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.
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.
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 |
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Cyramza | Stomach Neoplasms | Solution for infusion | 10 mg / mL | Intravenous s injection | Eli Lilly Nederland B.V. | December 19, 2014 |
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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 |
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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 |
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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 |
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We provide high-quality Ramucirumab (IgG1κ type) for use in IF, IP, Neut, FuncS, ELISA, FC, ICC and most other immunological methods. For lab research use only, not for diagnostic, therapeutic or any in vivo human use.
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
For research use only. Not intended for any clinical use.
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