P09.15 Genomic landscape and predictive biomarkers of primary EGFR-TKI resistance and long-term survival in advanced EGFR-mutant NSCLC: implications for immunotherapy strategies

Background The incidence of primary resistance to EGFR-TKI is 20 ~ 30%, but the mechanism of occurrence and the optimal therapeutic strategy after resistance are unclear. This population may have unique molecular or immune characteristics. The aim of this study was to investigate the genomic alterations, PD-L1 expression, and immunotherapeutic efficacy after EGFR-TKI resistance in patients with primary EGFR-TKI resistance.Methods We retrospectively analyzed 98 patients with advanced EGFR-mutant NSCLC who developed primary resistance (disease progression) within 3 months after first- or second-line use of EGFR-TKI versus 137 patients who had disease progression within 18 months after use of EGFR-TKI. Baseline tumor samples were subjected to next-generation sequencing (520 gene panel) and PD-L1 immunohistochemistry (22C3 antibody). The efficacy of immunotherapy (objective response rate, progression-free survival, overall survival) after TKI treatment was evaluated.Result Among the primary resistance cohort, 56 patients had comprehensive baseline NGS results, while 62 patients in the long-term survival cohort had complete NGS data. In the primary resistance group, concomitant genetic alterations included TP53 (68.4%), other EGFR variants (31.6%), MET (12.3%), RB1 (10.3%), and RBM10 (10.5%). The long-term survival cohort exhibited TP53 (53.3%), other EGFR variants (26.7%), LRP1B (15.0%), CTNNB1 (13.3%), and PIK3CA (10.0%). No statistically significant differences were observed in co-occurring genomic alterations between the two cohorts (all P>0.05). However, the primary resistance cohort exhibited a significantly higher number of total genomic alterations compared to the long-term survival cohort (P=0.013). PD-L1 expression was assessed in 65 primary resistance patients and 103 long-term survivors, with significantly higher PD-L1 expression observed in the primary resistance cohort (P