Abstract
INTRODUCTION: In the phase IV, open-label, single-arm study NCT01203917, first-line gefitinib 250 mg/d was effective and well tolerated in Caucasian patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (previously published). Here, we report EGFR mutation analyses of plasma-derived, circulating-free tumor DNA. METHODS: Mandatory tumor and duplicate plasma (1 and 2) baseline samples were collected (all screened patients; n = 1060). Preplanned, exploratory analyses included EGFR mutation (and subtype) status of tumor versus plasma and between plasma samples. Post hoc, exploratory analyses included efficacy by tumor and plasma EGFR mutation (and subtype) status. RESULTS: Available baseline tumor samples were 1033 of 1060 (118 positive of 859 mutation status known; mutation frequency, 13.7%). Available plasma 1 samples were 803 of 1060 (82 positive of 784 mutation status known; mutation frequency, 10.5%). Mutation status concordance between 652 matched tumor and plasma 1 samples was 94.3% (95% confidence interval [CI], 92.3-96.0) (comparable for mutation subtypes); test sensitivity was 65.7% (95% CI, 55.8-74.7); and test specificity was 99.8% (95% CI, 99.0-100.0). Twelve patients of unknown tumor mutation status were subsequently identified as plasma mutation-positive. Available plasma 2 samples were 803 of 1060 (65 positive of 224 mutation status-evaluable and -known). Mutation status concordance between 224 matched duplicate plasma 1 and 2 samples was 96.9% (95% CI, 93.7-98.7). Objective response rates are as follows: mutation-positive tumor, 70% (95% CI, 60.5-77.7); mutation-positive tumor and plasma 1, 76.9% (95% CI, 65.4-85.5); and mutation-positive tumor and mutation-negative plasma 1, 59.5% (95% CI, 43.5-73.7). Median progression-free survival (months) was 9.7 (95% CI, 8.5-11.0; 61 events) for mutation-positive tumor and 10.2 (95% CI, 8.5-12.5; 36 events) for mutation-positive tumor and plasma 1. CONCLUSION: The high concordance, specificity, and sensitivity demonstrate that EGFR mutation status can be accurately assessed using circulating-free tumor DNA. Although encouraging and suggesting that plasma is a suitable substitute for mutation analysis, tumor tissue should remain the preferred sample type when available.