CLINICAL DEVELOPMENT PROGRAM

Transcription

1 CLINICAL DEVELOPMENT PROGRAM The safety and efficacy of the agents under investigation have not been established. There is no guarantee that the agents will receive regulatory approval and become commercially available for

2 ADVANCING CANCER CARE THROUGH INNOVATION AREA OF RESEARCH: CANCER ANGIOGENESIS AND TUMOR MICROENVIRONMENT AREA OF RESEARCH: CANCER CELL SIGNALING AREA OF RESEARCH: IMMUNO-ONCOLOGY The safety and efficacy of the agents under investigation have not been established. There is no guarantee that the agents will receive regulatory approval and become commercially available for 2 3

3 For more than 5 decades, Lilly Oncology has been dedicated to delivering innovative solutions that improve the care of people living with cancer. Because no two cancer patients are alike, Lilly Oncology is committed to developing novel treatment approaches. Our quest is to accelerate the pace and progress of cancer care by developing a broad portfolio of therapies, including those tailored to unique patients and those that modulate the immune system. To learn more about Lilly Oncology s commitment to cancer, please visit LillyOncologyPipeline.com. Patient-Tailored Approach Lilly Oncology is committed to the development of patient-tailored therapeutics that integrate disease and target biology with drug characteristics to optimize treatments for individual patients. Key to this approach is Lilly s growing comprehensive catalogue of biomarkers. Our multidisciplinary approach to tailored therapeutics allows for the translation of molecular and cellular discoveries into clinically meaningful outcomes. Drug Discovery Lilly Oncology is devoted to discovering and developing novel therapeutics to improve cancer care. We believe that maximal patient benefit will come through tailored combination therapies that target not just the cancer cells but also the associated tumor microenvironment and host immune system. The safety and efficacy of the agents under investigation have not been established. There is no guarantee that the agents will receive regulatory approval and become commercially available for Lilly s R&D efforts are focused on three key areas: tumor signaling, tumor microenvironment, and the immune system. Our portfolio contains a diverse mix of small molecules, biologics, and antibody-drug conjugates that targets each of these key areas and provides the substrate for rational combinations. 4 5

