EGFR mutation detection in circulating cell-free DNA of lung adenocarcinoma patients: analysis of LUX-Lung 3 and 6

Abstract

Background: In the Phase III LUX-Lung 3/6 (LL3/LL6) trials in epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma patients, we evaluated feasibility of EGFR mutation detection using circulating cell-free DNA (cfDNA) and prognostic and predictive utility of cfDNA positivity (cfDNA+).

Methods: Paired tumour and blood samples were prospectively collected from randomised patients. Mutations were detected using cfDNA from serum (LL3) or plasma (LL6) by a validated allele-specific quantitative real-time PCR kit.

Results: EGFR mutation detection rates in cfDNA were 28.6% (serum) and 60.5% (plasma). Mutation detection in blood was associated with advanced disease characteristics, including higher performance score, number of metastatic sites and bone/liver metastases, and poorer prognosis. In patients with common EGFR mutations, afatinib improved progression-free survival vs chemotherapy in cfDNA+ (LL3: HR, 0.35; P=0.0009; LL6: HR, 0.25; P<0.0001) and cfDNA- (LL3: HR, 0.46; P<0.0001; LL6: HR, 0.12; P<0.0001) cohorts. A trend towards overall survival benefit with afatinib was observed in cfDNA+ patients.

Conclusions: Plasma cfDNA is a promising alternative to biopsy for EGFR testing. Detectable mutation in blood was associated with more advanced disease and poorer prognosis. Afatinib improved outcomes in EGFR mutation-positive patients regardless of blood mutation status.

Figure 1

Patient disposition in LUX-Lung 3 and LUX-Lung 6. ^aPatients who were EGFR mutation positive based on tissue biopsy at screening. Abbreviations: cfDNA=cell-free DNA; EGFR=epidermal growth factor receptor.

Figure 2

Kaplan–Meier curves of PFS. Kaplan–Meier curves of PFS according to the presence of an EGFR mutation by cfDNA analysis^a in patients with common EGFR mutations (Del19 or L858R; based on tumour biopsy) in (A) LUX-Lung 3 and (B) LUX-Lung 6. ^aPatients who were EGFR Del19 or L858R mutation positive based on tissue biopsy were grouped according to whether any EGFR mutation was detected by cfDNA analysis (cfDNA+ or cfDNA−). Abbreviations: cfDNA=cell-free DNA; cis=cisplatin; EGFR=epidermal growth factor receptor; gem=gemcitabine; pem=pemetrexed; PFS=progression-free survival.

Figure 3

Kaplan–Meier curves of OS. Kaplan–Meier curves of OS according to the presence of an EGFR mutation by cfDNA analysis^a in patients with common EGFR mutations (Del19 or L858R; based on tumour biopsy) in (A) LUX-Lung 3 and (B) LUX-Lung 6. ^aPatients who were EGFR Del19 or L858R mutation positive based on tissue biopsy were grouped according to whether any EGFR mutation was detected by cfDNA analysis (cfDNA+ or cfDNA−). Abbreviations: cfDNA=cell-free DNA; cis=cisplatin; EGFR=epidermal growth factor receptor; gem=gemcitabine; OS=overall survival; pem=pemetrexed.