Background: Circulating tumor DNA (ctDNA) harboring tumor-specific genetic and epigenetic aberrations allows for early detection and real-time monitoring of tumor dynamics. In this study, we aimed to evaluate the potential of parallel serial assessment of somatic mutation and methylation profile in monitoring the response to osimertinib of epidermal growth factor receptor (F.GFR) T790M-positive advanced lung adenocarcinoma patients. Methods: Parallel somatic mutation and DNA methylation profiling was performed on a total of 85 longitudinal plasma samples obtained from 8 stage IV osimertinib-treated EGFR T790M-positive lung adenocarcinoma patients. Results: Our results revealed a significant correlation between the by-patient methylation level with the maximum allele fraction (maxAF, P=0.0002). The methylation levels were significantly higher in the plasma samples of patients with detectable somatic mutations than patients without somatic mutations (P=0.0003) and healthy controls (P=0.0018). Moreover, analysis of both the DNA methylation level and maxAF revealed four trends of treatment response. Collectively, the decrease in methylation level and maxAF reflected treatment efficacy, while the gradual increase reflected impending disease progression (PD). Elevated methylation levels and maxAF were observed in 6 and 5 patients in an average lead-time of 3.0 and 1.9 months, respectively, prior to evaluation of PD using radiological imaging. Conclusions: DNA methylation profiling has the potential to predict disease relapse prior to evaluation through radiological modalities, suggesting that serial assessment of methylation level in combination with somatic mutation profiling are reliable methods for treatment monitoring. These methods should thus be incorporated with imaging modalities for a more comprehensive work-up of treatment response, particularly for patients treated with targeted therapies.