Finally we assessed the utility of monitoring cfDNA in terms
Finally, we assessed the utility of monitoring cfDNA in terms of predicting disease progression earlier than radiological progression. These patients may have a chance to receive subsequent chemotherapy before worsening symptoms. Although the number of the patients who experienced progression was relatively small, EW-7197 recurrence preceded radiological progression in a part of population (37.5%). However, Kaplan-Meier curve showed that cfDNA analysis was not superior to RECIST evaluation as a whole. As we did not investigate its impact on overall survival, clinical utility of plasma progression should not be conclusive. As a clinical trial, European Organization for Research and Treatment of Cancer is now conducting a randomized, phase II study to explore the significance of plasma progression .
There are some limitations in the current study. Although our study showed the significance of cfDNA monitoring in EGFR mutated NSCLC, we did not conduct in a real-time processing manner. Secondly, the mechanisms of resistance other than EGFR T790M in this assay could not be assessed. We are currently conducting a comprehensive molecular analyses using ultrasensitive next generation sequencing with the same samples. This result will provide useful answers to improve treatment strategy in our primary resistant patients.
Conclusion In conclusion, liquid biopsy is a useful method for prediction of durable efficacy and progression in a part of EGFR-mutated NSCLC patients. Applicability of sequential liquid biopsy in clinical practice should be explored in further study.
Funding source This study received financial support from Boehringer Ingelheim.
Conflict of interest statement
Introduction An increased understanding of the molecular drivers of oncogenesis and resistance in non-small lung cancer (NSCLC) has led to a rapid expansion in the number of targeted therapies available to patients. Accordingly, molecular diagnostics in NSCLC have rapidly expanded, with guidelines now recommending analysis of multiple biomarkers including EGFR and BRAF gene mutations and rearrangements in ALK and ROS. The most common activating mutations in EGFR, del19 and L858R, are predictive of response to tyrosine kinase inhibitors (TKIs) in the advanced setting. In patients receiving first or second generation TKIs, the emergent EGFR mutation (EGFRm) T790M accounts for 60% of resistant cases. Osimertinib, a third generation TKI selectively inhibits both sensitizing EGFRm and T790M and has demonstrated improvement in progression free survival (PFS) compared to first generation TKIs in the first-line setting [1,2]. The optimal sequencing of EGFR-TKIs remains unclear. Resistance mechanisms to EGFR-TKIs are heterogeneous and multiple aberrations may be present simultaneously . Although tumour tissue genotyping remains the gold standard in detection of driver mutations, testing of circulating cell-free DNA (ctDNA) from liquid biopsies is growing and is particularly useful for patients with insufficient tumour tissue or where there may be substantial risk to the patient from invasive diagnostic procedures. Many next generation sequencing (NGS) panels are available that allow simultaneous detection of multiple genes and mutation types relevant in NSCLC from ctDNA, with one recently approved by the Food and Drug Administration (FDA) as a companion diagnostic in the United States (Oncomine™ Dx Target Test, ThermoFisher, Waltham, MA). While repeat tumour biopsies may help characterise the evolution of resistance in patients receiving targeted therapy, this is challenging in lung cancer patients who often are not well enough to undergo serial biopsies, nor does an isolated biopsy reflect the potential heterogeneity of resistance mechanisms at play. Monitoring levels of cell free circulating tumour (ct) DNA has been shown to correlate with disease response and progression with higher levels of ctDNA emerging at the time of radiographic progression [4,5]. We explored ctDNA levels in patients with stage IV EGFRm lung cancer in different phases of therapy, including pre-treatment, during EGFR-TKI treatment, upon progression and with chemotherapy.