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. 2025 May;27(5):1967-1979.
doi: 10.1007/s12094-024-03727-7. Epub 2024 Sep 24.

Analysis of genomic alternations in epidermal growth factor receptor (EGFR)-T790M-mutated non-small cell lung cancer (NSCLC) patients with acquired resistance to osimertinib therapy

Ping-Chih Hsu  1   2 , John Wen-Cheng Chang  2   3 , Li-Chung Chiu  1   2 , Cheng-Ta Yang  1   2   4   5 , Scott Chih-Hsi Kuo  1   2 , Yueh-Fu Fang  1 , Chiao-En Wu  6   7
Affiliations

Analysis of genomic alternations in epidermal growth factor receptor (EGFR)-T790M-mutated non-small cell lung cancer (NSCLC) patients with acquired resistance to osimertinib therapy

Ping-Chih Hsu et al. Clin Transl Oncol. 2025 May.

Abstract

Background and objectives: Genomic alterations after resistance to osimertinib therapy in advanced T790M-mutated non-small cell lung cancer (NSCLC) are complex and poorly understood. In this study, we aimed to detect these genomic alternations via comprehensive next-generation sequencing (NGS) of tissue and liquid biopsies.

Patients and methods: From September 2020 to June 2021, 31 stage IIIB/IV T790M-mutated NSCLC patients who exhibited progressive disease after osimertinib therapy and provided written informed consent were recruited. Liquid and tissue biopsy samples for NGS testing were collected from 31 and 18 patients, respectively. Eighteen study patients had paired NGS data from tissue and liquid biopsies.

Results: With respect to the T790M mutation status, the preservation and loss rates were 33% and 67%, respectively, in both liquid and tissue biopsy samples. Five patients (16.1%) had the C797S mutation (4 liquid samples and 1 tissue sample). Two (6.5%) had MET mutations, 3 (9.7%) had BRAF-V600E mutations, and 1 (3.2%) had a KRAS-G12C mutation. Among the 18 patients who underwent tissue rebiopsies, those with preserved T790M mutation had significantly longer progression-free survival (PFS) with osimertinib therapy than those with T790M mutation loss (10.8 vs. 5.0 months, P = 0.045). Among all patients, those with T790M mutation loss in liquid biopsy samples had longer PFS after osimertinib therapy (10.8 vs. 7.5 months, P = 0.209) and postprogression survival (17.7 vs. 9.6 months, P = 0.132) than those with preserved T790M mutation based on liquid biopsies.

Conclusions: NGS using either tissue or liquid biopsy samples from advanced T790M-mutated NSCLC patients with acquired resistance to osimertinib therapy can detect various genomic alternations. Future studies focusing on subsequent tailored therapies on the basis of NGS results are warranted.

Keywords: Acquired resistance; Epidermal growth factor receptor mutation; Non-small cell lung cancer (NSCLC); Osimertinib; T790M; Tyrosine kinase inhibitor.

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Conflict of interest statement

Declarations. Conflict of interest: All the authors declare that they have no conflicts of interest.

Figures

Fig. 1
Fig. 1
Summary of the genomic alterations in tissue and liquid biopsies from all the study patients
Fig. 2
Fig. 2
Pie chart of the NGS results of A tissue biopsies and B liquid biopsies
Fig. 3
Fig. 3
The clinical outcomes of all study patients. A The median PFS of patients receiving osimertinib therapy was 10. 6 months (95% CI 8.0–13.2). B The median postosimertinib progression survival of all study patients was 17.1 months (95% CI 11.9–22.4). C The median OS of all study patients was 28.5 months (95% CI 18.5–38.5)
Fig. 4
Fig. 4
Treatment length of EGFR-TKIs
Fig. 5
Fig. 5
Comparison of clinical outcomes between patients with different postprogression T790M mutation statuses in tissue biopsies. A Comparison of the median PFS of osimertinib-treated patients. B Comparison of the median postprogression survival. C Comparison of the median OS
Fig. 6
Fig. 6
Comparison of clinical outcomes between patients with different postprogression T790M mutation statuses in liquid biopsies. A Comparison of the median PFS of osimertinib-treated patients. B Comparison of the median postprogression survival. C Comparison of the median OS
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