Gefitinib treatment in EGFR mutated caucasian NSCLC: circulating-free tumor DNA as a surrogate for determination of EGFR status

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.

Trial registration: ClinicalTrials.gov NCT00388206.

FIGURE 1.

Patient flow diagram. ^aAll screened patients. Used to calculate the correlation between clinical characteristics and tumor EGFR mutation status and the comparison of EGFR mutation status between tumor DNA and plasma-derived circulating-free tumor DNA. ^bOne patient of EGFR mutation-positive ineligible status was treated in error and included in the evaluable-for-safety population. A total of 107 patients therefore started study treatment. ^cFull analysis set population. Used to summarize efficacy data and for the comparison of EGFR mutation status in plasma and tumor samples. ^dNumber of patients with EGFR mutation-positive tumors (n = 118) used as the denominator for the percentage calculation. ^eNumber of patients started on treatment (n = 107) used as the denominator for the percentage calculation. EGFR, epidermal growth factor receptor. Reproduced, in part, from Douillard et al. Br J Cancer 2014;110:55–62.

FIGURE 2.

Tumor sample flow diagram. EGFR, epidermal growth factor receptor.

FIGURE 3.

Objective response rate according to EGFR mutation (and subtype) status for patients who were tumor EGFR mutation positive, tumor and plasma 1 EGFR mutation positive, and tumor EGFR mutation positive and plasma EGFR mutation negative. Reproduced, in part, from Douillard et al. Br J Cancer 2014;110:55–62.