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Background: Resistance to PD1/L1 immune checkpoint inhibitors (ICIs) in advanced NSCLC patients is observed in about 80% of individuals with no robust predictive biomarker yet. The PIONeeR trial (NCT03493581) aims to predict such resistances through a comprehensive multiparametric biomarkers analysis. Methodology: Among the >300 advanced NSCLC patients (pts) recruited in PIONeeR, we focused on the first 137 ≥2nd line ECOG PS0-1 pts treated with single-agent nivolumab, pembrolizumab or atezolizumab. Tumor tissue was collected at baseline and pts were re-biopsied at 6 weeks, and blood-sampled every cycle throughout the 24 weeks post C1D1. Response to PD1/L1 ICIs was assessed by RECIST 1.1 every 6 weeks. Immune contexture was characterized in tumor & blood of each pt through FACS for circulating immune cell subtypes quantification and endothelial activation, blood soluble factors dosage, dual- & multiplex IHC/digital pathology to quantify immune cells infiltrating the tumor, WES for TMB & ICI plasma dosage, leading to 331 measured biomarkers in addition to routine clinical parameters. Multivariable (MV) logistic regression was used to examine the association of each biomarker (controlled by sex, age, smoking status, histological type & PDL1+ Tumor Cells) with the risk of Early Progression (EP), i.e. within 3.5 months of treatment. Multivariable Cox regression analysis was conducted for association with PFS and OS. Results: Overall, the 137 pts were mainly male (64%), smokers (92%) and 1% PDL1+ TC in 36% of the cases, and 21% of pts were still on treatment at data cut-off. Archived samples were available for 80% of pts at inclusion and re-biopsy was available in 52.9% of these cases. The median follow up was 19.8 months, 22.5% of pts did not progress at data cut-off while 62% presented EP. Tumor Cytotoxic T-cells density, especially PD1+ were lower in EP (MV OR=0.45, p=0.022); conversely, higher proportions of circulating cytotoxic T-cells and activated T-cells (HLA-DR+) were observed in EP (MV OR=3.8, p65% inter-pt variability was observed in plasma exposures for all ICIs, with 8-10% of pts displaying trough levels below the target engagement threshold. Data will be presented through unsupervised clustering algorithms & multi-modal supervised learning methods. Changes after 6 weeks of treatment will be analyzed to further investigate drugs mechanisms of action. Conclusion: The PIONeeR trial provides with the 1st comprehensive biomarkers’ analysis to establish predictive models of resistance in advanced NSCLC pts treated with PD1/L1 ICIs and highlights how tumor and circulating biomarkers are complementary. Citation Format: Laurent Greillier, Florence Monville, Vanina Leca, Frédéric Vely, Stephane Garcia, Joseph Ciccolini, Florence Sabatier, Gilbert Ferrani, Nawel Boudai, Lamia Ghezali, Marcellin Landri, Clémence Marin, Mourad Hamimed, Laurent Arnaud, Melanie Karlsen, Kevin Atsou, Sivan Bokobza, Pauline Fleury, Arnaud Boyer, Clarisse Audigier-Valette, Stéphanie Martinez, Hervé Pegliasco, Patrice Ray, Lionel Falchero, Antoine Serre, Nicolas Cloarec, Louisiane Lebas, Stephane Hominal, Patricia Barre, Sarah Zahi, Ahmed Frikha, Pierre Bory, Maryannick Le Ray, Lilian Laborde, Virginie Martin, Richard Malkoun, Marie Roumieux, Julien Mazieres, Maurice Perol, Eric Vivier, Sebastien Benzekry, Jacques Fieschi, Fabrice Barlesi. Comprehensive biomarkers analysis to explain resistances to PD1-L1 ICIs: The precision immuno-oncology for advanced non-small cell lung cancer (PIONeeR) trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB120.