Clinical Development Program for More Than 50 Years

Clinical Development Program For more than 50 years,

Lilly has been dedicated to delivering life-changing medicines Lilly Oncology is committed to the development of patient-tailored therapeutics that integrate disease and target biology with drug characteristics in order to optimize treatments for and support to people living with cancer and those who care for individual patients. Our multidisciplinary approach allows for the translation of molecular them. Lilly is determined to build on this heritage and continue and cellular discoveries into clinically meaningful outcomes. Key to this approach is Lilly’s extensive and growing catalog of biomarkers. making life better for all those affected by cancer around the world.

Lilly Oncology is dedicated to developing and delivering innovative new medicines that will make a meaningful difference to cancer patients. Building on our work in cancer treatment, we are developing new medicines as fast as possible to help people living with cancer fight their disease. For us this means putting an intense focus on the latest scientific advances and collaborating with doctors, other researchers, advocates, and payers to ensure our medicines bring value to people living with cancer.

To learn more about Lilly’s commitment to people with cancer, please visit LillyLoxoOncologyPipeline.com.

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 the uses being investigated.

2 3 Clinical Development Pipeline MOLECULES IN CLINICAL DEVELOPMENT

PHASE 3 PHASE 2 PHASE 1

BTK Inhibitor BTK Inhibitor Aurora A Kinase Inhibitor Selective ER Degrader PIRTOBRUTINIB PIRTOBRUTINIB LY3295668 LY3484356

BRUIN CLL-321, NCT04666038 BRUIN, NCT03740529 NCT04106219 EMBER-2, NCT04647487 CLL/SLL CLL/SLL or NHL Neuroblastoma Breast Cancer BRUIN MCL-321, NCT04662255 EMBER, NCT04188548* MCL Breast Cancer or Endometrial Cancer CDK4 & 6 Inhibitor CDK4 & 6 Inhibitor ABEMACICLIB ABEMACICLIB CDK4 & 6 Inhibitor VEGF Receptor-2 Antagonist ABEMACICLIB monarcHER, NCT02675231 NCT02057133* RAMUCIRUMAB Breast Cancer Breast Cancer

MONARCH 2, NCT02107703 Next MONARCH 1, NCT02747004 NCT04238819 NCT02789345* Breast Cancer Breast Cancer Pediatric Cancer NSCLC MONARCH 3, NCT02246621 NCT03703466 Breast Cancer Breast Cancer IDH1 Inhibitor MONARCH plus, NCT02763566 CYCLONE 2, NCT03706365 LY3410738 Breast Cancer Prostate Cancer

monarchE, NCT03155997 CYCLONE 1, NCT04408924 NCT04603001 Breast Cancer Prostate Cancer Advanced Hematologic Malignancies eMonarcHER, NCT04752332 NCT04521686 Breast Cancer PDGFRα Antibody Advanced Solid Tumors OLARATUMAB PD-1 Inhibitor CANCER TYPE SINTILIMAB NCT03086369 KRAS G12C Inhibitor Pancreatic Cancer LY3537982 Advanced Solid Tumors ORIENT-11, NCT03607539 NSCLC NCT04956640* RET Inhibitor NSCLC, CRC, or Other Advanced Breast Solid Tumors SELPERCATINIB RET Inhibitor Gastrointestinal SELPERCATINIB LIBRETTO-001, NCT03157128 PDGFRα Antibody NSCLC, MTC, PTC, or Genitourinary LIBRETTO-531, NCT04211337 Other Advanced Solid Tumors OLARATUMAB MTC LIBRETTO-121, NCT03899792 NCT03126591 Gynecologic LIBRETTO-431, NCT04194944 Pediatric Cancer Sarcoma NSCLC Hematologic LIBRETTO-432, NCT04819100 NSCLC VEGF Receptor-2 Antagonist RAMUCIRUMAB Lung

CAMPFIRE, NCT04145349 * This clinical trial is being conducted with one or more VEGF Receptor-2 Antagonist Neurologic Pediatric Cancer additional investigational molecules in the pipeline. RAMUCIRUMAB CAMPFIRE, NCT04145700 Pediatric Cancer The safety and efficacy of the agents under Sarcoma REACH-2, NCT02435433 investigation have not been established. Hepatocellular Carcinoma There is no guarantee that the agents Thyroid RELAY, NCT02411448 will receive regulatory approval and NSCLC become commercially available for the uses being investigated.

