%0 Journal Article %A Sonja Althammer %A Tze Heng Tan %A Andreas Spitzmüller %A Lorenz Rognoni %A Tobias Wiestler %A Thomas Herz %A Moritz Widmaier %A Marlon C. Rebelatto %A Helene Kaplon %A Diane Damotte %A Marco Alifano %A Scott A. Hammond %A Marie-Caroline Dieu-Nosjean %A Koustubh Ranade %A Guenter Schmidt %A Brandon W. Higgs %A Keith E. Steele %T Automated image analysis of NSCLC biopsies to predict response to anti-PD-L1 therapy %D 2019 %R 10.1186/s40425-019-0589-x %J Journal for ImmunoTherapy of Cancer %P 121 %V 7 %N 1 %X Background Immune checkpoint therapies (ICTs) targeting the programmed cell death-1 (PD1)/programmed cell death ligand-1 (PD-L1) pathway have improved outcomes for patients with non-small cell lung cancer (NSCLC), particularly those with high PD-L1 expression. However, the predictive value of manual PD-L1 scoring is imperfect and alternative measures are needed. We report an automated image analysis solution to determine the predictive and prognostic values of the product of PD-L1+ cell and CD8+ tumor infiltrating lymphocyte (TIL) densities (CD8xPD-L1 signature) in baseline tumor biopsies.Methods Archival or fresh tumor biopsies were analyzed for PD-L1 and CD8 expression by immunohistochemistry. Samples were collected from 163 patients in Study 1108/NCT01693562, a Phase 1/2 trial to evaluate durvalumab across multiple tumor types, including NSCLC, and a separate cohort of 199 non-ICT- patients. Digital images were automatically scored for PD-L1+ and CD8+ cell densities using customized algorithms applied with Developer XD™ 2.7 software.Results For patients who received durvalumab, median overall survival (OS) was 21.0 months for CD8xPD-L1 signature-positive patients and 7.8 months for signature-negative patients (p = 0.00002). The CD8xPD-L1 signature provided greater stratification of OS than high densities of CD8+ cells, high densities of PD-L1+ cells, or manually assessed tumor cell PD-L1 expression ≥25%. The CD8xPD-L1 signature did not stratify OS in non-ICT patients, although a high density of CD8+ cells was associated with higher median OS (high: 67 months; low: 39.5 months, p = 0.0009) in this group.Conclusions An automated CD8xPD-L1 signature may help to identify NSCLC patients with improved response to durvalumab therapy. Our data also support the prognostic value of CD8+ TILS in NSCLC patients who do not receive ICT.Trial registration ClinicalTrials.gov identifier: NCT01693562.Study code: CD-ON-MEDI4736-1108.Interventional study (ongoing but not currently recruiting).Actual study start date: August 29, 2012.Primary completion date: June 23, 2017 (final data collection date for primary outcome measure).Abbreviations:ANOVAAnalysis of varianceCD8Cluster of differentiation 8CIConfidence intervalICTImmune checkpoint therapyIHCImmunohistochemistryNRNot reachedNSCLCNon-small cell lung cancerORRObjective response rateOSOverall survivalPD1Programmed cell death-1PD-L1Programmed cell death ligand-1PFSProgression-free survivalPPVPositive predictive valueRECISTResponse Evaluation Criteria in Solid TumorsTCTumor cellTILTumor infiltrating lymphocyteTMBTumor mutational burden %U https://jitc.bmj.com/content/jitc/7/1/121.full.pdf