Comparison of Post-Resistance Treatment Outcomes in EGFR-Mutated NSCLC Patients Following Third-Generation EGFR-TKI Therapy: A Retrospective Cohort Study.

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.