Ramucirumab Overview

Introduction of Ramucirumab

Ramucirumab (LY3009806, IMC-1121B, trade name Cyramza), a fully human monoclonal antibody (mAb) selectively targeted against vascular endothelial growth factor (VEGF) receptor 2 (VEGFR-2), has received Food and Drug Administration (FDA) approval for several malignancies. Ramucirumab was developed by ImClone Systems Inc. (now a part of Eli Lilly and Company) and was isolated from a native phage display library from Dyax. It is indicated for treatment of (1) advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma as a single agent or in combination with paclitaxel after fluoropyrimidine-containing or platinum-containing chemotherapy, (2) metastatic colorectal cancer in combination with irinotecan, fluorouracil, and leucovorin (FOLFIRI) after disease progression on or after previous therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine, and (3) metastatic non-small-cell lung cancer (NSCLC) in combination with docetaxel after disease progression with or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase mutations should have also experienced treatment failure with an FDA-approved targeted therapy before treatment with ramucirumab for NSCLC. Due to its mechanism of action, ramucirumab has the potential for activity in many malignancies and is being evaluated in clinical trials for additional indications.

Mechanism of Action of Ramucirumab

Angiogenesis, which means the formation of new blood vessels, is an important mechanism for the transport of essential nutrients, oxygenated blood, growth factors, hormones, and proteolytic enzymes to the cells. Angiogenesis affects the hemostasis by controlling the coagulation pathway and is also involved metastases of tumor cells. VEGF and VEGF-receptors (VEGFRs) play a vital role in both physiological and pathological angiogenesis. Multiple signaling pathways were triggered by the activation of VEGF/VEGFR axis that results in survival, proliferation, and migration of endothelial cells. Furthermore, VEGF is also associated with vessel permeability, causing malignant effusions. However, VEGF over-expression has been associated with worsening progression of the tumors and prognosis in several kinds of solid carcinomas. The mechanism of angiogenesis involves various VEGF ligands like VEGF-A to-E, placental growth factor and VEGFRs like VEGFR-1, -2, and -3, which are present on the surface of endothelial cells. VEGF-A is the main ligand, which is associated with neo-angiogenesis, lymphangiogenesis, and tumor permeability. VEGFR-1 and VEGFR-2 are the tyrosine kinase receptors for the ligand VEGF-A. VEGFR-2 involved in neo-angiogenesis, endothelial intracellular signaling, and lymphangiogenesis is associated with stronger signal transmission and is responsible for most of the actions of VEGF-A. VEGFR-2 is also frequently over-expressed in tumor vasculature than normal vasculature and is responsible for tumor spread. Inhibition of tumor growth and spread is noticed by blocking the VEGFR-2 signaling pathway by antibodies directed against either VEGF-A or VEGFR-2 and VEGFR-2 tyrosine kinase inhibitors. Various anti-VEGF antibodies are used in clinical practice, only few drugs have been evaluated which directly and specifically inhibits VEGFR-2. Ramucirumab has strong affinity to the extracellular domain of VEGFR-2 and thus binds there. Unlike all other angiogenic inhibitors, the anti-angiogenic activity of this fully human monoclonal antibody is because of its exclusive binding to human VEGFR-2, which is the main receptor involved in angiogenesis. Inhibition of this receptor activation impedes VEGF-A mediated neo-angiogenesis, which ultimately results in reduced tumor vascularity and growth.

