Bristol-Myers Squibb is actively conducting translational medicine research to further our understanding of cancer biology and to identify which patient populations may be more likely to derive benefit from Immuno-Oncology (I-O) agents. Biomarkers and Clinical Exploratory Imaging and Bioinformatics and Pharmacodiagnostics and Translational Technologies Integrated Sciences (PDx) Pharmacometrics Research

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Collaboration Biomarkers and Clinical Exploratory Imaging and Bioinformatics and Pharmacodiagnostics Pharmacology and Translational Technologies Integrated Sciences (PDx) Pharmacometrics Research

/ Biomarkers and Pharmacodiagnostics (PDx) Our vision is for tumor biology to inform treatment selection for each patient at each stage of therapy

Collaboration Areas of Focus in Research

Inflamed Tumor Tumor Antigens: Microenvironment: Biomarkers to identify Biomarkers within the tumor, T hypermutation and neo- cells or microenvironment that antigens that may predict may predict response response to I-O Inflamed Tumor Tumor Antigen

Tumor Immune Host Environment: Suppression: Biomarkers to characterize the Biomarkers related to host environment, beyond the mechanisms of resistance via Tumor Immune tumor microenvironment, which specific immune pathways that Suppression may reveal immune-related may be addressed with I-O mechanisms predictive of treatment response

Pharmacodiagnostics (PDx): Diagnostic tests for biomarker expression that may predict patient response prior to treatment Areas of Focus in Biomarker Research

Inflamed Tumor Microenvironment: For example, PD-L1 is expressed in a Biomarkers within the tumor, T variety of healthy cell types and tumor cells. PD-L1 binds to the PD-1 receptor cells or microenvironment that on T cells, inhibiting T cell activation.1-2 may predict response PD-L1 may be expressed only on a portion of the tumor cell and expression levels may change overInflamed time.3 Tumor CLICK TO VIEW VIDEO > Tumor Antigen

Tumor Immune Suppression Areas of Focus in Biomarker Research

Inflamed Tumor Tumor Antigen

Tumor Immune Suppression: Biomarkers related to mechanisms of resistance via Tumor Immune specific immune pathways that Suppression may be addressed with I-O treatment For example, CSF1R is a receptor on the surface of macrophages and other cells of the myeloid lineage.1 High levels of CSF1, the ligand for CSF1R, may indicate that tumors are using CSF1R pathway to drive immunosuppression.2-4 Areas of Focus in Biomarker Research

Tumor Antigens: Biomarkers to identify For example, a growing body hypermutationof and neo- research suggests that assessing the quantity of mutations carriedantigens by that may predict a tumor—the tumor mutation response to I-O burden—may predict the likelihood that a patient could benefit from Inflamed Tumor certain I-O therapies.1-3 Tumor Antigen CLICK TO LEARN MORE >

Tumor Immune Suppression Areas of Focus in Biomarker Research

Inflamed Tumor Tumor Antigen

Host Environment: Biomarkers to characterize the host environment, beyond the Tumor Immune tumor microenvironment, which Suppression may reveal immune-related mechanisms predictive of response

For example, markers in microorganisms (i.e., microbiome) may play a role in developing resistance to I-O treatment1 Pharmacodiagnostics

Inflamed Tumor Tumor Antigen

Tumor Immune Suppression

PD-L1 assays are in vitro diagnostic tests used to detect PD-L1 in certain types of cancer. This test can help determine appropriate treatment. 1 Pharmacodiagnostics (PDx): Diagnostic tests for biomarker expression that may predict patient response prior to treatment Pharmacodiagnostics

Biomarkers and Clinical Exploratory Imaging and Bioinformatics and Pharmacodiagnostics Pharmacology and Translational Technologies Integrated Sciences (PDx) Pharmacometrics Research

Inflamed Tumor Tumor Antigen /

Tumor Immune Suppression

PD-L1 assays are in vitro diagnostic tests used to detect PD-L1 in certain types of cancer. This test can help determine appropriate treatment. 1 Pharmacodiagnostics (PDx) Diagnostic tests for biomarker expression Collaborationthat may predict patient response prior to treatment Biomarkers and Clinical Exploratory Imaging and Bioinformatics and Pharmacodiagnostics Pharmacology and Translational Technologies Integrated Sciences (PDx) Pharmacometrics Research Imaging and Technologies State-of-the-art technology / and complex analytical platforms help us answer basic research questions

