Optimal Treatment Strategies for EGFR Mutant Advanced Lung Adenocarcinoma Patients with Targeted Therapy Resistance and Correlation Analysis of PD-L1 Expression with ICI Efficacy

Background Third-generation tyrosine kinase inhibitors (TKIs) have become the standard treatment for advanced epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma. Currently, after developing resistance to third-generation EGFR-TKIs, treatment regimens based on platinum-based dual-agent chemotherapy yield limited clinical benefit. Method This retrospective study analyzed patients who progressed on first-line third-generation EGFR-TKIs between March 2019 and September 2024 and received second-line chemotherapy-based regimens. Patients were further stratified based on PD-L1 expression status and immune checkpoint inhibitor (ICI) use to assess the correlation between PD-L1 expression and ICI efficacy. Results Among 107 patients who progressed on third-generation TKIs as first-line therapy, 35 received chemotherapy (CP), 29 received chemotherapy combined with anti-angiogenic (BCP), 22 received chemoimmunotherapy (ACP), and 21 received chemoimmunotherapy combined with anti-angiogenic therapy (ABCP). Second-line median progression-free survival (mPFS2) were 4.89 months, 6.74 months, 7.80 months, and 8.00 months, respectively. Non-ICIs group vs. ICIs group: mPFS2 was 5.06 months vs. 8.00 months, P = 0.031. In PD-L1-negative, positive, and strong subgroups, the Non-ICIs group vs. ICIs group showed mPFS2 of 5.32 months vs. 6.68 months, P = 0.724; 4.89 months vs. 8.63 months, P = 0.009, and 3.11 months vs. 13.52 months, P < 0.001. Conclusion Among patients with EGFR-TKI resistance, combination immunochemotherapy with or without anti-angiogenic therapy demonstrates distinct advantages over chemotherapy alone. Adding ICIs in PD-L1-positive patients improves progression-free survival, with greater clinical benefit observed at higher PD-L1 expression levels. Within the immunotherapy cohort, PD-L1-high patients show a trend toward more pronounced benefit from ICIs.