Ramucirumab

Ramucirumab
IUPAC name	Ramucirumab
CAS number	947687-13-0
DrugBank	DB09073
ATC prefix	L01
ATC suffix	XC10
UNII	48J5E6B30T
Synonyms	IMC-1121B

Ramucirumab. It is a monoclonal antibody medication designed to inhibit angiogenesis by targeting the vascular endothelial growth factor receptor 2 (VEGFR-2). Developed by Eli Lilly and Company, it is used in the treatment of several advanced carcinomas, including those of the stomach, lung, and colorectum. Its mechanism involves binding to VEGFR-2 to block the activity of vascular endothelial growth factor (VEGF) ligands, thereby starving tumors of their blood supply.

Medical uses

Ramucirumab is approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency for use in specific oncology settings. It is indicated, often in combination with paclitaxel, for advanced gastric cancer or gastroesophageal junction adenocarcinoma after prior chemotherapy with a fluoropyrimidine or platinum agent. In non-small cell lung cancer, it is used with docetaxel following progression on platinum-based chemotherapy. For metastatic colorectal cancer, it is combined with FOLFIRI regimen after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Clinical trials, such as the REGARD trial and RAINBOW trial, established its efficacy in improving overall survival and progression-free survival in these populations.

Adverse effects

Common adverse reactions include hypertension, diarrhea, and headache. More serious risks involve hemorrhage, arterial thromboembolism, and gastrointestinal perforation, which are class effects of VEGF pathway inhibitors. Infusion-related reactions can occur, and like other antiangiogenic agents, it carries warnings for impaired wound healing and reversible posterior leukoencephalopathy syndrome. Monitoring of blood pressure, proteinuria, and thyroid function is recommended during treatment, as outlined in prescribing information from the FDA.

Pharmacology

As a human IgG1 monoclonal antibody, ramucirumab specifically binds to the extracellular domain of VEGFR-2 with high affinity. This binding competitively inhibits the interaction of VEGF-A, VEGF-C, and VEGF-D with the receptor, blocking downstream signal transduction pathways such as those mediated by MAPK/ERK pathway and PI3K/AKT/mTOR pathway. The inhibition suppresses endothelial cell proliferation, migration, and survival, leading to reduced tumor vasculature and oxygenation. Its pharmacokinetics are consistent with other therapeutic antibodies, exhibiting a long elimination half-life allowing for intravenous administration every two to three weeks.

History

The development of ramucirumab originated from research at ImClone Systems, which was later acquired by Eli Lilly and Company. The pivotal REGARD trial, a global phase III clinical trial published in The Lancet, demonstrated survival benefit in advanced gastric cancer, leading to its first FDA approval in 2014. Subsequent approvals were based on trials like RAINBOW, REVEL, and RAISE, which evaluated its use in gastric, lung, and colorectal cancers, respectively. These studies were conducted in collaboration with numerous international institutions, including Dana-Farber Cancer Institute and European Organisation for Research and Treatment of Cancer.

Society and culture

Ramucirumab is marketed under the brand name Cyramza by Eli Lilly and Company. Its development and pricing have been subjects of discussion within health economics and oncology communities, particularly regarding the cost of targeted therapy for advanced cancers. The drug has been included in treatment guidelines by organizations such as the National Comprehensive Cancer Network and the European Society for Medical Oncology. Access to the medication varies globally, influenced by healthcare system differences and drug reimbursement policies in countries like Japan and Australia.

Research

Ongoing clinical investigations are exploring ramucirumab in other malignancies, including hepatocellular carcinoma in combination with durvalumab, and biliary tract cancer. Studies are also evaluating its efficacy in breast cancer and urothelial carcinoma. Research into biomarkers, such as levels of circulating VEGF or VEGFR-2, aims to predict patient response. Furthermore, combination strategies with immunotherapy agents like pembrolizumab and other tyrosine kinase inhibitors are active areas of investigation within the National Cancer Institute clinical trials network.

Category:Monoclonal antibodies Category:Antineoplastic drugs Category:Eli Lilly and Company