Collaboration IMAGING GENOMICS & & SAMPLE FUNCTIONAL BIOLOGY MANAGEMENT

Molecular imaging allows Mapping, characterizing and Method of single-cell System for storing and researchers to study specific quantifying gene expression analysis that allows for cell organizing samples for targets and guide treatment and mutations to allow for a sorting, detection of efficient future use decisions without invasive deeper understanding of biomarkers and a better procedures disease biology and understanding of cell mechanisms of drug biology response Biomarkers and Clinical Exploratory Imaging and Bioinformatics and Pharmacodiagnostics Pharmacology and Translational Technologies Integrated Sciences (PDx) Pharmacometrics Research

IMAGING GENOMICS & FLOW CYTOMETRY & SAMPLE GENETICS / FUNCTIONAL BIOLOGY MANAGEMENT

Molecular imaging allows Mapping, characterizing and Method of single-cell System for storing and researchers to study specific quantifying gene expression analysis that allows for cell organizing samples for targets and guide treatment and mutations to allow for a sorting, detection of disease efficient future use decisions without invasive deeper understanding of biomarkers and a better procedures disease biology and understanding of cell mechanisms of drug biology response

Collaboration Biomarkers and Clinical Exploratory Imaging and Bioinformatics and Pharmacodiagnostics Pharmacology and Translational Technologies Integrated Sciences (PDx) Pharmacometrics Research Bioinformatics and Integrated Sciences Applying cutting-edge methods for/ integrative analysis of large-scale, complex biological data and developing actionable insights to drive development

Collaboration Gene expression network derived from analysis of Loss of CDKN2A is associated with TCGA RNA sequencing data reduced estimates of T cells in the tumor microenvironment in some cancers

Our Translational Bioinformatics team uses cutting-edge methods to perform integrative data analysis. We study the interplay of tumor genomes, their regulation and the tumor microenvironment to further our understanding of response to I-O agents.

Our comprehensive analysis of The Cancer Genome Atlas (TCGA) identified networks of co-expressed genes that can be used to identify specific types of immune cells in the tumor microenvironment. In some tumors, certain genetic mutations correlate with the abundance of such cells. Partnerships with leading data bioinformatics companies enhance our in-house capabilities.

Gene expression network derived from analysis of Loss of CDKN2A is associated with TCGA RNA sequencing data reduced estimates of T cells in the tumor microenvironment in some cancers

Our Translational Bioinformatics team uses cutting-edge methods to perform integrative data analysis. We study the interplay of tumor genomes, their regulation and the tumor microenvironment to further our understanding of response to I-O Our team analyzes tumor mutation agents. burden, RNA sequencing, cytokine, and other large-scale biomarker data sets generated from Our comprehensive analysis of The Cancer Genome Atlas (TCGA) identified clinical trials. networks of co-expressed genes that can be used to identify specific types of immune cells in the tumor microenvironment. In some tumors, certain genetic mutations correlate with the abundance of such cells. The mandate of integrated sciences is to integrate, analyze and synthesize data derived from both external and internal studies addressing fundamental translational questions in I-O to develop actionable insights and hypotheses that help drive discovery and clinical development Biomarkers and Clinical Exploratory Imaging and Bioinformatics and Pharmacodiagnostics Pharmacology and Translational Technologies Integrated Sciences (PDx) Pharmacometrics Research The mandate of integrated sciences is to integrate, analyze and synthesize data derived from both external and internal studies addressing fundamental / translational questions in I-O to develop actionable insights and hypotheses that help drive discovery and clinical development.

Collaboration Biomarkers and Clinical Exploratory Imaging and Bioinformatics and Pharmacodiagnostics Pharmacology and Translational Technologies Integrated Sciences (PDx) Pharmacometrics Research Clinical Pharmacology and Pharmacometrics (CP&P) Our combined CP&P team is fully integrated across all phases of / development to validate MOA of novel targets using mechanistic modeling, predict how assets may work together in combination in humans and identify the optimal safe and effective dose in patients through modeling and simulation

Collaboration Mechanistic Modeling (QSP) Fuels New Questions and Continued Exploration in Immuno-Oncology

Hypothesis Testing Prior Knowledge

Hypothesis Testing

Model Application Model Development

Hypothesis dx 1 = f ()x , x ,..., x Generation dt 1 1 2 n dx 2 = f ()x , x ,..., x dt 2 1 2 n ... dx n = f ()x , x ,..., x dt n 1 2 n Mechanistic Modeling (QSP) Fuels New Questions and Continued Exploration in Immuno-Oncology

Hypothesis Testing Prior Knowledge

Hypothesis The hypotheses Testing Prior knowledge can simulated from the QSP be integrated into a model can be tested in theoretical model of the clinical studies. cancer-immunity cycle.

