Abstract 74P
Background
Immune checkpoint inhibitor (ICI)-based treatment has revolutionized the cancer therapy landscape, displaying durable response in patients with advanced stage disease. However, only a small fraction of patients responds to this treatment. It is therefore critical to identify reliable biomarkers for response and understand the mechanisms underlying resistance. Here we examined host-mediated effects occurring in response to ICI treatment and their contribution to therapy resistance in stage IV non-small cell lung cancer (NSCLC) patients.
Methods
Plasma samples were obtained at baseline and early-on treatment from NSCLC patients as part of an ongoing multi-center clinical trial (NCT04056247), along with comprehensive clinical data. Proteomic profiling of plasma samples was performed using proximity-extension assay (PEA) technology. Machine learning algorithms were then used to stratify between responders and non-responders based on a training set (n=78) and an independent validation set (n=30). Bioinformatic analysis was performed in order to identify biological pathways unique to responders and non-responders.
Results
A signature comprised of 8 proteins and 2 clinical parameters was found to predict outcome for ICI treatment. The validation set displayed an area under the curve (AUC) of the receiver operating characteristics (ROC) curve of 0.79 (p-value = 0.006), and specificity and negative predictive value of 0.81 and 0.77, respectively. Using statistical analysis, differentially expressed proteins and differential clinical parameters between responders and non-responders were identified. Biological pathway enrichment analysis showed that ICI treatment induces pro-tumorigenic biological pathways in non-responders, including immune cell-related processes and cell proliferation. A comparison between ICI mono-therapy and ICI-chemo combination therapy revealed pathways unique to each treatment modality.
Conclusions
Our study demonstrates the potential clinical utility of analyzing proteomic changes in the plasma during ICI therapy, specifically for the discovery of novel predictive biomarkers for response in NSCLC patients.
Clinical trial identification
NCT04056247.
Editorial acknowledgement
Legal entity responsible for the study
OncoHost.
Funding
OncoHost.
Disclosure
Y. Shaked: Financial Interests, Personal, Member of the Board of Directors: OncoHost; Financial Interests, Personal, Stocks/Shares: OncoHost. C. Lahav, M. Harel, E. Jacob, I. Sela, G. Yahalom, Y. Elon, O. Sharon: Financial Interests, Personal, Full or part-time Employment: OncoHost. A. Dicker: Financial Interests, Personal, Stocks/Shares: OncoHost; Financial Interests, Personal, Advisory Role: EMD Serono; Financial Interests, Personal, Advisory Role: Jasson; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Thirdbridge; Financial Interests, Personal, Advisory Role: Accordant; Financial Interests, Personal, Advisory Role: Cybrexa Therapetics; Financial Interests, Personal, Advisory Role: Alcimed; Financial Interests, Personal, Advisory Role: Oranomed; Financial Interests, Personal, Advisory Role: IBA; Financial Interests, Personal, Expert Testimony: Wilson Socini. J. Bar: Financial Interests, Personal, Advisory Role: AbbVie; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Boheringer Ingelheim; Financial Interests, Personal, Advisory Role: Causalis; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Takeda; Non-Financial Interests, Institutional, Other, Local PI: AstraZeneca; Non-Financial Interests, Institutional, Research Grant: ImmuneAI; Non-Financial Interests, Institutional, Other, Local PI: MSD; Non-Financial Interests, Institutional, Invited Speaker, Local investigator: Novartis; Non-Financial Interests, Institutional, Research Grant: OncoHost; Non-Financial Interests, Institutional, Other, Local PI: Roche; Non-Financial Interests, Institutional, Other, Local PI: Takeda. I. Wolf: Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: AstraZeneca. M.T. Moskovits: Financial Interests, Personal, Invited Speaker: AbbVie; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Research Grant: AstraZeneca. A. Zer: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Takeda; Financial Interests, Personal, Stocks/Shares: Nixio; Non-Financial Interests, Institutional, Research Grant: BMS. All other authors have declared no conflicts of interest.