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Published on: November 22, 2021
EGFR T790M relative mutation purity predicts osimertinib treatment efficacy in non-small cell lung cancer patients
Qiufan Zheng1, Shaodong Hong1, Yan Huang1
1Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, Guangdong, China.
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.
Insights
T790M relative mutation purity (RMP) in circulating tumor DNA predicts response to osimertinib in non-small cell lung cancer (NSCLC). This biomarker helps identify patients likely to benefit from this targeted therapy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Osimertinib is effective for EGFR T790M-positive NSCLC, but 30-40% of patients have limited response.
- Biomarkers are needed to predict osimertinib treatment efficacy.
- This study investigated circulating tumor DNA (ctDNA)-derived biomarkers for predicting osimertinib response.
Purpose of the Study:
- To evaluate the predictive value of baseline ctDNA biomarkers for osimertinib therapy in EGFR T790M-positive NSCLC patients.
- To identify novel biomarkers that can accurately predict treatment response and survival outcomes.
Main Methods:
- Targeted next-generation sequencing of ctDNA was performed on 54 NSCLC patients before osimertinib treatment.
- Analysis included maximum somatic allele frequency (MSAF), T790M relative mutation purity (RMP), and T790M relative mutation abundance (RMA).
- Statistical analyses assessed the association between these biomarkers and objective response rate (ORR) and progression-free survival (PFS).
Main Results:
- MSAF was not associated with ORR or PFS.
- T790M RMP quartiles significantly correlated with ORR and PFS (P for trend < 0.01).
- A T790M RMP cutoff of 0.24 identified distinct prognostic groups, with low RMP associated with better outcomes (HR=0.36, P=0.004).
- T790M RMA showed a trend towards association with ORR and identified prognostic groups (P=0.015), but T790M RMP demonstrated superior predictive value in multivariate analysis and as a continuous covariate for PFS (P=0.025).
- External validation confirmed T790M RMP's association with PFS.
Conclusions:
- T790M relative mutation purity (RMP) is an independent predictor of osimertinib treatment efficacy in NSCLC patients.
- T790M RMP serves as a valuable biomarker for predicting response and progression-free survival.
- This finding can aid in personalized treatment strategies for NSCLC.
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