Verification of a novel plasma eight-protein signature predicting long-term efficacy of first-line chemoimmunotherapy for advanced non-small cell lung cancer.

e20568 Background: Predicting immuno-chemotherapy (IC) response in advanced non-small cell lung cancer (aNSCLC) remains challenging. We previously developed and this study aimed to validate a plasma proteomic signature for predicting IC efficacy. Methods: 102 patients with EGFR/ALK wildtype aNSCLC who have received first-line immunotherapy plus chemotherapy were enrolled. Biological specimens were collected, including peripheral plasma, peripheral blood mononuclear cells (PBMCs), and tumor biopsies. Protein profiling was performed on plasma using the tumor-immunology panel on Olink platform. Transcriptome sequencing was conducted on PBMCs. PD-L1 and microvascular density (MVD) were evaluated by IHC on biopsy specimens. Results: From July 2020 to September 2023, an independent validation cohort were analyzed. The median follow-up was 14.8 months. The previously established signature stratified patients into high-risk (20.6%, n = 21) and low-risk (79.4%, n = 81) , with high-risk patients demonstrating significantly inferior PFS and OS (Table 1). Notably, the model exceeded the performance of PD-L1 Tumor Proportion Score (TPS) cutoff values of 1% or 50% in stratifying patient risk. Mechanistically, activated B cells (P < 0.05) were enriched in low-risk patients. High-risk patients demonstrated elevated plasma angiogenic proteins and a trend of higher MVD in tumor tissues. Conclusions: This verification study confirms the robust predictive value of our signature for IC outcomes in aNSCLC. The signature provides both prognostic stratification and biological insights that may guide therapeutic optimization. Risk group PFS/OS HR (95% CI)/Univariate cox p value/Univariate cox HR (95% CI)/Multivariate cox p value/Multivariate cox mPFS/OS /(month) (95% CI) p value High risk vs. Low risk PFS 2.35 (1.25-4.42) 0.008 2.25 (1.17-4.3) 0.015 15.1 (7-NR) vs. 21.5 (14.9-NR) 0.006 OS 3.16 (1.54-6.47) 0.002 2.82 (1.36-5.86) 0.005 15.5 (7.4-NR) vs. NR <0.001