4 CLINICAL DEVELOPMENT PROGRAM EARLY DEVELOPMENT GASTROINTESTINAL Notch Inhibitor Ang2 Antibody LY NCT * CDK4 and CDK6 Inhibitor Abemaciclib Breast Cancer, Melanoma, or NSCLC Abemaciclib NCT NCT CHK1 Inhibitor Prexasertib Head and Neck Cancer Prexasertib Prexasertib Prexasertib NCT NCT * NCT NCT * LY NCT CSF1R Antibody LY Breast Cancer or Prostate Cancer LY LY CDK4 and CDK6 Inhibitor NCT NCT * NCT LY LY LY PD-L1 Antibody NCT * LY PACT PDGFRα Antibody NCT Olaratumab Pediatric Cancer PI3K/mTOR Dual Inhibitor NCT NCT TGFβR1 Kinase Inhibitor TGFβR1 Kinase Inhibitor II NCT LY CXCR4 Peptide Antagonist LY Pancreatic Cancer NCT ERK1/2 Inhibitor LY NCT * LY NCT MET Antibody Emibetuzumab TIM-3 Antibody NCT * Type II Multikinase Inhibitor NCT * NCT VEGF Receptor-2 Antagonist NCT NCT NCT * NCT NCT LUNG Galunisertib Hepatocellular Carcinoma Galunisertib Hepatocellular Carcinoma NCT * NCT Galunisertib Hepatocellular Carcinoma Galunisertib Pancreatic Cancer NCT NCT Type II Multikinase Inhibitor NCT * VEGF Receptor-2 Antagonist Ramucirumab Gastric Cancer RAINFALL Ramucirumab Gastric Cancer Ramucirumab Hepatocellular Carcinoma REACH-2 Ramucirumab Gastric Cancer Ramucirumab Gastric Cancer Ramucirumab Gastric Cancer CDK4 and CDK6 Inhibitor Abemaciclib NSCLC JUNIPER Abemaciclib Squamous NSCLC Abemaciclib NSCLC Abemaciclib NSCLC NCT NCT NCT NCT NCT NCT NCT NCT NCT * NCT CHK1 Inhibitor Prexasertib SCLC NCT EGFR Antibody Necitumumab Squamous NSCLC Necitumumab Squamous NSCLC Necitumumab NSCLC Necitumumab NSCLC NCT NCT NCT * NCT MET Antibody Emibetuzumab NSCLC BALISE GENITOURINARY LY Prostate Cancer NCT PI3K/mTOR Dual Inhibitor LY Squamous NSCLC PI3K/mTOR Dual Inhibitor Ramucirumab Biliary Tract Cancer, Gastric Cancer, NSCLC, or TCC Ramucirumab Gastric Cancer, HCC, or NSCLC Ramucirumab Metastatic Colorectal Cancer Ramucirumab Pediatric Cancer LY T-ALL or T-LBL NCT TGFβR1 Kinase Inhibitor NCT NCT * VEGF Receptor-2 Antagonist Ramucirumab NSCLC RELAY Ramucirumab NSCLC VEGF Receptor-2 Antagonist Ramucirumab Bladder Cancer RANGE NCT NCT * NCT SARCOMA BREAST GYNECOLOGIC CDK4 and CDK6 Inhibitor Abemaciclib Breast Cancer MONARCH 2 Abemaciclib Breast Cancer MONARCH 3 Abemaciclib Breast Cancer Abemaciclib Breast Cancer monarche Abemaciclib Breast Cancer neomonarch Abemaciclib Breast Cancer monarcher Abemaciclib Breast Cancer nextmonarch 1 Abemaciclib Breast Cancer Abemaciclib Breast Cancer NCT * NCT * LY Merestinib Merestinib FGFR-3 Antibody-Drug Conjugate NCT Notch Inhibitor PDGFRα Antibody Merestinib Biliary Tract Cancer Galunisertib Hepatocellular Carcinoma or NSCLC NCT NCT NCT Abemaciclib Pancreatic Cancer Olaratumab Pancreatic Cancer LY LY CHK1 Inhibitor III HEMATOLOGIC NCT NCT NCT NCT NCT NCT NCT NCT * NCT PHASE PHASE PHASE III II I PDGFRα Antibody p38 MAP Kinase Inhibitor Ralimetinib Ovarian Cancer NCT Olaratumab Sarcoma ANNOUNCE Olaratumab Sarcoma Olaratumab Sarcoma ANNOUNCE-2 Olaratumab Sarcoma Olaratumab Sarcoma NCT NCT NCT NCT NCT * This clinical trial is being conducted in combination with one or more additional investigational molecules in the Lilly Oncology Pipeline. LY is owned by a 3rd party, Lilly retains rights. 6 7

5 Molecules in Clinical Development: Cancer Angiogenesis and Tumor Microenvironment Ang2 Antibody (LY ) CANCER ANGIOGENESIS AND TUMOR MICROENVIRONMENT Unlike normal tissue, cancer tissues maintain an active angiogenic process, which is a key hallmark of the neoplastic phenotype.1 This neoplastic microenvironment is an important component of both tumor growth and metastasis. Activated stroma and the dysregulated tumor microenvironment can directly support tumor cell growth, as well as allow cancers to evade detection and destruction by the host immune system. Lilly Oncology is utilizing a number of approaches to identify and develop new antiangiogenic agents as well as novel combinations of antiangiogenic agents. Our antiangiogenesis research efforts also include the study of biomarkers that may be used to identify patient subpopulations. In addition, Lilly Oncology has focused research efforts on approaches to target the peritumoral microenvironment. Angiogenesis, the growth of new blood vessels, plays a pivotal role in tumor growth, propagation, and metastasis. Angiopoietin2 (Ang2) promotes tumor angiogenesis and growth by destabilizing the Tie2-expressing vasculature, enhancing the endothelial cells response to angiogenic stimuli such as vascular endothelial growth factor (VEGF), and inducing Tie2-independent integrin-mediated sprouting tip cell migration.2,3 LY is a humanized and engineered IgG4 isotype antibody designed to bind to Ang2 with high affinity and neutralize Ang2-induced phospho-tie2.4 LY is being investigated in a phase I clinical trial. PDGFRα Antibody (Olaratumab, LY , IMC-3G3) Platelet-derived growth factor receptor α (PDGFRα) is expressed in multiple tumor types, and its aberrant activation has been implicated in cancer. Coexpression of PDGFRα and PDGFs, consistent with autocrine-mediated growth, has been reported in sarcomas and glioblastomas.5 Gene amplification and activating mutations of PDGFRα have been found in subsets of glioblastomas, non-small cell lung cancers, and gastrointestinal stromal tumors.5,6 PDGFRα expression has been associated with increased metastatic potential in preclinical models.7,8 Paracrine stimulation of PDGFRα-positive stromal cells has been shown in preclinical studies to enhance tumor growth by providing factors for angiogenesis and extracellular matrix remodeling.9,10 Olaratumab (LY , IMC-3G3) is a human IgG1 monoclonal antibody designed to bind to human PDGFRα with high affinity and block PDGF-AA, PDGF-BB, and PDGF-CC ligands from binding to the receptor.11,12 Olaratumab is being investigated in clinical trials in patients with pancreatic cancer or sarcoma, and in a phase I pediatric clinical trial. 8 9

