Digital pathology predicts PD-L1 expression in metastatic NSCLC patients treated with immunotherapy

BackgroundAmong numerous efforts to discover new biomarkers, PD-L1 expression stands alone, demonstrating its unique, although not perfect, ability to predict response to immune checkpoint inhibitors (ICIs). A specific morphology can be associated with PD-L1 expression, introducing new scenarios for ICIs response.MethodsI3LUNG is a global EU-project, aiming to predict response to ICIs through artificial intelligence (AI). Six countries (Italy, Germany, Greece, Spain, US and Israel) collected digital pathology slides (DPS), genomics, radiomics, and other pt characteristics. Square tiles [299x299px] at 10x magnification were extracted from each whole slide. A Generative Adversarial Networks (GANs) and normalization were used to reduce batch effect. A foundation model pretrained using Self Supervised Learning was employed to convert each tile into a vector. To focus on the tumor areas, we used uncertainty gated model. Attention Based Multiple Instance Learning, a deep learning method was performed for classification. Among the 5 centers able to provide DPS, one center was held out and the model was trained through 4-fold cross validation (1-fold, 1 center) to define hyperparameters. Two models were developed: one to distinguish between pt with high PD-L1 (³50%) vs low/negative (<50%) and another one between positive (³1%) and negative (<1%) pt.Results2188 pt were enrolled in the I3LUNG retrospective cohort treated in first or further line IO. Among, 474 pt with available DPS and PD-L1 status were considered for the analysis. PD-L1 expression was high, low (1-49%) and negative in 145 (37%), 129 (32%) and 127 (31%) pt within the training and 24 (33%), 23 (32%) and 26 (35%) among the validation set. PD-L1 high vs low/negative status through DPS were able to be predicted with an area under the curve (AUC) of 0.70; while for PD-L1 positive vs negative an AUC of 0.68.ConclusionsThis is the largest series to date demonstrating a correlation between morphological features and PD-L1 expression in lung cancer. This rapid and generalizable model suggests that PD-L1 high and negative have different morphological phenotypes. Within I3LUNG the integration of genomic and radiomic data is expected to improve the ability to assess patient prognosis.Clinical trial identificationNCT05537922.Legal entity responsible for the studyFondazione IRCCS Istituto Nazionale dei Tumori (INT).FundingEuropean Commission, Grant Horizon Europe, Project ID: 101057695.DisclosureA. Prelaj: Financial Interests, Personal, Other, Training of personnel: AstraZeneca, Italfarma; Financial Interests, Personal, Invited Speaker, The Hive Project: Discussant: Roche; Financial Interests, Personal, Advisory Board, Advisory board in Lung Cancer project: BMS; Financial Interests, Personal, Other, Travel Grant: Janssen; Financial Interests, Personal, Advisory Board: Janssen, AstraZeneca; Financial Interests, Personal, Invited Speaker: Medsir; Financial Interests, Institutional, Local PI: Bayer, BMS, Lilly, MSD; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Spectrum. C. Proto: Financial Interests, Personal, Advisory Board: Italfarmaco, AstraZeneca, BMS, MSD, Janssen; Financial Interests, Institutional, Funding: Novartis. A. Meya: Financial Interests, Personal, Other, Employee: MEDSIR. E. Felip: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Gilead, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Regeneron, Sanofi, Takeda, Turning Point, Pfizer, Genmab; Financial Interests, Personal, Invited Speaker: Amgen, Daiichi Sankyo, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, PeerVoice, Pfizer, Sanofi, Takeda, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Merck