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. 2021 Jan;16(1):77-84.
doi: 10.1007/s11523-020-00781-3. Epub 2020 Dec 3.

The Allele Frequency of EGFR Mutations Predicts Survival in Advanced EGFR T790M-Positive Non-small Cell Lung Cancer Patients Treated with Osimertinib

Anna Buder  1 , Maximilian J Hochmair  2 , Martin Filipits  3
Affiliations

The Allele Frequency of EGFR Mutations Predicts Survival in Advanced EGFR T790M-Positive Non-small Cell Lung Cancer Patients Treated with Osimertinib

Anna Buder et al. Target Oncol. 2021 Jan.

Abstract

Background: The allele frequency of epidermal growth factor receptor (EGFR) mutations could be a potential molecular biomarker for the outcome of osimertinib therapy.

Objective: The purpose of our study was to assess the clinical relevance of the allele frequency of EGFR mutations in plasma-based circulating tumor DNA (ctDNA) before starting osimertinib therapy in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) who had progressed under treatment with EGFR tyrosine kinase inhibitors (TKIs).

Patients and methods: We enrolled 141 patients with advanced EGFR T790M-positive NSCLC who underwent second-line osimertinib treatment. Plasma ctDNA was tested for EGFR-activating mutations (EGFR deletions in exon 19, L858R, L861Q, S768I) and T790M by means of droplet digital polymerase chain reaction (ddPCR).

Results: The allele frequency of EGFR-activating mutations in plasma ctDNA before osimertinib initiation ranged from 0 to 81,543 copies/ml and was independently associated with progression-free survival (PFS) and overall survival (OS) after adjusting for known clinicopathological risk factors (PFS: adjusted hazard ratio [HR] 1.26, 95% confidence interval [CI] 1.15-1.39, P < 0.0001; OS: adjusted HR 1.32, 95% CI 1.18-1.47, P < 0.0001). The allele frequency of T790M in plasma ctDNA before starting osimertinib therapy ranged from 0 to 38,092 copies/ml. Multivariate analyses showed that a higher T790M allele frequency was associated with a trend towards a shorter PFS (adjusted HR 1.19, 95% CI 0.99-1.42, P = 0.05) and a significantly shorter OS (adjusted HR 1.25, 95% CI 1.02-1.53, P = 0.03) of the patients.

Conclusion: A higher allele frequency of EGFR mutations, particularly EGFR-activating mutations, in plasma ctDNA is a poor prognostic marker. Further studies on the clinical utility of liquid biopsy are needed.

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Conflict of interest statement

Anna Buder has received honoraria from AstraZeneca. Maximilian J. Hochmair has received honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, and Roche and had consulting or advisory roles with Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, and Roche. Martin Filipits has received honoraria for advisory boards from Astra Zeneca, Bayer, Biomedica, Biorad, Boehringer Ingelheim, Myriad Genetics Inc., Pfizer, and Roche.

Figures

Fig. 1
Fig. 1
Kaplan–Meier curves for progression-free survival (a, c) and overall survival (b, d) according to the allele frequency of EGFR-activating mutations or the T790M mutation, and progression-free survival (e) and overall survival (f) according to the EGFR T790M/activating mutation ratio in plasma circulating tumor DNA before starting second-line osimertinib therapy. EGFR epidermal growth factor receptor
See this image and copyright information in PMC

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