WCLC 2025 - Posters & ePosters-P3.03.42 Immune-Related Gene Expression Profiling and ALK-TKI Efficacy for Patients With ALK-Rearranged Non-Small Cell Cancer

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This study investigated immune-related gene expression profiling (irGEP) in ALK-rearranged non-small-cell lung cancer (NSCLC) to explore tumor microenvironment characteristics and their relation to the efficacy of ALK tyrosine kinase inhibitors (ALK-TKIs), specifically alectinib. Conducted as a substudy of the prospective, multicenter ALCURE study, it included 52 advanced ALK-rearranged NSCLC patients receiving or scheduled for first-line alectinib therapy. Using the nCounter PanCancer IO 360 Panel, which analyzes 750 immune-related genes, researchers identified three distinct tumor clusters based on immune gene expression.<br /><br />The results demonstrated that tumors with high expression of CD8A, a marker for cytotoxic T cells, showed significantly better progression-free survival (median not reached) compared to CD8A-low tumors (median progression-free survival ~36.5 months), though this difference did not reach statistical significance (HR 0.49; P=0.16). Gene expression analysis revealed that CD8A-low tumors had upregulated angiogenesis-related genes including ANGPT2 (angiopoietin-2), FLT1 (VEGFR1), and MET, suggesting aberrant angiogenesis may impair T cell infiltration and contribute to resistance against immunotherapy and ALK-TKIs. Conversely, CD8A-high tumors exhibited enhanced epithelial–mesenchymal transition (EMT) signals.<br /><br />Furthermore, clustering of immune gene expression profiles showed significant survival differences among groups, with clusters enriched for T cell activation genes correlating with improved outcomes on alectinib. Differential gene expression analysis by PD-L1 status also highlighted immune regulatory genes, though the clinical impact was less pronounced.<br /><br />In conclusion, this largest irGEP analysis in ALK-rearranged NSCLC indicates that low CD8 T cell infiltration correlates with poorer alectinib response, possibly via angiogenesis-mediated immune exclusion. These findings suggest that anti-angiogenic therapies might enhance antitumor immunity and synergize with ALK-TKIs, offering a promising therapeutic strategy to overcome resistance in ALK-rearranged NSCLC. The study was supported by Chugai Pharmaceutical Co., Ltd.

Asset Subtitle

Takashi Kurosaki

Meta Tag

Speaker Takashi Kurosaki

Topic Tumor Biology – Translational Biology

Keywords

ALK-rearranged NSCLC

immune-related gene expression profiling

ALK tyrosine kinase inhibitors

alectinib

CD8A expression

tumor microenvironment

angiogenesis

epithelial–mesenchymal transition

T cell activation

anti-angiogenic therapy