Variations in EGFR ctDNA Correlates to the Clinical Efficacy of Afatinib in Non Small Cell Lung Cancer with Acquired Resistance.

Abstract

Monitoring of non small cell lung cancer (NSCLC) patients on afatinib after acquired resistance to 1st generation tyrosine kinase inhibitors is important. Circulating tumor DNA (ctDNA) offers an attractive means other than conventional tissue biopsy to characterize real time dynamic changes of the disease. In our study, we aim to ascertain the clinical value for ctDNA monitoring of NSCLC patients with acquired resistance for afatinib treatment. 200 patients positive for the activating epithermal growth factor receptor (EGFR) mutations were recruited for the study. Baseline molecular profiling for L858R, Exon 19 deletion and T790M were performed. Thereafter, serial blood samples were taken and patients were assessed by overall survival (OS) to determine the usefulness of ctDNA monitoring. At baseline, matched tumor biopsy and ctDNA analysis had a concordance agreement of 93.5% for L858R and exon 19 deletion. We also determined that a large proportion of patients had the drug resistance mutation T790M prior to starting afatinib and these patients were linked to a worse survival outcome. For patients that registered a drop in ctDNA levels after afatinib was administered, we observed that their survival outcome was more favorable (hazard ratio 1.56, (95% CI 1.04 to 2.43). ctDNA levels were mostly elevated after the 3rd sampling cycle. Our results suggest that ctDNA can be used to predict the clinical benefits of afatinib treatment. Pre and post blood sampling aids to identify patient groups that may benefit most from the treatment and ctDNA is relatively sensitive to address the dynamic changes of the disease at the molecular level.