Ramucirumab

Ramucirumab[1] (LY3009806, IMC-1121B, trade name Cyramza[2][3]) is a fully human monoclonal antibody (IgG1) developed for the treatment of solid tumors. This drug was developed by ImClone Systems Inc. It was isolated from a native phage display library from Dyax.

Ramucirumab
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetVEGFR2 (KDR)
Clinical data
Trade namesCyramza
AHFS/Drugs.comcyramza
License data
Routes of
administration		Intravenous infusion
ATC code
Legal status
Legal status
Pharmacokinetic data
MetabolismProbably proteases
Elimination half-life14 days
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
Chemical and physical data
FormulaC6374H9864N1692O1996S46
Molar mass143609.63 g·mol−1
 NY (what is this?)  (verify)

Approved uses

On 21 April 2014, the US Food and Drug Administration (FDA) 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, a phase III, international, randomized, double-blind, placebo-controlled study, that evaluated the safety and efficacy of ramucirumab combinated with best supportive care versus placebo.[4] This trial has been criticised for its use of a placebo control arm, which does not reflect standard of care in most Western countries.[5]

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.[6]

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.[7]

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.[8]

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.[9] 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.

Contraindications

Under the European approval, NSCLC therapy with ramucirumab is contraindicated when there is tumour cavitation, or if major vessels are involved.[10][11]

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%).[12]

Interactions

In studies, no interactions were observed with paclitaxel, docetaxel or irinotecan.[10][12]

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.[13]

Clinical trials

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.[14][15]

In June 2014, a phase III trial of the drug reported it failed to improve overall survival in liver cancer.[16]

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.[17] It is now in the RANGE phase III trial for this indication.[18]

Between 2016 and 2018, 26 hospitals in Italy conducted a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial to evaluate the safety and effectiveness of the anti-VEGFR-2 antibody ramucirumab combined with gemcitabine in patients with pretreated  pleural mesothelioma. Combining ramucirumab to standard second line gemcitabine significantly improved overall survival after failure of first-line chemotherapy, with a favourable safety profile.[19]

References
  1. Statement On A Nonproprietary Name Adopted By The USAN Council - Ramucirumab, American Medical Association.
  2. "FDA OKs Lilly's blockbuster hopeful ramucirumab for stomach cancer". FierceBiotech. 21 April 2014.
  3. "Cyramza official website".
  4. 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.
  5. Gyawali, Bishal (2017). "Low-value practices in oncology contributing to financial toxicity". ecancermedicalscience. 11: 727. doi:10.3332/ecancer.2017.727. PMC 5365336. PMID 28386297.
  6. 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.
  7. 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.
  8. 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.
  9. Research, Center for Drug Evaluation and (2019-05-10). "FDA approves ramucirumab for hepatocellular carcinoma". FDA.
  10. "Cyramza: EPAR – Product Information" (PDF). European Medicines Agency. 21 January 2015.
  11. Haberfeld, H, ed. (2017). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Cyramza 10 mg/ml Konzentrat zur Herstellung einer Infusionslösung.
  12. FDA Professional Drug Information on Cyramza.
  13. Ramucirumab (Cyramza) package insert
  14. Clinical trial number NCT00703326 for "Phase III Study of Docetaxel + Ramucirumab or Placebo in Breast Cancer" at ClinicalTrials.gov
  15. Carroll J (26 September 2013). "In another stinging setback, Eli Lilly's ramucirumab fails PhIII breast cancer study". Retrieved 27 September 2013.
  16. Philippidis A. "Lilly's Cyramza Fails Phase III Trial in Liver Cancer". Genetic Engineering & Biotechnology News.
  17. Levitan D (February 2016). "Added to Docetaxel Extends PFS in Urothelial Carcinoma". Cancer Network.
  18. Clinical trial number NCT02426125 for "A Study of Ramucirumab (LY3009806) Plus Docetaxel in Participants With Urothelial Cancer (RANGE)" at ClinicalTrials.gov
  19. Pinto, Carmine; Zucali, Paolo Andrea; Pagano, Maria; Grosso, Federica; Pasello, Giulia; Garassino, Marina Chiara; Tiseo, Marcello; Parra, Hector Soto; Grossi, Francesco; Cappuzzo, Federico; Marinis, Filippo de (2021-09-06). "Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial". The Lancet Oncology. 22 (10): 1438–1447. doi:10.1016/S1470-2045(21)00404-6. ISSN 1470-2045. PMID 34499874. S2CID 237471286.
  • "Ramucirumab". Drug Information Portal. U.S. National Library of Medicine.
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