Abstract 6042: Baseline serum level of IgG targeting annexin A2 is predictive of response to immunotherapy in patients with advanced NSCLC

Abstract Introduction: Despite the success of immune checkpoint blockers (ICBs), predicting which patients will respond to treatment remains a significant challenge, particularly in those with advanced NSCLC. Some circulating antibodies may serve as indicators of a pre-existing antitumor adaptive immune response. This study investigated the potential of baseline serum antibodies as predictors of response and survival in patients with advanced NSCLC undergoing ICB, chemotherapy, or ICB + chemotherapy. Materials and Methods: Baseline serum samples were collected from 256 patients with advanced NSCLC in two independent cohorts : the PREMIS cohort (NCT03984318, n=195 patients treated with either ICB alone (n=129) or combined chemo-immunotherapy (n=66)) and the MSN cohort (NCT02105168 - n=61 patients receiving first-line chemotherapy). Fluorescence intensities of IgG and IgM binding to individual human proteins were measured using the HuProt arrays containing over 20, 000 human proteins. Survival analyses, including Kaplan-Meier, Log-Rank test and Cox regression models, were conducted to determine the predictive value of identified antibodies. Response was defined by RECIST 1.1. Results: Few protein specific antibody levels were significantly different between responders and non-responders, including five that were significantly higher: ANXA2-IgG, METTL21B-IgG, SPHKAP-IgG, Lupus La-IgG, EDN1-IgG, and EFHC1-IgM. Four isoforms of the ANXA2 protein consistently exhibited elevated IgG antibody levels in responders, with a strong inter-isoform correlation (R>0.95, p<0.0001). These antibodies were correlated with baseline global IgG levels and antinuclear antibodies (ANA) status but not with tumor histology (squamous or non-squamous) or other clinical characteristics (including PD-L1 staining). ICB-treated patients with higher anti-ANXA2 IgG levels (n=23) had progression-free survival (PFS, Logrank p=0.02) and overall survival (OS, Logrank p=0.008) as compared to intermediate (n=86) and low (n=20) patients in ICB-treated patients. This effect was also suggested in the chemo-immunotherapy group (although not significant) but was absent in patients treated with chemotherapy without ICB. After adjusting for global IgG levels, anti-ANXA2 IgG levels independently predicted PFS and OS in ICB-treated patients. Conclusion: Pre-existing humoral immunity against ANXA2 predicts response and survival in advanced NSCLC treated with ICB. Annexin A2 (ANXA2) has been implicated in immunosuppression, epithelial-to-mesenchymal transition (EMT), and poorer survival outcomes in cancer patients. Baseline anti-ANXA2 IgG levels could therefore be used as biomarkers to predict benefits of ICB and allow for patient stratification. Also, ANXA2 could become a novel target for NSCLC immunotherapy. Citation Format: Matthieu Roulleaux Dugage, François-Xavier Danlos, Mélodie Bonvalet, Tyler Hulett, Sabine Messayke, Anne-Laure Voisin, Marie Naigeon, Jean Jouniaux, Aleksei Tikhonov, Chifaou Mohamed-Djalim, Severine Mouraud, Delphine Bredel, Scott Paschke, Mihaela Aldea, Pernelle Lavaud, David Planchard, Benjamin Besse, Nathalie Chaput, Aurélien Marabelle. Baseline serum level of IgG targeting annexin A2 is predictive of response to immunotherapy in patients with advanced NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6042.