificity of 96%.Median PFS was 13.1 versus 6.0 months for erlotinib and placebo, respectively, for those with baseline EGFR mutþ cfDNA [HR, 0.22; 95% confidence intervals (CI), 0.14–0.33, P < 0.0001] and 6.2 versus 6.1 months, respectively, for the EGFR mut cfDNA subgroup (HR, 0.83; 95%CI, 0.65–1.04,P1⁄40.1076). For patients with EGFR mutþ cfDNA at baseline, median PFS was 7.2 versus 12.0 months for cycle 3 EGFR mutþ cfDNA versus cycle 3 EGFR mut patients, respectively (HR, 0.32; 95% CI, 0.21–0.48, P < 0.0001); median OS by cycle 3 status was 18.2 and 31.9 months, respectively (HR, 0.51; 95% CI, 0.31–0.84, P 1⁄4 0.0066). Conclusions:Blood-based EGFRmutation analysis is relatively sensitive and highly specific. Dynamic changes in cfDNA EGFR mutation status relative tobaselinemaypredict clinical outcomes. Clin Cancer Res; 21(14); 3196–203. 2015 AACR.