Ramucirumab LY3009806 IMC-1121B

VEGF RECEPTOR-2 ANTAGONIST Ramucirumab, LY3009806, IMC-1121B | VEGF RECEPTOR-2 ANTAGONIST

Target 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.1-3

Molecule Ramucirumab (LY3009806, IMC-1121B) is a human IgG1 monoclonal antibody receptor antagonist that has been shown in vitro to bind to and block the activation of VEGF receptor-2 by blocking the binding of VEGF receptor ligands VEGF-A, VEGF-C, and VEGF-D.4,5

Clinical Development Ramucirumab is being investigated in clinical trials in patients with hepatocellular carcinoma, non-small cell lung cancer, or pediatric sarcoma.

References: 1. Adams RH, Alitalo K. Nat Rev Mol Cell Biol. 2007;8(6):464-478. 2. Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23(5):1011-1027. 3. Olsson AK, et al. Nat Rev Mol Cell Biol. 2006;7(5):359-371. 4. Lu D, et al. J Biol Chem. 2003;278(44):43496-43507. 5. Zhu Z, et al. Leukemia. 2003;17(3):604-611.

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 Adams RH and Alitalo K1; Hicklin DJ and Ellis LM2 3 Ramucirumab, LY3009806, IMC-1121B | VEGF RECEPTOR-2 ANTAGONIST

REACH-2 Key Inclusion Criteria Key Exclusion Criteria

A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Ramucirumab and Best Supportive Care (BSC) Versus Placebo and • Hepatocellular carcinoma (HCC) • Uncontrolled hypertension BSC as Second-line Treatment in Patients With Hepatocellular Carcinoma and Elevated Baseline Alpha-Fetoprotein (AFP) Following • Barcelona Clinic Liver Cancer stage C or B that is refractory or not • Esophageal or gastric varices requiring treatment First-line Therapy With Sorafenib* amenable to locoregional therapy • Ongoing or recent hepatorenal syndrome • At least one target lesion as defined by Response Evaluation Criteria in • Liver transplant (main and ME2 cohorts only; participants with prior Solid Tumors (RECIST) version 1.1 liver transplant may be eligible for OLE cohort) • Child-Pugh class A • Major surgery within 28 days Cohort 1: Cohort 1: Cohort 2 (ME2): Cohort 2 (ME2): • Baseline serum AFP ≥400 ng/mL • Arterial thrombotic event within 6 months Ramucirumab† Placebo† Ramucirumab† Placebo† • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 • Received prior therapeutic anticoagulation or chronic antiplatelet • Received prior sorafenib as the only systemic therapeutic intervention and agents, including nonsteroidal anti-inflammatory drugs experienced radiographically confirmed disease progression during or • History of or current hepatic encephalopathy (any grade) or ascites after discontinuation or discontinued sorafenib because of intolerance grade ≥2 Primary endpoint: (main and maximum extended enrollment [ME2] cohorts only) Overall survival • Received ≤2 prior systemic therapy regimens, excluding prior sorafenib or chemotherapy for the treatment of HCC (open-label expansion [OLE] cohort only) • Adequate hematologic and biochemical parameters OLE cohort: Ramucirumab†

Primary endpoint: The safety and efficacy Safety and tolerability of ramucirumab of the agents under Participants may continue treatment until discontinuation criteria are met. investigation have not been established. There is no guarantee that the agents will receive regulatory approval and * This clinical trial is being conducted globally. ME2 cohort is being conducted in China only. REACH-2 eligibility criteria, including become commercially available baseline serum AFP criterion, are based on the efficacy and safety results of REACH. for the uses being investigated. † Ramucirumab or placebo equivalent is administered 8 mg/kg intravenously on day 1 of a 14-day cycle.

