Abstract
BackgroundDespite 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.ResultsBaseline 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.ConclusionsThis study established the independent predictive role of T790M RMP in NSCLC patients receiving osimertinib treatment.
Highlights
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
The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) osimertinib is the current standard of care for patients with advanced EGFR-positive non-small cell lung cancer (NSCLC) who acquired T790M mutation after receiving earliergeneration TKIs therapy [1]
Some prior studies have indicated that quantification of the T790M relative mutation abundance (RMA), which calculated as T790M allelic fraction (AF)/EGFR driver AF, is associated with the efficacy of third-generation EGFR TKIs [5,6,7,8,9,10]
Summary
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 a need to identify biomarkers that accurately predict the response to osimertinib therapy. We investigated the predictive value of baseline circulating tumor DNAderived biomarkers on osimertinib therapy. The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) osimertinib is the current standard of care for patients with advanced EGFR-positive non-small cell lung cancer (NSCLC) who acquired T790M mutation after receiving earliergeneration TKIs therapy [1]. There is an urgent need to identify biomarkers that accurately predict for treatment response in NSCLC patients receiving osimertinib therapy. The proportion of T790M-positive clones within patient tumors may serve as a predictive biomarker for osimertinib treatment outcomes. Considering that not every cancer cell harbors the EGFR driver mutation, the T790M RMA value does not accurately represent the proportion of T790M mutant cells in a given patient
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