Mechanism of Action of Ramucirumab Fig.1 Mechanism of Action of Ramucirumab

Table 1. Clinical Projects of Ramucirumab*

NCT ID Status Conditions Lead Sponsor Update Time
NCT03904108 Not yet recruiting Carcinoma, Non-Small-Cell Lung ROGER S MD KERESZTES April 4, 2019
NCT03760822 Recruiting Stomach Cancer, Stomach Neoplasm, Gastric Cancer, Gastroesophageal Junction Adenocarcinoma Federation Francophone de Cancerologie Digestive November 30, 2018
NCT03502746 Recruiting Mesothelioma, Malignant Arkadiusz Z. Dudek, MD April 19, 2018
NCT03650764 Not yet recruiting Head and Neck Squamous Cell Carcinoma Washington University School of Medicine August 29, 2018
NCT02443883 Active, not recruiting Gastric Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma Eli Lilly and Company May 14, 2015
NCT03745430 Recruiting Pancreatic Adenocarcinoma Hellenic Cooperative Oncology Group November 19, 2018
NCT02520141 Recruiting Biliary Cancer M.D. Anderson Cancer Center August 11, 2015
NCT02564198 Recruiting Pediatric Solid Tumor, Refractory Tumor, Recurrent Tumor, CNS Malignancies Eli Lilly and Company September 30, 2015
NCT03909334 Not yet recruiting Non Small Cell Lung Cancer, EGFR Gene Mutation, Advanced Cancer, Metastatic Cancer Xiuning Le April 10, 2019
NCT03560973 Active, not recruiting Mesothelioma Gruppo Oncologico Italiano di Ricerca Clinica June 19, 2018
NCT02730247 Active, not recruiting Non-small Cell Lung Cancer Liza Villaruz, MD April 6, 2016
NCT03762564 Recruiting Squamous Cell Carcinoma of the Esophagus IKF Klinische Krebsforschung GmbH at Krankenhaus Nordwest December 3, 2018
NCT03689855 Not yet recruiting Non Small Cell Lung Cancer, NSCLC Washington University School of Medicine October 1, 2018
NCT02970539 Recruiting Gastric Cancer, Esophageal Cancer, Gastro-esophageal Cancer Kinex Pharmaceuticals Inc November 22, 2016
NCT02317991 Recruiting Gastroesophageal Cancer SCRI Development Innovations, LLC December 17, 2014
NCT02795858 Recruiting Carcinoid Tumors Dana-Farber Cancer Institute June 10, 2016
NCT02581215 Recruiting Pancreatic Cancer Walid Shaib, MD October 20, 2015
NCT03141034 Recruiting Gastric Adenocarcinoma, Gastro-esophageal Junction Adenocarcinoma Washington University School of Medicine May 4, 2017
NCT03520946 Recruiting Colorectal Cancer IKF Klinische Krebsforschung GmbH at Krankenhaus Nordwest May 10, 2018
NCT03686488 Recruiting Gastric Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma, Gastric Cancer H. Lee Moffitt Cancer Center and Research Institute September 27, 2018
NCT03863587 Not yet recruiting Gastric Adenocarcinoma Shanghai Henlius Biotech March 5, 2019
NCT01515306 Active, not recruiting Malignant Solid Tumor Eli Lilly and Company January 24, 2012
NCT02572687 Active, not recruiting Gastric Cancer, Gastroesophageal Junction Adenocarcinoma, Non-Small Cell Lung Cancer, Hepatocellular Carcinoma Eli Lilly and Company October 9, 2015
NCT02435433 Recruiting Hepatocellular Carcinoma Eli Lilly and Company May 6, 2015
NCT03008278 Recruiting Gastroesophageal Junction Adenocarcinoma, Recurrent Gastric Carcinoma, Stage IV Gastric Cancer AJCC v7 National Cancer Institute (NCI) January 2, 2017
NCT03193918 Recruiting Esophagogastric Adenocarcinoma Arog Pharmaceuticals, Inc. June 21, 2017
NCT03739801 Not yet recruiting Locally Advanced Unresectable Gastric Adenocarcinoma, Metastatic Gastroesophageal Junction Adenocarcinoma, Metastatic Unresectable Gastric Adenocarcinoma, Unresectable Gastroesophageal Junction Adenocarcinoma, Gastric Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma University of Southern California November 14, 2018
NCT02999295 Recruiting Gastric Cancer, Gastroesophageal Junction Region (GEJ) Cancer National Cancer Center, Japan December 21, 2016
NCT02426125 Active, not recruiting Urothelial Carcinoma Eli Lilly and Company April 24, 2015
NCT03081143 Active, not recruiting Advanced Gastric or EGJ Cancer IKF Klinische Krebsforschung GmbH at Krankenhaus Nordwest March 16, 2017
NCT02539225 Active, not recruiting Metastatic Gastric Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma Eli Lilly and Company September 2, 2015
NCT02597036 Active, not recruiting Solid Tumors Eli Lilly and Company November 4, 2015
NCT02314117 Active, not recruiting Metastatic Gastric Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma Eli Lilly and Company December 10, 2014
NCT03694002 Recruiting Locally Advanced Thymic Carcinoma, Metastatic Thymic Carcinoma, Recurrent Thymic Carcinoma, Unresectable Thymic Carcinoma Southwest Oncology Group October 3, 2018
NCT02789345 Active, not recruiting Non-small Cell Lung Cancer Eli Lilly and Company June 3, 2016
NCT02443324 Active, not recruiting Gastric Adenocarcinoma, Adenocarcinoma of the Gastroesophageal Junction, Non-small Cell Lung Cancer, Carcinoma, Transitional Cell, Biliary Tract Cancer Eli Lilly and Company May 13, 2015
NCT02898077 Recruiting Gastroesophageal Junction Adenocarcinoma, Gastric Adenocarcinoma Eli Lilly and Company September 13, 2016
NCT02661971 Recruiting Stomach Cancer, Gastroesophageal Junction Cancer IKF Klinische Krebsforschung GmbH at Krankenhaus Nordwest January 25, 2016
NCT02711553 Active, not recruiting Biliary Tract Cancer, Metastatic Cancer, Advanced Cancer Eli Lilly and Company March 17, 2016
NCT02411448 Active, not recruiting Metastatic Non-Small Cell Lung Cancer Eli Lilly and Company April 8, 2015
NCT03527108 Not yet recruiting Non Small Cell Lung Cancer Fox Chase Cancer Center May 16, 2018
NCT03766607 Not yet recruiting Gastric Cancer Korean South West Oncology Group December 6, 2018
NCT02934464 Recruiting Stomach Neoplasms Fondazione IRCCS Istituto Nazionale dei Tumori, Milano October 17, 2016
NCT01079780 Active, not recruiting Colorectal Cancer Pam Cogliano March 3, 2010
NCT00703326 Active, not recruiting Breast Cancer Eli Lilly and Company June 23, 2008
NCT01246986 Active, not recruiting Carcinoma, Hepatocellular Eli Lilly and Company November 24, 2010
NCT03395847 Recruiting Diseases of Oesophagus Stomach and Duodenum, Advanced Gastroesophageal Adenocarcinoma M.D. Anderson Cancer Center January 10, 2018
NCT02079636 Active, not recruiting Carcinoma, Non-small Cell Lung Eli Lilly and Company March 6, 2014
NCT02213289 Recruiting Adenocarcinoma University of Chicago August 11, 2014
NCT03872947 Recruiting Solid Tumor, Colon Cancer, Cholangiocarcinoma, Bladder Cancer, Ovarian Cancer, Gastric Cancer, Palpable Subcutaneous Malignant Lesions Toray Industries, Inc March 13, 2019
NCT03704077 Not yet recruiting Gastric Cancer, Cancer of the Stomach, Stomach Cancer, Gastroesophageal Junction Bristol-Myers Squibb October 12, 2018
NCT02791334 Recruiting Solid Tumor, Microsatellite Instability-High (MSI-H) Solid Tumors, Cutaneous Melanoma, Pancreatic Cancer, Breast Cancer (HR+HER2-) Eli Lilly and Company June 6, 2016
NCT03798626 Not yet recruiting Colorectal Cancer, Gastroesophageal Cancer, Renal Cell Carcinoma Novartis Pharmaceuticals January 10, 2019
NCT03743428 Recruiting Colorectal Neoplasms Shenzhen People's Hospital November 16, 2018
NCT03281369 Recruiting Gastric Adenocarcinoma or Gastroesophageal Junction Adenocarcinoma Hoffmann-La Roche September 13, 2017
NCT03271255 Recruiting Colorectal Neoplasms, Intestinal Neoplasms, Gastrointestinal Neoplasms, Digestive System Neoplasms Shenzhen People's Hospital September 5, 2017
NCT03694977 Recruiting Gastric Cancer Seoul National University Hospital October 3, 2018
NCT03251612 Recruiting Colorectal Cancer Metastatic Vejle Hospital August 16, 2017
NCT02645149 Not yet recruiting Melanoma Melanoma Institute Australia January 1, 2016
NCT03652467 Recruiting Hepatocellular Carcinoma Non-resectable Jinan Military General Hospital August 29, 2018