4 Please visit www.clinicaltrials.gov for more information on this clinical trial [NCT02435433]. 5 Ramucirumab, LY3009806, IMC-1121B | VEGF RECEPTOR-2 ANTAGONIST

CAMPFIRE Key Inclusion Criteria Key Exclusion Criteria

A Randomized, Open-Label Phase 1/2 Study Evaluating Ramucirumab in Pediatric Patients and Young Adults With Relapsed, Recurrent, • If in the US, aged 12 months to 29 years. If • Eligible for surgical resection at time of • History of hypertensive crisis or hypertensive or Refractory Desmoplastic Small Round Cell Tumor* in the EU, aged 36 months to 29 years and enrollment encephalopathy within 6 months of study >11 kg at study entry • Active infections requiring therapy, including enrollment • Relapsed, recurrent, or refractory HIV or hepatitis A, B, or C • Known hypersensitivity to ramucirumab, desmoplastic small round cell tumors • Prior allogeneic bone marrow or solid organ cyclophosphamide, vinorelbine, or any of the • Measurable disease as defined by Response transplant excipients of the medicinal product Ramucirumab† + cyclophosphamide‡ Evaluation Criteria in Solid Tumors (RECIST) • Major surgical, laparoscopic, or significant • Severe liver cirrhosis (Child-Pugh class B or ‡ § + vinorelbine§ Cyclophosphamide + vinorelbine version 1.1 traumatic injury within 28 days prior to worse), cirrhosis with a history of hepatic • Received at least one prior line of systemic enrollment. Surgical or other wounds must encephalopathy, clinically meaningful ascites treatment (including neoadjuvant/adjuvant be adequately healed prior to enrollment resulting from cirrhosis and requiring ongoing chemotherapy), including approved therapies treatment with diuretics and/or paracentesis, • Evidence of active bleeding, a bleeding or history of hepatorenal syndrome for which the patient is eligible diathesis or vasculitis, or a history of significant Primary endpoint: • Discontinued all previous treatments for (grade ≥3) bleeding event, hemoptysis or • Bowel obstruction, history or presence of Progression-free survival cancer or investigational agents ≥7 days prior pulmonary hemorrhage, a DVT or PE requiring inflammatory enteropathy or extensive to study entry and recovered from select medical intervention, or esophageal varices intestinal resection, Crohn’s disease, acute effects to grade ≤2 for alopecia and within 3 months prior to enrollment ulcerative colitis, or chronic diarrhea decreased tendon reflex, and to grade ≤1 for • History of central nervous system arterial/ • Urinary outflow obstruction, grade 2 || all other effects at the time of enrollment venous thromboembolic events, including hematuria, or noninfectious cystitis at the • Adequate hematologic and organ function transient ischemic attack or cerebrovascular time of screening for at least 7 days prior to first dose of accident within 6 months prior to study • Severe and/or uncontrolled concurrent study drug|| enrollment, myocardial infarction or unstable medical disease or psychiatric illness/social • Female participants of childbearing angina within the prior 6 months, New York situation that, in the opinion of the potential must have a negative urine or Heart Association (NYHA) grade ≥2 investigator, could cause unacceptable safety The safety and efficacy serum pregnancy test within 7 days prior congestive heart failure, serious and risks or compromise protocol compliance inadequately controlled cardiac arrhythmia, of the agents under to randomization. Male and female • Prior treatment with/progression on participants must agree to use highly significant vascular disease, or clinically combination cyclophosphamide and investigation have not been effective contraception for the duration of significant peripheral vascular disease vinorelbine regimen; prior treatment established. There is no the study and up to 3 months following the • History of fistula, gastrointestinal ulcer or with ramucirumab guarantee that the agents will last dose of ramucirumab and vinorelbine, perforation, or intra-abdominal abscess * This clinical trial is being conducted globally. and 12 months following the last dose of within 3 months of study enrollment receive regulatory approval and † Ramucirumab is administered intravenously (IV). cyclophosphamide ‡ Cyclophosphamide is administered PO. become commercially available § Vinorelbine is administered IV. for the uses being investigated. || Additional criteria apply.

