ABSTRACT: BACKGROUND:Despite the impressive anti-tumor activity of osimertinib in epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer (NSCLC) patients, 30-40% of patients still show limited response. There is therefore a need to identify biomarkers that accurately predict the response to osimertinib therapy. In this study, 54 patients with targeted next-generation sequencing of circulating tumor DNA before osimertinib treatment and known T790M positivity were included. We investigated the predictive value of baseline circulating tumor DNA-derived biomarkers on osimertinib therapy. RESULTS:Baseline maximum somatic allele frequency (MSAF) level was not associated with objective response rate (ORR) (P?=?0.886) and progression-free survival (PFS) (P?=?0.370) of osimertinib treatment. T790M relative mutation purity (RMP, defined here as the ratio of T790M AF to MSAF) quartiles were found to be significantly associated with ORR (P for trend?=?0.002) and PFS (P for trend?=?0.006), and a cut off value of 0.24 identified two distinct prognostic groups [Hazard ratio (HR)?=?0.36 for low T790M RMP, 95% confidence interval (CI) 0.18-0.72, P?=?0.004). Additionally, although T790M relative mutation abundance (RMA, defined as T790M AF/EGFR driver AF) quartiles were not significantly associated with ORR (P for trend?=?0.063), a cut off value of 0.30 also identified two distinct prognostic groups (HR?=?0.43 for low T790M RMA, 95% CI 0.22-0.85, P?=?0.015). However, in multivariate analysis, grouping of T790M RMP showed a better predictive value (HR?=?0.46, 95% CI 0.20-1.05, P?=?0.066) than T790M RMA (HR?=?0.71, 95% CI 0.31-1.61, P?=?0.409). Moreover, T790M RMP as continuous covariate was independently predictive of PFS (HR?=?0.15, 95% CI 0.03-0.79, P?=0.025), while T790M RMA was not (HR?=?1.14, 95% CI 0.49-2.66, P?=0.766). An external validation cohort further confirmed the T790M RMP was significantly associated with PFS of osimertinib therapy. CONCLUSIONS:This study established the independent predictive role of T790M RMP in NSCLC patients receiving osimertinib treatment.