Table 2. Approved Drugs of Ramucirumab**

INN (trade name) Therapeutic area Dose Strength Route Company Marketing start Market
Cyramza Advanced Gastric or Gastro-Esophageal Junction Adenocarcinoma, non-small cell lung cancer, metastatic colorectal cancer Solution for infusion 10 mg / mL Intravenous s injection ELI LILLY AND CO April 21, 2014 Overview
Cyramza Stomach Neoplasms Solution for infusion 10 mg / mL Intravenous s injection Eli Lilly Nederland B.V. December 19, 2014 Golimumab Overview
Cyramza Advanced Gastric or Gastro-Esophageal Junction Adenocarcinoma, non-small cell lung cancer, metastatic colorectal cancer Solution for infusion 10 mg / mL Intravenous s injection Eli Lilly Canada Inc September 10, 2015 Golimumab Overview
Cyramza Advanced Gastric or Gastro-Esophageal Junction Adenocarcinoma, non-small cell lung cancer, metastatic colorectal cancer Solution for infusion 10 mg / mL Intravenous s injection Eli Lilly Australia Pty Ltd Pty Ltd July 23, 2015 Golimumab Overview
Cyramza Advanced Gastric or Gastro-Esophageal Junction Adenocarcinoma, non-small cell lung cancer, metastatic colorectal cancer Solution for infusion 10 mg / mL Intravenous s injection Eli Lilly Japan K.K. June 20, 2016 Overview

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References
* The table was excerpted from the following website
https://clinicaltrials.gov/ct2/results?cond=&term=Ramucirumab
** Information presented in the table were collected from the following website:
http://search.tga.gov.au/s/search.html?collection=tga-artg&profile=record&meta_i=82744
https://www.ema.europa.eu/en/medicines/human/EPAR/cyramza
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125477
https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=92855
http://search.tga.gov.au/s/search.html?collection=tga-artg&profile=record&meta_i=227352
http://www.pmda.go.jp/PmdaSearch/iyakuDetail/GeneralList/4291429

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