6 Molecules in Clinical Development: Cancer Angiogenesis and Tumor Microenvironment Molecules in Clinical Development: Cancer Angiogenesis and Tumor Microenvironment TGFβR1 Kinase Inhibitor (Galunisertib, LY H 2 O) The transforming growth factor β (TGFβ) signaling pathway is complex and results in tumor suppressor or tumor-promoting activity depending on the cellular context in which the pathway is active. As many cancers progress to more aggressive disease states, the tumor suppressor arm of TGFβ signaling is lost and, instead, tumor cells proliferate. In contrast, TGFβ overexpression in advanced disease enhances tumor growth, suppresses the immune system, and exacerbates invasive and metastatic tumor cell behavior. 13 TGFβ worsens immunosuppression by inhibiting cytotoxic cells such as CD8+ CTLs and NK cells and enhancing suppressive immune cells called T regulatory cells and myeloid-derived suppressor cells. 14 Galunisertib (LY monohydrate) is a small molecule that has been shown in vitro to block TGFβ signaling Galunisertib is being investigated in clinical trials in patients with hepatocellular carcinoma and in phase I clinical trials in immuno-oncology. VEGF Receptor-2 Antagonist (Ramucirumab, LY , IMC-1121B) Angiogenesis is a tightly regulated, multiple-step process, which results in the formation of new blood vessels from preexisting vasculature and is an important component in the development and progression of malignant disease. Signaling by vascular endothelial growth factor (VEGF) receptor-2 in endothelial cells plays a role in inducing normal and pathologic angiogenesis and is activated by binding of ligands VEGF-A, VEGF-C, and VEGF-D Ramucirumab (LY , IMC-1121B) is a human IgG1 monoclonal antibody receptor antagonist designed to bind and block activation of VEGF receptor-2 by blocking the binding of VEGF receptor ligands VEGF-A, VEGF-C, and VEGF-D. 23,24 Ramucirumab is being investigated in clinical trials in patients with bladder cancer, gastric cancer, hepatocellular carcinoma, non-small cell lung cancer, or pediatric cancer, and in phase I clinical trials, including combination clinical trials in immuno-oncology. TGFβR1 Kinase Inhibitor II (LY ) The transforming growth factor β (TGFβ) signaling pathway is complex and results in tumor suppressor or tumor-promoting activity depending on the cellular context in which the pathway is active. As many cancers progress to more aggressive disease states, the tumor suppressor arm of TGFβ signaling is lost and, instead, tumor cells proliferate. In contrast, TGFβ overexpression in advanced disease enhances tumor growth, suppresses the immune system, and exacerbates invasive and metastatic tumor cell behavior. 13 TGFβ worsens immunosuppression by inhibiting cytotoxic cells such as CD8+ CTLs and NK cells and enhancing suppressive immune cells called T regulatory cells and myeloid-derived suppressor cells. 14 LY is a small molecule that has been shown in vitro to block TGFβ signaling. 19 LY is being investigated in a phase I clinical trial