Model Application Model Development

Hypothesis dx 1 = f ()x , x ,..., x Generation dt 1 1 2 n dx 2 = f ()x , x ,..., x dt 2 1 2 n ... The theoretical model of The QSP model can then be dx the cancer-immunityn = cyclef ()x , x ,..., x used to generate hypotheses dt n 1 2 n through simulation of potential can be converted into a clinical biomarker/tumor mathematical QSP model. responses. Mechanistic Modeling (QSP) Fuels New Questions and Continued Exploration in Immuno-Oncology Biomarkers and Clinical Exploratory Imaging and Bioinformatics and Pharmacodiagnostics Pharmacology and Translational Technologies Integrated Sciences (PDxHypothesis) Testing PharmacometricsPrior KnowledgeResearch

Hypothesis The hypotheses Testing Prior knowledge can simulated from the QSP / be integrated into a model can be tested in theoretical model of the clinical studies. cancer-immunity cycle.

Model Application Model Development

Hypothesis dx 1 = f ()x , x ,..., x Generation dt 1 1 2 n dx 2 = f ()x , x ,..., x dt 2 1 2 n ... The theoretical model of The QSP model can then be dx the cancer-immunityn = cyclef ()x , x ,..., x used to generate hypotheses dt n 1 2 n through simulation of potential can be converted into a clinical biomarker/tumor Collaboration mathematical QSP model. responses. Biomarkers and Clinical Exploratory Imaging and Bioinformatics and Pharmacodiagnostics Pharmacology and Translational Technologies Integrated Sciences (PDx) Exploratory Pharmacometrics Research Translational Research / Experimentation generates internal data to enable scientific discovery

Collaboration Experimentation provides We leverage existing and Insights gained from this the knowledge and data to advanced clinical assays to research can quickly be form hypotheses that can explore and test new implemented in prospective be tested in the clinic hypotheses using biologic clinical trials to enhance and samples accelerate our pipeline Experimentation provides We leverage existing and Insights gained from this the knowledge and data to advanced clinical assays to research can quickly be form hypotheses that can explore and test new implemented in prospective be tested in the clinic hypotheses using biologic clinical trials to enhance and samples accelerate our pipeline

SINGLE CELL GENOMICS: : Leveraging next generation Study of proteins and how technologies to examine sequence they interact within tumor information from individual cells. microenvironment. Conducting Research to Understand the Immune System in Patients with Cancer

TISSUE BLOOD Genetics/genomics experiments to tissue Fresh tissue Whole Blood Comprehensive samples phenotyping

Cell isolation for Functional assays: functional assays PBMC signaling, cytokine induction FFPE

Plasma Plasma analytes IHC/Proteomics

Frozen tissue PAXgene Gene expression: mRNA and miRNA Conducting Research to Understand the Immune System in Patients with Cancer Biomarkers and Clinical Exploratory Imaging and Bioinformatics and Pharmacodiagnostics Pharmacology and Translational Technologies TISSUEIntegrated SciencesBLOOD G(PDxenetics/genomics) Pharmacometrics Research experiments to tissue Fresh tissue Whole Blood Comprehensive samples phenotyping

Cell isolation for Functional assays: functional assays / PBMC signaling, cytokine induction FFPE

Plasma Plasma analytes IHC/Proteomics Mass Spectrometry

Frozen tissue PAXgene Gene expression: mRNA and miRNA Collaboration Biomarkers and Clinical Exploratory Imaging and Bioinformatics and Pharmacodiagnostics Pharmacology and Translational Technologies Integrated Sciences (PDx) Pharmacometrics Research Collaboration

Bristol-Myers Squibb has long believed the future of cancer / research is dependent on investments in science and partnerships. Collaboration is integrated into our organizational framework across translational medicine and R&D

Collaboration Our scientific collaborations with academic centers around the globe expand our research ACADEMIC capabilities and accelerate our COLLABORATION collective ability to advance the science.

We seek to partner with other I-O experts to expand our translational medicine BUSINESS DEVELOPMENT capabilities. A global peer-to-peer collaboration between Bristol-Myers Squibb and academia that aims to advance I-O Our scientific collaborations science and translational medicine to benefit patients. with academic centers around CLICK TO LEARN MORE> the globe expand our research ACADEMIC capabilities and accelerate our COLLABORATION collective ability to advance Research collaborations with select European the science. research institutions to appropriately accelerate, expand and more effectively advance I-O research.

We seek to partner with other Working with partners like Foundation Medicine and GRAIL I-O experts to expand our helps to drive the identification, translational medicine BUSINESS validation and application of DEVELOPMENT capabilities. predictive biomarkers. Our robust translational medicine program informs key areas of research, including:

Disease targeting and responsive patient segmentation

Ideal treatment strategies, including combinations, for each patient

Optimal dosing, schedule and clear understanding of MOA