Ramucirumab

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Definition
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Ramucirumab is a human IgG1 monoclonal antibody that recognizes and binds to VEGF receptor 2. Vascular endothelial growth factor receptor 2, or VEGF R2 for short, is a tyrosine kinase, a key mediator initiated and maintained by VEGF-induced blood vessel growth. VEGF receptor 2 is essential for adequate vascular supply of a tumor parenchyma. This also explains that in many malignant tumours the receptor protein VEGF R2 is upregulated (Aprile G et al. 2014).

Pharmacodynamics (Effect)
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Ramucirumab docks to the extracellular domain of the receptor VEGF R2. This receptor blockade prevents the ligands VEGF-A, VEGF-C and VEGF-D from binding to their physiological receptor. Thus, ramucirumab prevents ligand-stimulated activation of VEGF receptor-2 and the downstream signalling cascades, including p44/p42 mitogen-activated protein kinases, thereby inhibiting ligand-induced proliferation and migration of human endothelial cells. This prevents the growth and neogenesis of blood vessels. The vascular supply of the tumor is continuously reduced. This antibody is produced by the mouse myeloma cell line NS0.

The mean half-life is 14 days, the clearance 0.015l/h.

Indication
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Ramucirumab has been approved since September 2019 for the treatment of adults with advanced or inoperable hepatocellular carcinoma who have previously been treated with the active substance sorafenib and in whom the blood serum alpha-fetoprotein level of the tumor marker serum is significantly elevated (over 400 ng per ml).

Pregnancy/nursing period
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Women of childbearing potential / Contraception in women: Women of childbearing potential must use effective contraception measures during and up to 3 months after treatment.

Pregnancy: There are no data on the use of Ramucirumab in pregnant women. If a patient becomes pregnant during treatment with ramucirumab, she must be informed of the potential risk to pregnancy and the risk to the fetus.

Breastfeeding: It is not known whether ramucirumab passes into breast milk. Excretion into milk and oral uptake are considered to be low. As a risk to the breastfed newborn / infant cannot be excluded, women should discontinue breastfeeding during therapy with ramucirumab and should not breastfeed for at least 3 months after the end of therapy.

Complication(s)
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Fertility: Data on the effect of Ramucirumab on human fertility are not available. Based on animal studies, it is believed that female fertility is likely to be impaired during treatment with ramucirumab.

Undesirable effects
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Hypertension: In studies, 11 out of 100 people experienced significant hypertension, 18% headaches. Edema of the lower legs or feet was also observed.

The influence of ramucirumab in patients with severe or non-healing wounds: As ramucirumab is an anti-angiogenic therapy and has the potential to have a negative influence on wound healing, ramucirumab therapy must be discontinued at least 4 weeks before a planned operation. If a patient experiences complications in wound healing during therapy, treatment with ramucirumab must be interrupted until the wound has completely healed.

Liver failure: In patients with severe liver cirrhosis (Child-Pugh B or C), cirrhosis with hepatic encephalopathy, clinically significant ascites due to cirrhosis or a hepatorenal syndrome, ramucirumab must be used with caution. There is very limited safety and efficacy data available for such patients.

Hepatic encephalopathy: A higher incidence of hepatic encephalopathy has been reported in HCC patients treated with ramucirumab than in placebo patients. Patients should be monitored for clinical signs and symptoms of hepatic encephalopathy. If patients develop hepatic encephalopathy or hepatorenal syndrome, their treatment with ramucirumab must be terminated definitively.

Fistulas: Patients treated with ramucirumab may have an increased risk of developing fistulas. If fistulas develop, treatment with ramucirumab must be discontinued permanently.

Proteinuria: A higher incidence of proteinuria has been reported in ramucirumab patients than in placebo patients. Patients must be monitored for the development or worsening of proteinuria during ramucirumab therapy. Ramucirumab must be discontinued definitively if protein excretion is >3 g/24 h or if nephrotic syndrome occurs.

Stomatitis: An increased incidence of stomatitis has been reported in patients receiving ramucirumab in combination with chemotherapy compared to patients treated with placebo plus chemotherapy. Symptomatic treatment should be started immediately if stomatitis occurs.

Renal failure: Limited safety data are available for ramucirumab therapy in patients with severe renal failure (creatinine clearance 15 to 29 ml/min).

Skin: Effluvium and alopecia are very common. Erythrodysaesthesia syndrome (hand-foot syndrome) is often expected (Cyramza Fachinformation).

Preparations
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Cyramza®

Note(s)
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Ramucirumab was approved as Cyramza® by the U.S. Food and Drug Administration (FDA) in April 2014 under an accelerated review process. In the EU, ramucirumab is approved for the treatment of certain cancers of the stomach, colon, lung and liver.

Literature
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  1. Aprile G et al (2014) Ramucirumab: preclinical research and clinical development. Onco Targets Ther 7:1997-2006.
  2. Cyramza Scientific Information https://www.lilly-pharma.de/de/pdf/fachinformation/fachinformation_cyramza.pdf (accessed 9.9.2020 - 20.15 hrs)
  3. Khan U et al (2019) Ramucirumab for the treatment of gastric or gastro-esophageal junction cancer. Expert Opinion Biol Ther 19:1135-1141.
  4. Maione P et al (2017) The Role of the Antiangiogenetic Ramucirumab in the Treatment of Advanced Non Small Cell Lung Cancer. Curr Med Chem 24:3-13.
  5. Noguerido A et al. (2018) The safety of ramucirumab for the treatment of colorectal cancer. Expert Opinion Drug Saf 17:945-951.
  6. Shitara K et al (2015) Ramucirumab for gastric cancer. Expert Rev Gastroenterol Hepatol 9:133-139.
  7. Tabernero J et al (2015) Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 16:499-508.

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Last updated on: 29.10.2020