The efficacy of targeted therapy in ALK-positive non-small-cell lung cancer patients and analysis of MET/PD-L1 expression status

Background: Anaplastic lymphoma kinase-targeted tyrosine kinase inhibitors (ALK-TKIs) have revolutionized the treatment of non-small-cell lung cancer (NSCLC). However, several key issues remain unresolved. Specifically, the impact of prior chemotherapy on ALK-TKI efficacy is unclear, the impact of MET overexpression on ALK-TKI efficacy remains unclear, and the dynamic changes in programmed death ligand 1 (PD-L1) expression during the development of TKI resistance are not fully understood. Objective: This study aimed to evaluate the efficacy of ALK-TKIs across different treatment lines, analyze the impact of MET expression on treatment outcomes, and investigate changes in PD-L1 expression before and after the development of resistance. Design: Retrospective cohort study. Methods: A retrospective analysis was conducted on 259 patients with ALK-positive NSCLC treated at Zhejiang Cancer Hospital between 2011 and 2022 to compare the efficacy of ALK-TKIs administered as first-line therapy versus after chemotherapy. Immunohistochemical staining was used to assess MET and PD-L1 expression. Survival analysis was performed using the Kaplan–Meier method and the log-rank test. Results: Crizotinib showed no significant difference in progression-free survival (PFS) or overall survival (OS) between first-line and post-chemotherapy use (PFS: p = 0.803; OS: p = 0.761). For second-generation ALK-TKIs, first-line treatment had numerically longer PFS compared to post-chemotherapy (alectinib: 41 vs 24 months; ceritinib: 30 vs 8 months), but these differences were not statistically significant after adjustment ( p = 0.120 and 0.284, respectively). OS did not differ significantly between the two treatment sequences for either drug. Notably, among patients treated with alectinib, those with MET overexpression had significantly shorter PFS (12 vs 42 months; p = 0.011) and OS (41 months vs not reached; p = 0.001) compared with MET-negative patients. There was no significant change in PD-L1 expression following resistance ( p = 0.248). Conclusion: ALK-TKIs have shown a tendency to improve patient survival in both first-line and post-chemotherapy settings. Among patients treated with alectinib, there appears to be a trend toward shorter PFS and OS in those with MET overexpression. In a limited number of matched samples, PD-L1 expression did not change significantly after TKI resistance, although a slight increase was observed.