7 Molecules in Clinical Development: Cancer Cell Signaling CDK4 and CDK6 Inhibitor (Abemaciclib, LY ) CANCER CELL SIGNALING Cancer is a complex and heterogeneous disease composed of hundreds of tumor subtypes, each with a unique genetic profile. Deep sequencing and molecular analysis have revealed many of the underlying drivers of cancer and provide information on the patterns and processes that allow tumors to evolve traits that promote their own growth and survival.1 At Lilly Oncology, our cancer signaling efforts are focused on oncogenic targets, including growth factor receptors, oncogenic RAS signaling, developmental pathway signaling, and deregulated cell cycle genes. Emerging programs also target metabolic (glycolysis, folate pathway, and amino acid metabolism) and epigenetic (methylation and chromatin remodeling) pathways. Many human tumors acquire alterations, which can lead to the activation of cyclin-dependent kinases (CDKs) CDK4 and CDK6. These alterations include mutations that directly activate CDK4 and CDK6, gene amplifications, which increase expression of various protein activators such as cyclin D, as well as genetic losses, which reduce expression of protein inhibitors such as p16. These various mechanisms as well as loss of retinoblastoma (Rb) can lead to an enhanced proliferative potential by decreasing dependency on external growth factors and mitogenic signaling pathways, which are required to stimulate growth under normal conditions.25,26 Abemaciclib (LY ) has been shown in vitro to be a selective ATP-competitive inhibitor of CDK4 and CDK6 kinase activity that prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation.27,28 Abemaciclib is being investigated in clinical trials in patients with breast cancer, non-small cell lung cancer, or pancreatic cancer, including a combination clinical trial in immuno-oncology, and in a phase I clinical trial. CHK1 Inhibitor (Prexasertib, LY ) Checkpoint kinase 1 (CHK1) is a global regulator of the mammalian cell cycle. In addition to regulating DNA damage checkpoints, CHK1 plays a central role in normal DNA replication, resolving replication stress, progression to mitosis, and cytokinesis. Inhibition of CHK1 in the absence of DNA damage can cause impaired DNA replication, loss of DNA damage checkpoints, premature entry into mitosis with highly fragmented DNA, and cell death via replication catastrophe.29 Prexasertib (LY ) is a small molecule that in vitro preferentially binds to and inhibits CHK1 and, to a lesser extent, inhibits CHK2, thus inducing DNA double-strand breaks, a loss in checkpoint function, increased replication stress, and cell death.29 Prexasertib is being investigated in clinical trials in patients with head and neck cancer or small cell lung cancer, and in phase I clinical trials

8 Molecules in Clinical Development: Cancer Cell Signaling Molecules in Clinical Development: Cancer Cell Signaling CHK1 Inhibitor III (LY ) Checkpoint kinase 1 (CHK1) is a global regulator of the mammalian cell cycle. In addition to regulating DNA damage checkpoints, CHK1 plays a central role in normal DNA replication, resolving replication stress, progression to mitosis, and cytokinesis. Inhibition of CHK1 in the absence of DNA damage can cause impaired DNA replication, loss of DNA damage checkpoints, premature entry into mitosis with highly fragmented DNA, and cell death via replication catastrophe. 29 LY * is a small molecule that in vitro binds to and inhibits CHK1. 30 LY * is being developed externally and investigated in a phase I clinical trial. * LY is owned by a 3rd party, Lilly retains rights. EGFR Antibody (Necitumumab, LY , IMC-11F8) Epidermal growth factor receptor (EGFR) is a member of the ErbB (erythroblastic leukemia viral oncogene homolog) family of receptor tyrosine kinases. Canonical EGFR activation involves the binding of seven peptide growth factors: EGF, transforming growth factor-α (TGFα), heparin-binding EGF-like growth factor (HBEGF), amphiregulin (AREG), betacellulin (BTC), epiregulin (EREG), and epigen (EPGN). 31 EGFR activation occurs in response to ligand stimulation and/or genetic alterations of the EGFR gene, such as somatic mutations, amplifications, or deletions. Activated EGFR induces downstream signaling through the MAPK (mitogen-activated protein kinases), PI3K/ AKT (phosphoinositide 3-kinase/v-Akt murine thymoma viral oncogene), and PLCγ (phospholipase Cγ) signal transduction pathways that mediate cell proliferation, cell survival, and cell migration, respectively, thereby contributing to neoplastic transformation and tumor growth. 32,33 Necitumumab (LY , IMC-11F8) is a recombinant IgG1 human monoclonal antibody designed to bind and block the ligand binding site of EGFR Necitumumab is being investigated in clinical trials in patients with non-small cell lung cancer, including a combination clinical trial in immuno-oncology. ERK1/2 Inhibitor (LY ) The mitogen-activated protein kinase (MAPK) pathway is a key regulator of cellular proliferation and survival. Abnormalities of the MAPK pathway are common in many cancers, including cutaneous melanoma, uveal melanoma, colorectal cancer, non-small cell lung cancer, pancreatic ductal adenocarcinoma, and many others. 37 Extracellular signal-regulated kinases (ERK1/2), also known as MAPK3 (ERK1) and MAPK1 (ERK2), are serine threonine kinases that serve as critical downstream targets in the MAPK signaling pathway. 38 They play a central role in transmitting extracellular signals from activated receptor tyrosine kinases. ERK1/2 signaling phosphorylates the p90 ribosomal S6 kinase (RSK) and regulates several additional downstream cytoplasmic and nuclear targets involved in cell cycle, cell proliferation, cell growth, and cell survival. 37 LY is a small molecule that has been shown in vitro to be a selective inhibitor of ERK1/2. 39 LY is being investigated in a phase I clinical trial. FGFR Inhibitor (LY ) The fibroblast growth factor receptor (FGFR) family consists of four members FGFR-1, FGFR-2, FGFR-3, and FGFR-4 which mediate cellular signaling after binding to their high-affinity ligands, the FGFs. The FGF/FGFR signaling pathway has been shown to mediate cell proliferation, migration, motility, and survival. Autophosphorylation of FGFR is required for activation of FGF-induced downstream signaling. The aberrant regulation of this pathway has been implicated in many forms of human malignancies. 40 It has also been determined that activation of the FGF/FGFR pathway may lead to increased tumor angiogenesis and play a role in tumor resistance to antiangiogenic agents and other chemotherapies. 40,41 LY is a small molecule that has been shown in vitro to inhibit autophosphorylation of FGFR-1, FGFR-2, FGFR-3, and FGFR-4. 42,

