The presence of EGFR-sensitising mutations in patients with advanced lung adenocarcinoma is the gold-standard biomarker for prediction of suitability for first-line EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy.1, 2, 3, 4, 5 EGFR mutations are detected usually in tumour tissue; however, in clinical practice, use of biopsy specimens might not always be possible because of suboptimum quantity, inadequate tissue quality, or intratumoral heterogeneity.
Research in context
Evidence before this study
We searched PubMed from Jan 1, 2006, to July 31, 2017, and proceedings of international meetings (eg, American Society of Clinical Oncology annual meeting), with the keywords “cell-free DNA”, “circulating tumor DNA”, and “EGFR mutation”. We restricted our search to the English language. Several prospective studies have validated use of circulating tumour DNA (ctDNA) for detection of EGFR mutations; however, these studies did not use ctDNA-based EGFR mutation detection as a selection criterion to guide EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment. Our search yielded no prospective clinical trials of EGFR-TKIs as first-line therapy in patients with advanced non-small-cell lung cancer who underwent ctDNA-based EGFR mutation analysis.
Added value of this study
To the best of our knowledge, our prospective clinical trial (BENEFIT) is the first to report the efficacy of first-line gefitinib with ctDNA-based EGFR mutation status as a screening criterion, and provides clinical evidence for use of ctDNA-based EGFR mutation status to ascertain eligibility for EGFR-TKI treatment. We investigated the diagnostic use of plasma ctDNA-based EGFR mutation detection using droplet digital PCR in patients with advanced lung adenocarcinoma receiving the EGFR-TKI gefitinib as first-line treatment. We also analysed dynamically EGFR-sensitising and EGFR-resistance mutation status in relation to clinical outcomes through to disease progression.
Implications of all the available evidence
The proportion of patients achieving an objective response and the duration of progression-free survival recorded in our trial are similar to those reported in previous studies using tissue-based EGFR mutation detection. Thus, EGFR mutation detection in patients with EGFR-positive plasma ctDNA could be used prospectively to select patients with advanced lung adenocarcinoma for first-line EGFR-TKI therapy when an insufficient tumour specimen is available for tissue-based EGFR mutation detection. Dynamic alterations in EGFR-sensitising and EGFR-resistance mutations could be used to predict disease progression, ahead of radiological results.
Circulating tumour DNA (ctDNA) in blood provides an alternative to tumour samples for EGFR mutation analysis. In Europe and the USA, cell-free DNA-based EGFR mutation analysis is approved by the European Medicines Agency and the US Food and Drug Administration (FDA), respectively, for detection of EGFR mutations if tumour tissue is scant, as a selection criterion for first-line EGFR-TKI therapy. In many studies, EGFR mutation status has been investigated in matched peripheral blood and tumour tissue in patients with advanced non-small-cell lung cancer (NSCLC), and researchers have reported retrospectively that patients with ctDNA-based EGFR mutation status had superior clinical outcomes with EGFR-TKIs to patients without EGFR mutations.6, 7, 8, 9, 10, 11, 12, 13 Furthermore, in several studies, the high specificity (92–100%) and positive predictive value (94·0–98·6%) of ctDNA-based EGFR mutation detection was validated prospectively, with tissue as reference.7, 10, 14, 15
In 2018, Ramalingam and colleagues16 showed that ctDNA genotyping for the EGFR Thr790Met mutation in plasma samples was an ideal predictor to guide third-generation EGFR-TKI treatment. However, EGFR-sensitising and EGFR-resistance mutations in ctDNA had diverse sensitivity (43–80%) when using tumour genotyping status as reference.16 Quantitative PCR techniques with potentially increased sensitivity—eg, droplet digital PCR (ddPCR) and BEAM (beads, emulsion, amplification, magnetics) digital PCR—have been used to genotype EGFR mutations in ctDNA and monitor dynamic gene alterations during EGFR-TKI therapy.12, 17, 18 Yung and colleagues12 reported that dynamic alterations of EGFR mutation status detected by ddPCR in ctDNA from patients with NSCLC could predict treatment response and monitor progressive disease. Also, Oxnard and colleagues19 reported that emergence of the EGFR mutation Thr790Met up to 16 weeks before radiographic progression could be used to guide subsequent treatment. Intratumoral heterogeneity is recognised to be one of the molecular mechanisms of resistance to EGFR-TKI therapy, and substantial alterations of a patient's genetic makeup can take place during treatment and at progression. Thus, dynamic monitoring of gene aberrances in ctDNA, and generation of an integrated genomic profile from high-throughput next-generation sequencing (NGS), could help to tailor targeted treatment for individual patients in clinical practice.
Despite study findings showing the feasibility of detection and monitoring of EGFR mutations in ctDNA, the application of blood-based mutation analysis into routine clinical practice has several limitations. First, previous results came from retrospective biomarker analyses, which need to be verified in prospective trials using ctDNA-based genotyping to ascertain targeted therapy.20 Second, in some prospective studies, dynamic changes of ctDNA EGFR mutations during EGFR-TKI treatment were assessed. However, most studies did subgroup analyses. To undertake a prospective study of dynamic monitoring of plasma EGFR mutations is difficult.14, 15 Finally, previous studies typically only focused on detection of one driver gene, rather than multiple sensitive or resistant alterations, which might affect clinical outcomes.
The third-generation EGFR-TKI osimertinib has been approved by the FDA as one of the standard options for first-line therapy based on findings of the FLAURA study.21 However, this first-line indication has not been approved in most Asian countries, which is why we chose to assess gefitinib in our study. The strategy of use of osimertinib in patients with the EGFR Thr790Met mutation after resistance to first-generation EGFR-TKIs is widely acceptable in China.22 Here, we report the results of Blood Detection of EGFR Mutation For Iressa Treatment (BENEFIT), in which we aimed to assess prospectively the diagnostic and clinical use of ctDNA-based EGFR mutation detection by ddPCR in patients with lung adenocarcinoma receiving gefitinib as first-line treatment. We also analysed dynamic alterations of EGFR-sensitising and EGFR-resistance mutations in relation to clinical outcomes.