Area of Research: Cancer Angiogenesis and Tumor Microenvironment

VEGF Receptor-2 AntagonistRamucirumab, LY3009806, IMC-1121B

Adams RH and Alitalo K1; Hicklin DJ and Ellis LM2

Primary endpoint: Overall survival

Participants may continue treatment until discontinuation criteria are met.

Cohort 1: Ramucirumab†

Cohort 1: Placebo†

Cohort 2 (ME2): Ramucirumab†

Cohort 2 (ME2): Placebo†

OLE cohort: Ramucirumab†

Primary endpoint: Safety and tolerability of ramucirumab

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.

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TargetAngiogenesis 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

MoleculeRamucirumab (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 DevelopmentRamucirumab is being investigated in clinical trials in patients with gastric cancer, hepatocellular carcinoma, non-small cell lung cancer, or pediatric cancer, and in phase I clinical trials in early development, including combination clinical trials in immuno-oncology.

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.

REACH-2: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Ramucirumab and Best Supportive Care (BSC) Versus Placebo and BSC as Second-line Treatment in Patients With Hepatocellular Carcinoma and Elevated Baseline Alpha-Fetoprotein (AFP) Following First-line Therapy With Sorafenib*

* This clinical trial is being conducted globally. ME2 cohort is being conducted in China only. REACH-2 eligibility criteria, including baseline serum AFP criterion, are based on the efficacy and safety results of REACH.

† Ramucirumab or placebo equivalent is administered 8 mg/kg intravenously on day 1 of a 14-day cycle.

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VEGF Receptor-2 Antagonist | Ramucirumab, LY3009806, IMC-1121B

Key Inclusion Criteria• Hepatocellular carcinoma (HCC)

• Barcelona Clinic Liver Cancer stage C or B that is refractory or not amenable to locoregional therapy

• At least one target lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

• Child-Pugh class A

• Baseline serum AFP ≥400 ng/mL

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Received prior sorafenib as the only systemic therapeutic intervention and experienced radiographically confirmed disease progression during or after discontinuation or discontinued sorafenib because of intolerance (main and maximum extended enrollment [ME2] cohorts only)

• Received only one prior systemic therapy regimen, excluding prior sorafenib for the treatment of HCC (open-label expansion [OLE] cohort only)

• Adequate hematologic and biochemical parameters

Key Exclusion Criteria• Uncontrolled hypertension

• Esophageal or gastric varices requiring treatment

• Ongoing or recent hepatorenal syndrome

• Prior liver transplant

• Major surgery within 28 days

• Arterial thrombotic event within 6 months

• Received prior therapeutic anticoagulation or chronic antiplatelet agents, including nonsteroidal anti-inflammatory drugs

• History of or current hepatic encephalopathy (any grade) or ascites grade ≥2

Please visit www.clinicaltrials.gov for more information on this clinical trial [NCT02435433].

Pipeline information is current through October 23, 2019.

VV-OTHR-US-DEL-0216 10/2019 PRINTED IN USA © Lilly USA, LLC 2019. All rights reserved.

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