9 Molecules in Clinical Development: Cancer Cell Signaling Molecules in Clinical Development: Cancer Cell Signaling FGFR-3 Antibody-Drug Conjugate (LY ) The fibroblast growth factor receptor (FGFR) family consists of four members FGFR-1, FGFR-2, FGFR-3, and FGFR-4 which mediate cellular signaling after binding to their high-affinity ligands, the FGFs. The FGF/FGFR signaling pathway has been shown to mediate cell proliferation, migration, motility, and survival. Autophosphorylation of FGFR is required for activation of FGF-induced downstream signaling. The aberrant regulation of this pathway has been implicated in many forms of human malignancies. 40 It has also been determined that activation of the FGF/FGFR pathway may lead to increased tumor angiogenesis and play a role in tumor resistance to antiangiogenic agents and other chemotherapies. 40,41 LY is an antibody-drug conjugate (ADC) comprised of anti-fgfr-3 antibody conjugated to a microtubule inhibitor, DM4. 44 LY is being investigated in a phase I clinical trial. MET Antibody (Emibetuzumab, LY ) MET, the hepatocyte growth factor (HGF) receptor, is a tyrosine kinase receptor. In tumor cells, MET signaling is activated either by binding HGF, its only known ligand, or, in the case of overexpression or amplification of MET, by ligand-independent activation/dimerization. 45 Both ligand-dependent and ligand-independent MET activation trigger downstream signaling pathways known to be involved in tumor cell proliferation, protection from apoptosis, and metastasis. In addition, pathway activation is believed to act as a resistance mechanism to other cancer therapies. 46,47 Dysregulation of the MET pathway is an important feature of many human malignancies, including lung, breast, and colorectal. Emibetuzumab (LY ) is a bivalent, monoclonal MET antibody with no functional agonistic activity designed to block both ligand-dependent and ligand-independent MET signaling by its dual mode of action. 48 Notch Inhibitor (LY ) The Notch receptor, on the surfaces of progenitor cells and cancer cells, binds neighboring cell-surface ligands DLL or JAGGED. 49 On ligand binding, the intramembrane protease γ-secretase cleaves the Notch intracellular domain (NICD). NICD translocates to the nucleus, where it regulates the transcription of Notch pathway genes, 49 which, in normal mammalian cells, are essential for development and tissue homeostasis. 49,50 Dysregulation of Notch signaling due to mutation or amplification, or overexpression of ligands and/or receptors, is implicated in a number of malignancies. 49,51 LY is a small molecule that has been shown in vitro to inhibit Notch signaling. It prevents release of NICD by inhibiting proteolytic activity of γ-secretase complex and thereby decreasing Notch signaling and its downstream biologic effects. 51 LY is being investigated in a clinical trial in patients with T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma, and in phase I clinical trials. p38 MAP Kinase Inhibitor (Ralimetinib, LY Dimesylate) p38 mitogen-activated protein (MAP) kinase is activated in response to inflammatory stimuli (eg, tumor necrosis factor, interleukin-6), growth factors (eg, vascular endothelial growth factor, fibroblast growth factor, insulin-like growth factor), and cellular stress (eg, chemotherapeutic challenge). These conditions are prevalent in the initiation and progression of tumor growth and during the development of metastases. In addition to promoting cancer cell survival and growth, p38 also enhances invasion and metastasis Ralimetinib (LY dimesylate) is a small molecule that in vitro preferentially binds to and inhibits p38 MAP kinase. 55,56 Ralimetinib is being investigated in a clinical trial in patients with ovarian cancer. Emibetuzumab is being investigated in a combination therapy trial in patients with non-small cell lung cancer and in a multi-cohort phase I combination therapy trial

