WCLC 2025 - Posters & ePosters-EP.06.56 Genomic and Immune Characteristics Linked to Second-Line Combination Immunotherapy Outcome in EGFR-Mutated Advanced NSCLC

EP.06.56 Genomic and Immune Characteristics Linked to Second-Line Combination Immunotherapy Outcome in EGFR-Mutated Advanced NSCLC

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This study investigated genomic and immune biomarkers linked to outcomes of second-line therapy combining immune checkpoint inhibitors (ICIs), anti-angiogenic agents, and chemotherapy in 11 patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) resistant to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Tumor tissue and blood samples underwent comprehensive genomic profiling targeting 437 cancer-related genes, and tumor immune cell infiltration was analyzed using multiplex immunohistochemistry.<br /><br />All 10 evaluable patients retained EGFR mutations, primarily exon 19 deletions (40%) and L858R mutations (50%). Concurrent TP53 mutations were the most frequent co-alteration (40%) and correlated significantly with shorter progression-free survival (PFS) (hazard ratio [HR] 8.25, p=0.028). Conversely, patients exhibiting a higher ratio of minimum to maximum variant allele frequency (mmVAF ≥0.3) in tumor tissue had prolonged PFS (HR 0.10, p=0.016). Immune profiling revealed that increased density of tumor-infiltrating CD56^bright natural killer (NK) cells strongly associated with better PFS outcomes (HR 1.71x10^-10, p=0.003). Additionally, a higher maximum somatic allele frequency (MSAF) in circulating tumor DNA (ctDNA) predicted worse PFS (HR 6.99, p=0.039).<br /><br />These findings suggest that TP53 mutation status, mitochondrial mutation allele frequency levels, and the extent of CD56^bright NK cell infiltration may serve as predictive biomarkers for guiding personalized second-line immunotherapy strategies in EGFR-mutated advanced NSCLC patients. The study emphasizes the importance of integrating genomic and immune landscape information to optimize treatment selection after EGFR-TKI failure. Further validation in larger patient cohorts is needed to confirm these biomarkers' clinical utility and refine therapeutic approaches.

Asset Subtitle

Lailing Li

Meta Tag

Speaker Lailing Li

Topic Pathology and Biomarkers

Keywords

EGFR-mutated NSCLC

second-line therapy

immune checkpoint inhibitors

anti-angiogenic agents

chemotherapy

TP53 mutations

progression-free survival

variant allele frequency

CD56bright natural killer cells

circulating tumor DNA