4 5 CDK4 & 6 Inhibitor | ABEMACICLIB, LY2835219 Many human tumors acquire alterations, which can lead to the activation of cyclin-dependent kinases (CDKs). These alterations include mutations that directly activate CDK4 & 6, gene amplifications, which increase expression of various protein activators such as D-type cyclins, as well as genetic losses, which reduce expression MOLECULES IN CLINICAL DEVELOPMENT 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.1,2 Abemaciclib (LY2835219) has been shown in vitro to be a selective ATP-competitive inhibitor of CDK4 & 6 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.3,4

ABEMACICLIB is being investigated in clinical trials in patients with breast cancer, pediatric cancer, or prostate cancer.

PD-1 Inhibitor | SINTILIMAB, LY3342901 The interaction of programmed cell death protein 1 (PD-1) transmembrane protein receptor, which is found in lymphocytes and monocytes, with its natural ligands programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2), is one of the major pathways exploited by cancer cells for immune evasion.5-7 The PD-1/ ligand interactions strongly counteract T-cell antigen receptor (TCR) signal transduction and subsequently attenuate cytokine production, T-cell survival, and proliferation.8 Sintilimab (LY3342901) is a recombinant, fully human anti–PD-1 monoclonal antibody that has been shown in preclinical studies to bind to PD-1 and block interactions between PD-1 and PD-L1/PD-L2 to restore antitumor immunity.9 Sintilimab enhances T-cell function, including antitumor responses, through blockade of PD-1 binding to PD-L1 and PD-L2, which are expressed in antigen presenting cells.9,10

SINTILIMAB is being investigated in a clinical trial in patients with non-small cell lung cancer.

6 7 MOLECULES IN CLINICAL DEVELOPMENT

PDGFRα Antibody | OLARATUMAB, LY3012207, IMC-3G3 Selective ER Degrader | LY3484356 Platelet-derived growth factor receptor α (PDGFRα) is expressed in multiple tumor types, and its aberrant Estrogen signaling plays an important role in organ development and growth. In certain cancers, abnormal activation has been implicated in cancer. Coexpression of PDGFRα and PDGFs, consistent with autocrine- estrogen signaling via the estrogen receptor is a key component of tumor growth.32 Disruption of estrogen mediated growth, has been reported in sarcomas and glioblastomas.11 Gene amplification and activating mutations signaling by selective estrogen receptor degraders (SERDs) is one of the treatment options for patients with of PDGFRα have been found in subsets of glioblastomas, non-small cell lung cancers, and gastrointestinal estrogen-receptor-positive (ER+) cancers. stromal tumors.11,12 PDGFRα expression has been associated with increased metastatic potential in preclinical LY3484356 is an orally available SERD that has demonstrated the inhibition of estrogen signaling and subsequent models.13,14 Paracrine stimulation of PDGFRα-positive lung stromal cells has been shown in preclinical studies to inhibition of cell proliferation in ER-expressing tumor models. potentially support new lesion development in the lung.15-17 Olaratumab (LY3012207, IMC-3G3) is a human IgG1 monoclonal antibody that has been shown in vitro to bind to human PDGFRα with high affinity and block PDGF-AA, PDGF-BB, and PDGF-CC ligands from binding to the LY3484356 is being investigated in clinical trials in patients with breast cancer or endometrial cancer. receptor.18,19

OLARATUMAB is being investigated in clinical trials in patients with pancreatic cancer or sarcoma.

VEGF Receptor-2 Antagonist | RAMUCIRUMAB, LY3009806, 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 RET Inhibitor | SELPERCATINIB, LOXO-292, LY3527723 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 Rearranged during transfection (RET) fusions have been identified in approximately 2% of non-small cell lung VEGF-D.33-35 cancer,20,21 10% to 20% of papillary thyroid cancer,22,23 and a subset of colon and other cancers.24-26 RET point Ramucirumab (LY3009806, IMC-1121B) is a human IgG1 monoclonal antibody receptor antagonist that has been mutations account for approximately 60% of medullary thyroid cancer.27-29 Cancers that harbor activating RET shown in vitro to bind to and block the activation of VEGF receptor-2 by blocking the binding of VEGF receptor fusions or RET mutations depend primarily on this single constitutively activated kinase for their proliferation and ligands VEGF-A, VEGF-C, and VEGF-D.36,37 survival. This dependency renders such tumors highly susceptible to small-molecule inhibitors targeting RET. Selpercatinib (LOXO-292, LY3527723) is a highly selective, potent, CNS-active small-molecule inhibitor of RET. Selpercatinib possesses nanomolar potency against diverse RET alterations, including RET fusions, activating RET RAMUCIRUMAB is being investigated in clinical trials in patients with hepatocellular carcinoma, point mutations, and acquired resistance mutations. Selpercatinib has been shown in vitro and in vivo to exhibit non-small cell lung cancer, or pediatric sarcoma. high selectivity for RET, with limited activity against other tyrosine kinases.30,31

SELPERCATINIB is being investigated in clinical trials in patients with medullary thyroid cancer, non-small cell lung cancer, papillary thyroid carcinoma, pediatric cancer, or other advanced solid tumors.