10 Molecules in Clinical Development: Cancer Cell Signaling PI3K/mTOR Dual Inhibitor (LY ) The PI3K/mTOR (phosphoinositide 3-kinase/mammalian target of rapamycin) pathway is stimulated by a variety of growth factors and their receptors and regulates cell metabolism, cell growth, cell survival, cell proliferation, cell motility, and angiogenesis. The PI3K/AKT/mTOR pathway is thought to be one of the most frequently mutated pathways in cancer,57,58 leading to cancer progression and resistance to existing treatments.58,59 LY is a selective inhibitor of class I PI3K isoforms, mtor, and DNA-PK. Inhibition of PI3K/mTOR signaling by LY causes G1 cell-cycle arrest and results in broad antiproliferative activity in cancer cell panel screens. In vivo, LY demonstrates high bioavailability with dose-dependent target engagement and exhibits potent in vivo antitumor efficacy via intermittent target inhibition.57,60 LY is being investigated in clinical trials in patients with non-small cell lung cancer or prostate cancer, including a combination therapy trial, and in phase I clinical trials, including a multi-cohort combination therapy trial. Type II Multikinase Inhibitor (Merestinib, LY ) Targets of merestinib, such as MET (the hepatocyte growth factor [HGF] receptor), RON (MST1R), AXL, MERTK, MKNK1/2, and Tie2/TEK, are oncokinases. In tumor cells, MET signaling is activated either by binding HGF, its only known ligand, or, in the case of overexpression or amplification of MET, by ligand-independent activation/dimerization.45 Both ligand-dependent and ligand-independent MET activation trigger downstream signaling pathways known to be involved in tumor cell proliferation, protection from apoptosis, and metastasis. In addition, pathway activation is believed to act as a resistance mechanism to other cancer therapies.46,47 Several of the targets of merestinib, such as RON/MST1R, AXL, MERTK, MKNK1/2, and Tie2/TEK, also play a role in immune cell functions, especially myeloid cell functions These targets of merestinib are in the tumor microenvironment and provided some of the rationale behind preclinical in vivo studies showing a strong synergy of merestinib with PD-L1 blockade in syngeneic mouse cancer models.66 Merestinib (LY ) is a small molecule kinase inhibitor that has been shown in vitro to be a reversible type II ATP-competitive inhibitor of MET. Preclinical testing also has shown merestinib to inhibit several other receptor tyrosine oncokinases, including MST1R, FLT3, AXL, MERTK, TEK, ROS1, NTRK1/2/3, and DDR1/2, and the serine/ threonine kinases MKNK1/2.67,68 Merestinib is being investigated in a clinical trial in patients with biliary tract cancer and in phase I clinical trials