6 Please visit www.clinicaltrials.gov for more information on this clinical trial [NCT04145349]. 7 Ramucirumab, LY3009806, IMC-1121B | VEGF RECEPTOR-2 ANTAGONIST

CAMPFIRE Key Inclusion Criteria Key Exclusion Criteria

A Randomized, Open-Label Phase 1/2 Study Evaluating Ramucirumab in Pediatric Patients and Young Adults With Relapsed, Recurrent, • If in the US, aged 12 months to 29 years. If • Eligible for surgical resection at time of • Nonhealing wound, unhealed or incompletely or Refractory Synovial Sarcoma* in the EU, aged 36 months to 29 years and enrollment healed fracture, or a compound bone fracture >11 kg at study entry • Active infections requiring therapy, including at the time of enrollment • Relapsed, recurrent, or refractory synovial HIV or hepatitis A, B, or C • Known hypersensitivity to ramucirumab, sarcoma • Prior allogeneic bone marrow or solid organ gemcitabine, docetaxel, or agents formulated • Measurable disease as defined by Response transplant with polysorbate 80 Evaluation Criteria in Solid Tumors (RECIST) • Major surgical, laparoscopic, or significant • Severe liver cirrhosis (Child-Pugh class B or † ‡ § ‡ § Ramucirumab + gemcitabine + docetaxel Gemcitabine + docetaxel version 1.1 traumatic injury within 28 days prior to worse), cirrhosis with a history of hepatic • Received at least one prior line of systemic enrollment. Surgical or other wounds must be encephalopathy, clinically meaningful ascites treatment (including neoadjuvant/adjuvant adequately healed prior to enrollment resulting from cirrhosis and requiring ongoing chemotherapy) that contains ifosfamide and/ treatment with diuretics and/or paracentesis, • Evidence of active bleeding, a bleeding or history of hepatorenal syndrome or doxorubicin, or any approved therapies for diathesis or vasculitis, or a history of significant Primary endpoint: which they are eligible (grade ≥3) bleeding event, hemoptysis or • Bowel obstruction, history or presence of Progression-free survival • Discontinued all previous treatments for pulmonary hemorrhage, a DVT or PE requiring inflammatory enteropathy or extensive cancer or investigational agents ≥7 days medical intervention, or esophageal varices intestinal resection, Crohn’s disease, prior to study entry and recovered from the within 3 months prior to enrollment ulcerative colitis, or chronic diarrhea acute effects to grade ≤2 for alopecia and • History of central nervous system arterial/ • Severe and/or uncontrolled concurrent decreased tendon reflex and to grade ≤1 for venous thromboembolic events, including medical disease or psychiatric illness/social || all other effects at the time of enrollment transient ischemic attack or cerebrovascular situation that, in the opinion of the • Adequate hematologic and organ function for accident within 6 months prior to study investigator, could cause unacceptable safety at least 7 days prior to first dose of study drug|| enrollment, myocardial infarction or unstable risks or compromise protocol compliance • Female participants of childbearing potential angina within the prior 6 months, New York • Prior treatment with/progression on must have a negative urine or serum Heart Association (NYHA) grade ≥2 congestive combination gemcitabine and docetaxel The safety and efficacy pregnancy test within 7 days prior to heart failure, serious and inadequately controlled cardiac arrhythmia, significant of the agents under randomization. Male and female participants must agree to use highly effective vascular disease, or clinically significant investigation have not been contraception for the duration of the study peripheral vascular disease established. There is no and up to 3 months following the last dose of • History of fistula, gastrointestinal ulcer or guarantee that the agents will ramucirumab and 6 months following the perforation, or intra-abdominal abscess within * This clinical trial is being conducted globally. last dose of docetaxel and gemcitabine 3 months of study enrollment receive regulatory approval and † Ramucirumab is administered intravenously (IV). ‡ Gemcitabine is administered IV. • History of hypertensive crisis or hypertensive become commercially available § Docetaxel is administered IV. encephalopathy within 6 months of study for the uses being investigated. || Additional criteria apply. enrollment

8 Please visit www.clinicaltrials.gov for more information on this clinical trial [NCT04145700]. 9 Ramucirumab, LY3009806, IMC-1121B | VEGF RECEPTOR-2 ANTAGONIST

10 11 Active Trials Currently Not Enrolling

[NCT02411448] Lung Cancer [NCT02789345] Lung Cancer RELAY: A Study of Ramucirumab (LY3009806) in A Study of Ramucirumab (LY3009806) or Combination With Erlotinib in Participants With Necitumumab (LY3012211) Plus Osimertinib EGFR Mutation-Positive Metastatic NSCLC in Participants With Lung Cancer