A novel decision-making tool for first-line treatment selection in metastatic non-small cell lung cancer based on plasma proteome profiling

Importance Advanced stage non-small cell lung cancer (NSCLC) patients with no driver mutations are typically treated with immune checkpoint inhibitor (ICI)-based therapy, either in the form of monotherapy or concurrently with chemotherapy, while treatment modality selection is based mainly on programmed death ligand 1 (PD-L1) expression levels in the tumor. However, PD-L1 assays are only moderately predictive of therapeutic benefit. Objective To develop a novel decision-making tool for physicians treating NSCLC patients on whether to administer immune checkpoint inhibitor (ICI) therapy alone or in combination with chemotherapy. Design, setting, and participants This multicenter observational study includes patients from an ongoing clinical trial (PROPHETIC; [NCT04056247][1]). Patients were recruited from 13 different centers (total n=425; 58 patients were excluded) from June 2016 and June 2021. Plasma samples were obtained prior to treatment initiation, and deep proteomic profiling was conducted. PROphet® computational model for predicting clinical benefit (CB) probability at 12 months was developed based on the plasma proteomic profile. The model performance was validated in a blinded manner. Following validation, training and prediction was performed over the entire cohort using cross-validation methodology. The patients were divided into four groups based on their PD-L1 expression level combined with their CB probability, and the survival outcome was examined for each group. The data were analyzed from July to October 2022. Main outcome and measures Clinical benefit from ICI-based treatment, overall survival (OS) and progression-free survival (PFS). Results The model displayed strong predictive capability with an AUC of 0.78 (p-value = 5.00e-05), outperforming a PD-L1-based predictive model (AUC = 0.62; p-value 2.76e-01), and exhibited a significant difference in OS and PFS between patients with low and high CB probabilities. When combining CB probability with PD-L1 expression levels, four patient subgroups were identified; (i) patients with PD-L1≥50% and a negative PROphet result who significantly benefit from ICI-chemotherapy combination therapy compared to ICI monotherapy; (ii) patients with PD-L1≥50% and a positive PROphet result who benefit similarly from either treatment modalities; (iii) patients with PD-L1<50% and a negative PROphet result who do not benefit from either treatment modalities; (iv) patients with PD-L1<50% and a positive PROphet score who benefit from combination therapy. Conclusions and relevance The PROphet® model displayed good performance for prediction of CB at 12 months based on a plasma sample obtained prior to treatment. Our findings further demonstrate a potential clinical utility for informing treatment decisions for NSCLC patients treated with ICIs by adding resolution to the PD-L1 biomarker currently used to guide treatment selection, thereby enabling to select the most suitable treatment modality for each patient. ### Competing Interest Statement MH, CL, IS and ND are employees of OncoHost. IK, ALB, ML, RK, ET, MAA, CBA and MG declare no potential conflicts of interest. CP receives research grants from Amgen, AstraZeneca, Boehringer Ingelheim, Novartis, Roche and Takeda, as well as consultant and/or advisory board fees from AstraZeneca, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Gilead, Novartis, Roche and Takeda. NR received honoraria for advisory and speaker services from Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Daiichi-Sankyo, GlaxoSmithKline, Hoffmann-La Roche, Janssen, MSD, Merck, Pfizer, Symphogen and Takeda. AZ reports personal fees from AstraZeneca, MSD, Novartis, Roche, Steba and Takeda. MM reports consulting fees from Boehringer Ingelheim, Roche, AstraZeneca, MSD, BMS, Abbvie, Takeda and Pomicell. HN receives research grants from AstraZeneca, Spectrum Pharmaceuticals, Lilly, Merck KGaA, and MSD. AA receives research grants from BMS and personal and consulting fees from BMS, Roche, Pfizer, AstraZeneca, Takeda and Novartis. IW reports consulting fees from Novartis, MSD, BMS and Roche. YL receives research grants from Merck, MacroGenics, Tolero Pharmaceuticals, AstraZeneca, Blueprint Medicines, Harpoon Therapeutics, Sun Pharma Advanced Research, Kyowa Pharmaceuticals, Tesaro and Bayer HealthCare, as well as honorarium from Clarion Healthcare and consultant and/or advisory board fees from AstraZeneca and Novocure. RL received honoraria from BMS, MSD, Pfizer and Roche and has an advisory role in Pfizer. AD reports personal fees from the following: Roche, Janssen, Self Care Catalysts, Albert Einstein Medical College, Alcimed, Oranomed, IBA, Deallus, Genentech, CVS. DPC reports personal fees from the following: AbbVie, Adaptimmune, Agenus, Amgen, Ariad, AstraZeneca, Biocept, Boehringer Ingelheim, Celgene, Clovis, Daiichi Sankyo (DSI), EMD Serono, Flame Biosciences, Foundation Medicine, G1Therapeutics/Intellisphere, GenePlus, Genentech/Roche, GlaxoSmithKline, Gloria Biosciences, Gritstone, Guardant Health, Humana, Incyte, Inivata, Inovio, Janssen, Kyowa Kirin, Loxo Oncology, Merck, MSD, Nexus Oncology, Novartis, Oncocyte, Palobiofarma, Pfizer, prIME Oncology, Stemcentrx, Takeda Oncology and Teva. DG receives institutional research grants from Amgen, AstraZeneca, Genentech, and Merck, as well as consultant and/or advisory board fees from AstraZeneca, Roche-Genentech, Guardant Health, IO Biotech, Oncocyte, Lilly, Merck, and Novartis. He is the Chief Medical Officer for the International Society of Liquid Biopsy. ### Funding Statement This study was funded by OncoHost LTD ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional Review Board of Asklepios Kliniken GmbH gave ethical approval for this work. Institutional Review Board of Heidelberg University Hospital and National Center for Tumor Diseases, Heidelberg gave ethical approval for this work. Institutional Review Board of Rambam Medical Center gave ethical approval for this work. Institutional Review Board of Hadassah Hebrew University Medical Center gave ethical approval for this work. Institutional Review Board of Tel-Aviv Sourasky Medical Center gave ethical approval for this work. Institutional Review Board of Meir Medical Center gave ethical approval for this work. Institutional Review Board of Emek Medical Center gave ethical approval for this work. Institutional Review Board of Kaplan Medical Center gave ethical approval for this work. Institutional Review Board of Rabin Medical Center Davidoff Cancer Centre gave ethical approval for this work. Institutional Review Board of Assuta Hospital gave ethical approval for this work. Institutional Review Board of Shamir Medical Center gave ethical approval for this work. Institutional Review Board of Bnai Zion Medical Center gave ethical approval for this work. Institutional Review Board of Roswell Park Comprehensive Cancer Center gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04056247&atom=%2Fmedrxiv%2Fearly%2F2023%2F01%2F31%2F2022.12.01.22282769.atom