11 Molecules in Clinical Development: Immuno-Oncology CSF1R Antibody (LY , IMC-CS4) IMMUNO-ONCOLOGY Lilly Oncology has a broad and integrated strategy to modulate the immune system and effectively target cancer. This strategy involves leveraging the company s robust existing portfolio of molecules that target and modulate the immune-suppressive environment that surrounds tumors, deep expertise in antibody technology and chemistry to develop molecules that modulate T-cell function, and novel approaches to redirect activated T cells to tumors. Several internal clinical programs are in place to systematically target inhibitory and pro-tumorigenic pathways in the tumor and immune microenvironment, including pathways such as those driven by the engagement of receptors for TGFβ, CSF1, CXCL12, EGF, and VEGF signaling; in the clinical space, the company has also established external collaborations to evaluate the potential of combining AXL, CDK4 and CDK6, CSF1R, CXCR4, DDR1, DDR2, EGFR, FLT3, MERTK, MET, MKNK1, MKNK2, NTRK1, NTRK2, NTRK3, PDGFRα, RON, ROS1, TGFβR1, Tie2, TIM-3, VEGFR2, or folate pathway inhibition with checkpoint agents. Preclinical research programs are focused on the targeting of checkpoint inhibitor and agonist receptors, both as conventional antibodies and as bispecific antibodies that recognize two targets, with additional programs focused on identifying novel receptors and ligands that modulate T-cell activity. Finally, Lilly has entered into programmatic preclinical collaboration with Immunocore Ltd. and BioNTech AG to develop potent T-cell redirection strategies. Colony-stimulating factor 1 receptor (CSF1R), also known as macrophage colony-stimulating factor receptor (M-CSFR), is a cell-surface receptor for its ligands, colony-stimulating factor 1 (CSF1) and IL-34.69,70 CSF1R plays an important role as regulator of the development, morphology, survival, and functions of tissue macrophages as well as tumor-associated macrophages (TAMs). CSF1 is involved in the recruitment and survival of macrophages in tumors. Increased CSF1 expression is implicated in tumor progression and metastasis, and is associated with poor prognosis in some cancers.71 LY (IMC-CS4) is a human IgG1 monoclonal antibody designed to target the CSF1R, preventing ligands CSF1 and IL-3470 from binding to the receptor and inhibiting TAMs from receiving CSF1 signals, decreasing their survival and relieving the effect of TAMs in the tumor.72 LY (IMC-CS4) is being investigated in phase I clinical trials, including a collaboration clinical trial with another immuno-oncology agent. CXCR4 Peptide Antagonist (LY ) CXC chemokine receptor type 4 (CXCR4) is a G protein-coupled chemokine receptor for stromal-derived factor 1 (SDF-1) that is functionally expressed or overexpressed in a number of different cancer types and within the tumor microenvironment.73,74 CXCR4 plays an important role in tumor growth, invasion, survival, angiogenesis, and metastasis.75 It was recently demonstrated that CXCR4 and SDF-1 interactions play a role in T-cell infiltration and redistribution within the tumors.76 LY is a peptide antagonist that has been shown in vitro to bind to the chemokine receptor CXCR4 and to block the binding of the SDF-1 ligand, thereby inhibiting subsequent receptor activation LY is being investigated in a phase I collaboration clinical trial with another immuno-oncology agent