Sharp & Dohme; Financial Interests, Personal, Member of Board of Directors, Independent member: Grifols; Financial Interests, Institutional, Local PI, Clinical Trial: AstraZeneca AB, AbbVie, Amgen, Bayer Consumer Care AG, BeiGene, Boehringer Ingelheim GmbH, Bristol Myers Squibb International Corporation, Daiichi Sankyo Inc., Exelixis Inc., F. Hoffmann-La Roche Ltd., Genentech Inc., GSK Research and Development Limited, Janssen Cilag International NV, Merck Sharp & Dohme Corp, Merck KGAA, Mirati Therapeutics Inc., Novartis Pharmaceutica SA, Pfizer, Takeda Pharmaceuticals International; Financial Interests, Institutional, Local PI: Nuvalent; Non-Financial Interests, Leadership Role, President (2021-2023): SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Member, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform); Non-Financial Interests, Member, Member of the Scientiffic Advisory Committee: CAC Hospital Universitari Parc Taulí. M. Reck: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Lilly, MSD, Merck, Novartis, Regeneron, Roche, Sanofi, GSK, Pfizer; Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, BMS, BioNTech, Boehringer-Ingelheim, Daiichi Sankyo, Gilead, MSD, Mirati, Pfizer, Regeneron, Roche, Sanofi, GSK, Lilly; Financial Interests, Personal, Other, Member of DMSB: Daiichi Sankyo; Financial Interests, Personal, Coordinating PI: AstraZeneca; Financial Interests, Institutional, Steering Committee Member: Amgen, Boehringer-Ingelheim, BeiGene, Daiichi Sankyo, GSK, BMS, Lilly, MSD, Regeneron, Roche; Financial Interests, Institutional, Local PI: Pfizer Seagen. F.G.M. De Braud: Financial Interests, Personal, Invited Speaker: Amgen, Ambrosetti, Ambrosetti, BMS, Dephaforum, ESO, Healthcare Research & Pharmacoepidemiology, Incyte, MSD, Merck Group, Nadirex, Pfizer, Roche, Sanofi, Seagen, Servier, Accmed, Dynamicom Education; Financial Interests, Personal, Other, Think Thank: MCCann Health; Financial Interests, Personal, Other, Consultant: Mattioli 1885; Financial Interests, Personal, Other: Novartis; Financial Interests, Personal, Other, Consultant Advisory Board: AstraZeneca, BMS, EMD Serono, Incyte, MSD, Menarini, NMS Nerviano Medical Science, Novartis, Pierre Fabre, Roche, Sanofi; Financial Interests, Personal, Other, Consultant Adv Board: Taiho; Financial Interests, Personal, Coordinating PI: BMS, Basilea Pharmaceutica International AG, DAICHI SANKIO Dev. Limited, Exelixis Inc., F.Hoffmann-LaRoche Ltd., IQVIA, Ignyta Operating Inc., Janssen-Cilag International NV, Kymab, Loxo Oncology Incorporated, MSD, MedImmune LCC, Merck KGAA, Merck Sharp & Dohme Spa, Novartis, Pfizer, Tesaro. G. Lo Russo: Financial Interests, Personal, Advisory Board: MSD, Novartis, AstraZeneca, BMS, Sanofi, Pfizer, Roche, Lilly, GSK; Financial Interests, Personal, Invited Speaker: Italfarmaco; Financial Interests, Institutional, Other, Contribute For Meeting Organization: Janssen; Financial Interests, Institutional, Other, Contribute For Meeting Organization: Bayern; Financial Interests, Personal, Other, Travel Accommodation: Amgen; Financial Interests, Institutional, Local PI: MSD, BMS, Roche, GSK, Celgene, Novartis, AstraZeneca, Amgen; Financial Interests, Local PI: Sanofi. M.C. Garassino: Financial Interests, Personal, Advisory Board: Eli Lilly, Seagen International GmbH, Eli Lilly, Incyte, GSK, Bayer Healthcare Pharmaceuticals, Blueprint Medicines, AstraZeneca UK, AstraZeneca and Daiichi Sankyo Oncology Teams, Roche, Daiichi Sankyo, Mirati Therapeutics, Inc., Daiichi Sankyo/AstraZeneca, AstraZeneca Poland, Daiichi Sankyo, Inc., MSD, Eli Lilly, Pfizer, AstraZeneca/MedImmune, Sanofi Genzyme corporation, Sanofi / Prex, Regeneron Pharmaceuticals, Eli Lilly, Mirati Therapeutics, Inc.; Financial Interests, Personal, Invited Speaker: WebMD, WebMD Oncology/Takeda, MSD Italia, Srl, GrupoPacifico-Secretaria Técnica ICAPEM/AstraZeneca, S.O.S S.r.l, Medscape, ecancer, Ideology; Financial Interests, Personal, Invited Speaker, Global Experts Meeting: AstraZeneca; Financial Interests, Personal, Other, AstraZeneca Spain: Invitation to a lung cancer investigator meeting: AstraZeneca; Financial Interests, Personal, Advisory Board, Advisory Boards: Takeda, Daiichi Sankyo, BeiGene; 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Financial Interests, Institutional, Local PI, Phase II - VISION: Merck KGaA; Financial Interests, Institutional, Local PI, Phase III MK-3475-715: Incyte Corporation; Financial Interests, Institutional, Local PI, Phase 1/2 (TRIDENT-1): Turning Point Therapeutics, Inc..; Financial Interests, Institutional, Local PI, HERTHENA-Lung01: A Phase 2: Daiichi Sankyo Development Ltd.; Financial Interests, Institutional, Local PI, Phase II ATLANTIC: AstraZeneca S.p.A.; Financial Interests, Institutional, Local PI, Clinical trial: Affimed; Financial Interests, Institutional, Local PI, Clinical trial poziotinib: spectrum; Non-Financial Interests, Principal Investigator, STYLE Trial: Pfizer; Non-Financial Interests, Principal Investigator, Studio TYME: Eli Lilly; Non-Financial Interests, Principal Investigator, People: MSD; Non-Financial Interests, Principal Investigator, FAME trial: Istituto Nazionale dei Tumori; Non-Financial Interests, Principal Investigator, POST-ALK: Istituto Nazionale dei Tumori; Non-Financial Interests, Principal Investigator, Bando finalizzata Mesotelioma: Istituto Nazionale dei Tumori; Non-Financial Interests, Principal Investigator, TERAVOLT: Istituto Nazionale dei Tumori; Non-Financial Interests, Principal Investigator, Progetto Timoma: Istituto Nazionale dei Tumori; Non-Financial Interests, Principal Investigator, APOLLO: Istituto Nazionale dei Tumori; Non-Financial Interests, Principal Investigator, Beverly: Istituto dei Tumori Pascale - Napoli; Non-Financial Interests, Principal Investigator, IND227: Istituto dei Tumori Pascale - Napoli; Non-Financial Interests, Principal Investigator, RAMES: GOIRC; Non-Financial Interests, Principal Investigator, Studio CHANCE: GOIRC; Non-Financial Interests, Principal Investigator, Creta trial: Sant'Orsola Malpighi - Bologna (Alma Mater Studiorum Università Bologna); Non-Financial Interests, Principal Investigator, MILES 5: Istituto dei Tumori Pascale - Napoli; Non-Financial Interests, Principal Investigator, LIPI: GUSTAVE-ROUSSY PARIGI LIPI TRIAL- no profit; Non-Financial Interests, Principal Investigator: AO Spedali Civili Brescia; Non-Financial Interests, Principal Investigator, phase III trial: European Thoracic Oncology Platform (ETOP); Non-Financial Interests, Leadership Role, Honorary President and Founder: Women for Oncology Italy; Non-Financial Interests, Other, Member of ASCO Scientific Committee (2018-2021): ASCO; Non-Financial Interests, Leadership Role, Board member: AIOT (Associazione Italiana Oncologia Toracica); Non-Financial Interests, Member: AIOM, AIOT; Non-Financial Interests, Member, WCLC annual congress Lung Cancer Track: WCLC; Non-Financial Interests, Member, Scientific Committee: IPOP (Italian lung cancer charity), TUTOR (Italian thymic malignancies charity); Non-Financial Interests, Member, Member since 2013-2018: EMA Scientific Advisory Group (SAG); Non-Financial Interests, Other, Scientific Programme Committee: AACR; Non-Financial Interests, Leadership Role, previous ESMO National Societies Committee Chair and ESMO Council Member: ESMO; Other, Travel, Accommodations, Expenses: Pfizer; Other, Relationships to Disclose Travel, Accommodations, Expenses: Roche, AstraZeneca; Other, travel and accommodation: Merck. All other authors have declared no conflicts of interest.