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Molecular characteristics and responses to EGFR tyrosine kinase inhibitors in non-small cell lung cancer patients with EGFR exon 19 insertions
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Molecular characteristics and responses to EGFR tyrosine kinase inhibitors in non-small cell lung cancer patients with EGFR exon 19 insertions
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Journal Article
Molecular characteristics and responses to EGFR tyrosine kinase inhibitors in non-small cell lung cancer patients with EGFR exon 19 insertions
2025
Overview
Background
Epidermal growth factor receptor (
EGFR
) exon 19 insertions (19ins) represent a unique subclass of exon 19 alterations that has a relatively low frequency. Here, we aimed to elucidate the molecular characteristics and response to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in lung cancer patients with
EGFR
19ins.
Methods
Next-generation sequencing was performed to profile the molecular characteristics of 83 non-small cell lung cancer (NSCLC) patients with
EGFR
19ins. Detailed molecular profiling and efficacy analyses were performed on these patients, with comparisons to 68
EGFR
19 deletion (19del) patients. Potential resistance mechanisms were also explored.
Results
The prevalence of
EGFR
19ins mutations was 0.17% of all the primary NSCLC patients.
EGFR
19ins variants identified were I740_K745dup (86.7%) and K745_E746insVPVAIK (13.3%). Concurrent mutations frequently observed were in
TP53
(50.6%),
CDKN2A
(12.0%),
PIK3CA
(10.8%),
LRP1B
(8.4%), and
SMAD4
(8.4%). Notably,
CTNNB1
was significantly associated with 19ins (
p
= 0.043). Efficacy analysis showed median progression-free survival (mPFS) for
EGFR
19ins patients receiving first-line EGFR-TKI treatment was significantly shorter than for
EGFR
19del patients (hazard ratio (HR) 1.98,
p
= 0.005). Gefitinib was significantly less effective compared to other first-generation TKIs (HR 19.86,
p
< 0.001). Furthermore, osimertinib did not generate favorable outcomes as 19dels in the first-line setting either (
p
= 0.025). Post-treatment samples revealed higher occurrences of
TP53
mutations (84.6%) and presence of
EGFR
T790M (23.1%) at progression, with case studies highlighting osimertinib’s limited efficacy post-first-line treatment.
Conclusions
Comprehensive analysis of
EGFR
19ins in lung cancer patients revealed genomic characteristics and clinical response, helping better inform clinical action and might facilitate the development of more precise therapeutic options for patients with these uncommon driver mutations.
Publisher
BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
Subject
/ Aged
/ Carcinoma, Non-Small-Cell Lung - drug therapy
/ Carcinoma, Non-Small-Cell Lung - genetics
/ EGFR
/ Epidermal growth factor receptors
/ ErbB Receptors - antagonists & inhibitors
/ Female
/ Genomes
/ High-Throughput Nucleotide Sequencing
/ Humans
/ Kinases
/ Lung Neoplasms - drug therapy
/ Male
/ Medicine
/ Mutation
/ Non-small cell lung carcinoma
/ NSCLC
/ Patients
/ Protein Kinase Inhibitors - therapeutic use
/ TKI
/ Tyrosine