8 9 MOLECULES IN CLINICAL DEVELOPMENT

Aurora A Kinase Inhibitor | LY3295668 Loxo Oncology at Lilly was created in December 2019, combining the Lilly Aurora kinases are believed to play a crucial role in cellular division by controlling chromosomal segregation. Research Laboratories oncology organization and Loxo Oncology, which was Defects in segregation can cause genetic instability, a condition highly associated with the formation of tumors. Aurora kinases—Aurora A, Aurora B, and Aurora C—are key mitotic regulators required for genome stability and acquired by Lilly in early 2019. Loxo Oncology at Lilly brings together the focus are frequently overexpressed in cancerous tumors. and spirit of a biotech with the scale and resources of large pharma, with LY3295668 has been shown in vitro and in vivo to be a highly selective Aurora A kinase inhibitor that targets 38 the goal of rapidly delivering impactful new medicines for people with cancer. cell-cycle dependency of sensitive tumors. Our approach centers on creating new oncology medicines that work early LY3295668 is being investigated in a clinical trial in patients with neuroblastoma. in clinical development and will matter to patients.

10 11 MOLECULES IN CLINICAL DEVELOPMENT

BTK Inhibitor | PIRTOBRUTINIB, LOXO-305 KRAS G12C Inhibitor | LY3537982 Bruton tyrosine kinase (BTK) inhibitors represent a major therapeutic advance in the treatment of patients with KRAS is the most common oncogene across all tumor types. KRAS G12C represents a KRAS mutation chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and B-cell malignancies by inducing durable in patients with non-small cell lung cancer (12% to 15%) and colorectal cancer (3%), and also occurs in responses.39-44 BTK is critical for the propagation of B-cell receptor signaling and is upregulated in many B-cell patients with other solid tumors such as pancreatic cancer and endometrial cancer (1% to 2%).53,54 malignancies as compared with normal B cells. BTK inhibition, both in vitro and in vivo, decreases proliferation LY3537982 is a selective covalent inhibitor of KRAS G12C; it demonstrates activity as monotherapy and in and survival signals.39 combination with other anticancer therapies in preclinical models. It has competitive pharmacokinetic Pirtobrutinib (LOXO-305) is an investigational, oral, highly selective, noncovalent BTK inhibitor. It possesses properties supporting its advancement into clinical testing. LY3537982 has been shown in vitro to target nanomolar potency independent of BTK C481 status in enzyme and cell-based assays. Pirtobrutinib has been the KRAS G12C mutation, thereby inhibiting mutant KRAS-dependent signaling. shown in preclinical studies to reversibly bind BTK, deliver consistently high target coverage regardless of BTK turnover rate, preserve activity in the presence of the C481 acquired resistance mutations, and avoid LY3537982 is being studied in a clinical trial in patients with non-small cell lung cancer, colorectal off-target kinases.45 cancer, or other advanced solid tumors.

PIRTOBRUTINIB is being investigated in clinical trials in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, or non-Hodgkin’s lymphoma.

IDH1 Inhibitor | LY3410738 The enzyme isocitrate dehydrogenase (IDH1) is mutated in a variety of cancers, including acute myeloid leukemia (AML), cholangiocarcinoma, chondrosarcoma, and glioma.46-49 These mutations are typically somatic gain-of- function mutations located in arginine 132 (R132) that grant IDH1 the ability to produce 2-hydroxyglutarate (2-HG).50 2-HG is an oncometabolite that promotes tumor development by inhibiting enzymes that maintain normal DNA and histone methylation, leading to hypermethylation associated with transcriptional dysregulation.50,51 As a result, IDH1-mutated cells become blocked in a progenitor-like state and contribute to tumor development both directly through cellular self-renewal and indirectly through cooperation with other oncogenic drivers.51 LY3410738 is a potent, selective, and covalent inhibitor of mutant IDH1 that has been shown in vitro and in vivo to rapidly inactivate mutant IDH1 and inhibit 2-HG production without impacting wild-type IDH1.52

LY3410738 is being investigated in clinical trials in patients with advanced hematologic malignancies or advanced solid tumors.

12 13 References

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14 15 To learn more about Lilly’s commitment to cancer research, please visit LillyLoxoOncologyPipeline.com.