Ramucirumab

Ramucirumab
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetVEGFR2 (KDR)
Names
Trade namesCyramza
Clinical data
Drug classVascular endothelial growth factor receptor (VEGFR) inhibitor[1][2]
Main usesStomach cancer, colorectal cancer, non-small cell lung cancer, hepatocellular cancer[1]
Side effectsTiredness, diarrhea, bleeding, headache, low sodium, swelling, kidney problems[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    use    		Intravenous infusion
    Typical dose8 to 10 mg/kg[2]
    External links
    AHFS/Drugs.comMonograph
    Legal
    License data
    Legal status
    Pharmacokinetics
    MetabolismProbably proteases
    Elimination half-life14 days
    Chemical and physical data
    FormulaC6374H9864N1692O1996S46
    Molar mass143609.63 g·mol−1

    Ramucirumab, sold under the brand name Cyramza, is a medication used to treat stomach cancer, colorectal cancer, non-small cell lung cancer, and hepatocellular cancer.[1] It is only used in certain advanced cases.[1] It is given by injection into a vein.[1]

    Common side effects include tiredness, diarrhea, bleeding, headache, low sodium, swelling, and kidney problems.[2] Other side effects may include gastrointestinal perforation, poor wound healing, high blood pressure, and blood clots.[2] Use in pregnancy may harm the baby.[2] It is a monoclonal antibody that attaches to vascular endothelial growth factor receptor (VEGFR) blocking its action.[1][2]

    Ramucirumab was approved for medical use in the United States and Europe in 2014.[2][1] In the United States 500 mg costs about 6,600 USD as of 2021.[3] In the United Kingdom this amount costs the NHS about £2,500.[4]

    Medical uses

    It was not recommended for either stomach cancer nor NSCLC by the UK NICE in 2016.[4]

    In 2014, the US approved ramucirumab as a single-agent treatment for advanced gastric cancer or gastro-esophageal junction (GEJ) adenocarcinoma after prior treatment with fluoropyrimidine- or platinum-containing chemotherapy. The approval was based on the results of the REGARD trial, that evaluated the safety and efficacy of ramucirumab combinated with best supportive care versus placebo.[5] This trial has been criticised for its use of a placebo control arm, which does not reflect standard of care in most Western countries.[6]

    Ramucirumab has also been studied in combination with paclitaxel (a type of chemotherapy) and received additional FDA approval on 5 November 2014 as a treatment for people with advanced gastric cancer or GEJ adenocarcinoma after prior treatment with fluoropyrimidine- or platinum-based chemotherapy. The approval was based on the results of the RAINBOW trial, that compared ramucirumab plus paclitaxel or paclitaxel alone.[7]

    On 12 December 2014, the FDA approved ramucirumab in combination with docetaxel for treatment of metastatic non-small-cell lung carcinoma (NSCLC) with disease progression during or after first-line platinum-containing chemotherapy. The approval was based on REVEL trial.[8]

    On 24 April 2015, ramucirumab was approved by FDA for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and fluoropyrimidine. The approval was based on the results of the RAISE trial, a phase III study, which compared ramucirumab plus irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) to FOLFIRI alone.[9]

    On 10 May 2019, ramucirumab was approved by FDA as a single agent treatment for hepatocellular carcinoma (HCC) in patients who have an alpha fetoprotein (AFP) of > 400 ng/mL and have been previously treated with sorafenib.[10] The approval was based on REACH-2 (NCT02435433), a multinational, randomized, double-blind, placebo-controlled, multicenter study in patients with advanced HCC with AFP > 400 ng/mL who had disease progression on or after sorafenib or who were intolerant. The estimated median overall survival (OS) was 8.5 months (7.0-10.6 months) for patients receiving ramucirumab and 7.3 months (5.4-9.1 months) for those receiving placebo.

    Dosage

    It is given at a dose of 8 to 10 mg/kg.[2]

    Contraindications

    NSCLC therapy with ramucirumab is contraindicated when there is tumour cavitation, or if major vessels are involved.[11][12]

    Side effects

    The most common adverse effects in a study investigating ramucirumab monotherapy were diarrhoea (14% of patients, as compared to 9% under placebo), hyponatraemia (low blood sodium levels; 6% versus 2%), headache (9% versus 3%), and high blood pressure (16% versus 8%).[13]

    Interactions

    In studies, no interactions were observed with paclitaxel, docetaxel or irinotecan.[11][13]

    Pharmacology

    Mechanism of action

    Ramucirumab is a direct VEGFR2 antagonist, that binds with high affinity to the extracellular domain of VEGFR2 and block the binding of natural VEGFR ligands (VEGF-A, VEGF-C and VEGF-D). These ligands are secreted by solid tumors to promote angiogenesis (formation of new blood vessels from pre-existing ones) and enhance tumor blood supply. Binding of ramucirumab to VEGFR2 leads to inhibition of VEGF-mediated tumor angiogenesis.[14]

    History

    This drug was developed by ImClone Systems Inc. It was isolated from a native phage display library from Dyax.

