Related Experiment Video
Updated: May 28, 2026
Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Comparison of Post-Resistance Treatment Outcomes in EGFR-Mutated NSCLC Patients Following Third-Generation EGFR-TKI
Xinyue Li1,2, Kaibo Ding2, Dujiang Liu1,2
1Department of Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang,China.
Abstract:
BackgroundThird-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become the first-line treatment for non-small cell lung cancer (NSCLC) with EGFR-sensitive mutations. The optimal treatment strategy after resistance to third-generation EGFR-TKIs still needs further exploration.MethodsThis retrospective study included patients with advanced lung adenocarcinoma who were consecutively enrolled at our hospital between January 2018 and July 2023. All patient data were fully de-identified prior to analysis, and no information that could directly or indirectly identify individual participants was included in this study. We evaluated the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) across various treatment strategies. We also explored the tumor microenvironment (TME) in a subset of patients.ResultsA total of 206 patients were included. Chemo-antiangiogenesis (47.6%) achieved longer mPFS than chemo-immunotherapy (8.00 vs. 5.70 months, p=0.033), with higher ORR (34.7% vs. 16.7%, p=0.003). Median OS was shorter in the immunotherapy group (25.83 vs. 32.33 months, p=0.012). TME analysis (n=27) revealed an immunosuppressive profile (low PD-L1, CCL5, CD8, granzyme B; high Foxp3). In EGFR exon 21 L858R patients, EGFR-TKI continuation was inferior to chemotherapy (mPFS: 3.53 vs. 8.00 months, p=0.001; ORR: 10.5% vs. 40.3%, p=0.015; DCR: 27.4% vs. 69.2%, p=0.009). In oligoprogressive disease, EGFR-TKIs plus radiotherapy improved OS (37.23 vs. 27.77 vs. 25.83 months, p=0.045). Platelet count, LDH, D-dimer, and smoking history were independent predictors of poor prognosis.ConclusionsChemo-antiangiogenesis remains a key treatment option after resistance. For oligoprogressive disease, continuing EGFR-TKIs with local radiotherapy may provide superior survival benefit. Chemo-immunotherapy appears less effective, potentially due to an immunosuppressive TME. Prospective validation is warranted.
Insights
Chemo-antiangiogenesis is effective after third-generation EGFR-TKIs resistance in non-small cell lung cancer (NSCLC). Combining EGFR-TKIs with radiotherapy benefits oligoprogressive disease, while chemo-immunotherapy shows limited efficacy.
Area of Science:
- Oncology
- Medical Science
Background:
- Third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are standard first-line treatment for EGFR-mutated non-small cell lung cancer (NSCLC).
- Optimal treatment strategies following resistance to third-generation EGFR-TKIs require further investigation.
Purpose of the Study:
- To evaluate the efficacy of various treatment strategies after resistance to third-generation EGFR-TKIs in advanced lung adenocarcinoma.
- To explore the tumor microenvironment (TME) and identify prognostic factors.
Main Methods:
- Retrospective analysis of 206 advanced lung adenocarcinoma patients treated between January 2018 and July 2023.
- Evaluation of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).
- Tumor microenvironment (TME) analysis in a subset of patients (n=27).
Main Results:
- Chemo-antiangiogenesis demonstrated superior PFS (8.00 vs. 5.70 months) and ORR (34.7% vs. 16.7%) compared to chemo-immunotherapy.
- Chemo-immunotherapy was associated with shorter median OS (25.83 vs. 32.33 months).
- EGFR-TKI continuation was inferior to chemotherapy in EGFR exon 21 L858R patients (mPFS: 3.53 vs. 8.00 months).
- EGFR-TKIs plus radiotherapy significantly improved OS in oligoprogressive disease (37.23 months).
- Low PD-L1, CCL5, CD8, granzyme B, and high Foxp3 characterized an immunosuppressive TME.
- Platelet count, LDH, D-dimer, and smoking history were independent predictors of poor prognosis.
Conclusions:
- Chemo-antiangiogenesis remains a primary treatment option following third-generation EGFR-TKI resistance.
- Combining EGFR-TKIs with radiotherapy offers survival benefits for oligoprogressive disease.
- Chemo-immunotherapy's limited efficacy may be linked to an immunosuppressive TME, warranting prospective validation.