12 Molecules in Clinical Development: Immuno-Oncology Molecules in Clinical Development: Immuno-Oncology PD-L1 Antibody (LY ) One mechanism by which tumor cells evade the immune system involves the upregulation of surface proteins that deliver inhibitory signals to cytotoxic T cells. Programmed cell death ligand 1 (PD-L1) is one such protein. PD-L1 is the predominant ligand for PD-1 and is expressed broadly in multiple tissues including T and B cells, dendritic cells, and macrophages, and is frequently upregulated in a broad range of cancers. 80 Tumor cell expression of PD-L1 is associated with reduced survival and an unfavorable prognosis in several cancer types LY is a monoclonal antibody designed to target PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, preventing its binding to PD-1 and CD80 (B7-1) receptors on the T cells. By blocking PD-L1, LY may facilitate the reactivation of tumor-reacting T cells, restoring their ability to induce an antitumor immune response. 90 LY is being investigated in a phase I clinical trial. TGFβR1 Kinase Inhibitor (Galunisertib, LY H 2 O) The transforming growth factor β (TGFβ) signaling pathway is complex and results in tumor suppressor or tumor-promoting activity depending on the cellular context in which the pathway is active. As many cancers progress to more aggressive disease states, the tumor suppressor arm of TGFβ signaling is lost and, instead, tumor cells proliferate. In contrast, TGFβ overexpression in advanced disease enhances tumor growth, suppresses the immune system, and exacerbates invasive and metastatic tumor cell behavior. 13 TGFβ worsens immunosuppression by inhibiting cytotoxic cells such as CD8+ CTLs and NK cells and enhancing suppressive immune cells called T regulatory cells and myeloid-derived suppressor cells. 14 Galunisertib (LY monohydrate) is a small molecule that has been shown in vitro to block TGFβ signaling Galunisertib is being investigated in clinical trials in patients with hepatocellular carcinoma and in phase I clinical trials in immuno-oncology. TGFβR1 Kinase Inhibitor II (LY ) The transforming growth factor β (TGFβ) signaling pathway is complex and results in tumor suppressor or tumor-promoting activity depending on the cellular context in which the pathway is active. As many cancers progress to more aggressive disease states, the tumor suppressor arm of TGFβ signaling is lost and, instead, tumor cells proliferate. In contrast, TGFβ overexpression in advanced disease enhances tumor growth, suppresses the immune system, and exacerbates invasive and metastatic tumor cell behavior. 13 TGFβ worsens immunosuppression by inhibiting cytotoxic cells such as CD8+ CTLs and NK cells and enhancing suppressive immune cells called T regulatory cells and myeloid-derived suppressor cells. 14 LY is a small molecule that has been shown in vitro to block TGFβ signaling. 19 LY is being investigated in a phase I clinical trial. TIM-3 Antibody (LY ) TIM-3, a co-inhibitory molecule, marks the most exhausted or dysfunctional populations of T cells in the tumor microenvironment and during chronic viral infection, and is often coexpressed with PD-1 and CTLA-4 on tumor-antigen-specific T cells in cancer patients Inhibiting TIM-3 provides the opportunity to enhance antitumor T-cell immunity. 94,95 The opportunity to combine it with a clinically validated checkpoint inhibitor such as PD-1 or PD-L1 antibodies is also being actively investigated for treatment of many other types of cancers as monotherapy and in combination therapies. 92 LY is a human monoclonal antibody (IgG1, Kappa, Fc-null) that specifically binds to and targets the inhibitory immune-receptor TIM-3 expressed on immune cells, blocks the interaction of TIM-3 with the ligands PtdSer, and partially blocks gal-9. By blocking the engagement of TIM-3 with its physiologic ligands, LY may block the triggering of inhibitory signals, rescue exhausted T cells within the tumor microenvironment, and facilitate the reactivation of tumor-reacting T cells, restoring their ability to effectively detect and kill tumor cells. LY has been engineered to lack Fc-related immune-effector function by selective mutagenesis of residues within the CH2 region of its IgG1 Fc region. LY is being investigated in a phase I combination clinical trial with another immuno-oncology agent

13 Molecules in Clinical Development: Immuno-Oncology Type II Multikinase Inhibitor (Merestinib, LY ) Targets of merestinib, such as MET (the hepatocyte growth factor [HGF] receptor), RON (MST1R), AXL, MERTK, MKNK1/2, and Tie2/TEK, are oncokinases. In tumor cells, MET signaling is activated either by binding HGF, its only known ligand, or, in the case of overexpression or amplification of MET, by ligand-independent activation/dimerization.45 Both ligand-dependent and ligand-independent MET activation trigger downstream signaling pathways known to be involved in tumor cell proliferation, protection from apoptosis, and metastasis. In addition, pathway activation is believed to act as a resistance mechanism to other cancer therapies.46,47 Several of the targets of merestinib, such as RON/MST1R, AXL, MERTK, MKNK1/2, and Tie2/TEK, also play a role in immune cell functions, especially myeloid cell functions These targets of merestinib are in the tumor microenvironment and provided some of the rationale behind preclinical in vivo studies showing a strong synergy of merestinib with PD-L1 blockade in syngeneic mouse cancer models.66 Merestinib (LY ) is a small molecule kinase inhibitor that has been shown in vitro to be a reversible type II ATP-competitive inhibitor of MET. Preclinical testing also has shown merestinib to inhibit several other receptor tyrosine oncokinases, including MST1R, FLT3, AXL, MERTK, TEK, ROS1, NTRK1/2/3, and DDR1/2, and the serine/ threonine kinases MKNK1/2.67,68 Merestinib is being investigated in a clinical trial in patients with biliary tract cancer and in phase I clinical trials

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15 All of the scientific images used in this booklet were captured by Lilly research scientists. To learn more about Lilly Oncology s commitment to cancer research, please visit LillyOncologyPipeline.com. ON /2017 PRINTED IN USA Lilly USA, LLC All rights reserved. Pipeline data through July 25, All breast cancer trial data are current through October 25, 2017.