    Research

    On September 26, 2013 the manufacturer Eli Lilly announced that its Phase III study for ramucirumab failed to hit its primary endpoint on progression-free survival among women with metastatic breast cancer.[15][16]

    In June 2014, a phase III trial of the drug reported it failed to improve overall survival in liver cancer.[17]

    In Feb 2016 it was reported that a phase II trial of adding ramucirumab to docetaxel improved progression-free survival (PFS) compared with docetaxel alone in locally advanced or metastatic urothelial carcinoma.[18] It is now in the RANGE phase III trial for this indication.[19]

    References

    1. 1 2 3 4 5 6 7 "Cyramza". Archived from the original on 24 October 2020. Retrieved 15 October 2021.
    2. 1 2 3 4 5 6 7 8 9 "Ramucirumab Monograph for Professionals". Drugs.com. Archived from the original on 24 September 2020. Retrieved 15 October 2021.
    3. ↑ "Cyramza Prices, Coupons & Patient Assistance Programs". Drugs.com. Retrieved 15 October 2021.
    4. 1 2 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 933. ISBN 978-0-85711-369-6.{{cite book}}: CS1 maint: date format (link)
    5. ↑ Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, et al. (January 2014). "Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial". Lancet. 383 (9911): 31–39. doi:10.1016/s0140-6736(13)61719-5. PMID 24094768. S2CID 41960459.
    6. ↑ "Archive copy". Archived from the original on 2021-03-02. Retrieved 2021-01-14.{{cite web}}: CS1 maint: archived copy as title (link)
    7. ↑ Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, et al. (October 2014). "Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial". The Lancet. Oncology. 15 (11): 1224–35. doi:10.1016/S1470-2045(14)70420-6. PMID 25240821. Archived from the original on 2021-08-29. Retrieved 2021-01-14.
    8. ↑ Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, et al. (August 2014). "Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial". Lancet. 384 (9944): 665–73. doi:10.1016/S0140-6736(14)60845-X. PMID 24933332. S2CID 5078660. Archived from the original on 2014-08-29. Retrieved 2021-01-14.
    9. ↑ Tabernero J, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, et al. (2015). "RAISE: A randomized, double-blind, multicenter phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab (RAM) or placebo (PBO) in patients (pts) with metastatic colorectal carcinoma (CRC) progressive during or following first-line combination therapy with bevacizumab (bev), oxaliplatin (ox), and a fluoropyrimidine (fp)". Journal of Clinical Oncology. 33 (3_suppl): 512. doi:10.1200/jco.2015.33.3_suppl.512.
    10. ↑ Research, Center for Drug Evaluation and (2019-05-10). "FDA approves ramucirumab for hepatocellular carcinoma". FDA. Archived from the original on 2020-12-22. Retrieved 2021-01-14.
    11. 1 2 "Cyramza: EPAR – Product Information" (PDF). European Medicines Agency. 21 January 2015. Archived (PDF) from the original on 30 April 2018. Retrieved 14 January 2021.
    12. ↑ Haberfeld, H, ed. (2017). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Cyramza 10 mg/ml Konzentrat zur Herstellung einer Infusionslösung.{{cite book}}: CS1 maint: unrecognized language (link)
    13. 1 2 FDA Professional Drug Information on Cyramza.
    14. ↑ "Ramucirumab (Cyramza) package insert" (PDF). Archived (PDF) from the original on 2020-10-29. Retrieved 2021-01-14.
    15. ↑ Clinical trial number NCT00703326 for "Phase III Study of Docetaxel + Ramucirumab or Placebo in Breast Cancer" at ClinicalTrials.gov
    16. ↑ Carroll J (26 September 2013). "In another stinging setback, Eli Lilly's ramucirumab fails PhIII breast cancer study". Archived from the original on 26 September 2013. Retrieved 27 September 2013.
    17. ↑ Philippidis A. "Lilly's Cyramza Fails Phase III Trial in Liver Cancer". Genetic Engineering & Biotechnology News. Archived from the original on 2016-04-09. Retrieved 2021-01-14.
    18. ↑ Levitan D (February 2016). "Added to Docetaxel Extends PFS in Urothelial Carcinoma". Cancer Network. Archived from the original on 2020-03-02. Retrieved 2021-01-14.
    19. ↑ Clinical trial number NCT02426125 for "A Study of Ramucirumab (LY3009806) Plus Docetaxel in Participants With Urothelial Cancer (RANGE)" at ClinicalTrials.gov
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