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Prognostic implications of uncommon EGFR exon 19 deletion-insertion mutations in non-small cell lung cancer treated
Renzhi Zhang1, Huan Yan2, Fang Tian2
1Early Clinical Trial Center/Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China; Department of Medical Oncology, Graduate Collaborative Training Base of Hunan Cancer Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
Purpose:
The sensitivity of various epidermal growth factor receptor (EGFR) mutations to different EGFR tyrosine kinase inhibitors (EGFR-TKI) varies significantly. This study evaluated the survival outcomes of patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR exon 19 deletion-insertion (19delins) to third-generation EGFR-TKIs administered as first- or second-line therapy.
Methods:
We retrospectively analyzed clinical, molecular, and survival data from 215 patients detected with EGFR 19delins between March 2020 and July 2024. To evaluate progression-free survival, 57 patients with EGFR 19del who received first-line third-generation EGFR-TKIs (cohort A), and 48 patients who received the same treatment as second-line therapy (cohort B) were selected using 1:1 propensity score matching and served as control group.
Results:
Thirty-nine unique EGFR 19delins genotypes were identified, with L747_P753delinsS (34.0 %), L747_A750delinsP (18.1 %), and E746_S752delinsV (9.8 %) being the top three variants. Patients with EGFR 19delins had significantly shorter median PFS compared with patients with common exon19del (first-line, 12.9 vs. 19.7 months, p = 0.0039; second-line, 7.9 vs. 10.5 months, p = 0.0387). Exploratory analyses indicated that L747_P753delinsS might be associated with poorer prognosis, while E746_S752delinsV appeared to show better outcomes with third-generation EGFR-TKIs, findings that require further validation.
Conclusion:
These findings show real-world evidence that patients with EGFR 19delins derive limited clinical benefit from third-generation EGFR-TKI therapy compared to those with common EGFR 19del mutations, suggesting the need for optimal treatment regimen in this patient population.
Insights
Patients with EGFR 19delins advanced non-small cell lung cancer (NSCLC) show limited benefit from third-generation EGFR-TKIs. This real-world evidence suggests a need for tailored treatment strategies for this specific mutation subgroup.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Epidermal growth factor receptor (EGFR) mutations are key drivers in non-small cell lung cancer (NSCLC).
- The efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) varies based on specific EGFR mutation profiles.
- EGFR exon 19 deletion-insertion (19delins) mutations represent a distinct subgroup with potentially different treatment responses.
Purpose of the Study:
- To evaluate the survival outcomes of patients with advanced NSCLC harboring EGFR 19delins mutations treated with third-generation EGFR-TKIs.
- To compare the efficacy of first- and second-line third-generation EGFR-TKIs in patients with EGFR 19delins.
- To identify specific 19delins genotypes and their association with treatment response.
Main Methods:
- Retrospective analysis of clinical, molecular, and survival data from 215 patients with EGFR 19delins.
- Propensity score matching was used to compare progression-free survival (PFS) between patients receiving first-line (n=57) and second-line (n=48) third-generation EGFR-TKIs.
- Identification and characterization of various EGFR 19delins genotypes.
Main Results:
- Thirty-nine unique EGFR 19delins genotypes were identified, with L747_P753delinsS, L747_A750delinsP, and E746_S752delinsV being the most frequent.
- Patients with EGFR 19delins exhibited significantly shorter median PFS compared to those with common exon 19 deletions in both first-line (12.9 vs. 19.7 months) and second-line (7.9 vs. 10.5 months) settings.
- Exploratory analysis suggested L747_P753delinsS may be linked to poorer prognosis, while E746_S752delinsV might show better outcomes, warranting further investigation.
Conclusions:
- Real-world data indicate limited clinical benefit of third-generation EGFR-TKIs for patients with EGFR 19delins NSCLC compared to common EGFR 19del mutations.
- The findings highlight the need for optimized treatment regimens for patients with this specific EGFR mutation.
- Further research is required to validate the prognostic and predictive value of specific EGFR 19delins genotypes.
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