In 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.[6] This trial has been criticised for its use of a placebo control arm, which does not reflect standard of care in most Western countries.[7]
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.[8]
In 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.[11] 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.
Under the European approval, NSCLC therapy with ramucirumab is contraindicated when there is tumour cavitation, or if major vessels are involved.[12][13]
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%).[14]
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.[15]
In February 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.[19] It is now in the RANGE phase III trial for this indication.[20]
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.[21]
^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): 1224–1235. doi:10.1016/S1470-2045(14)70420-6. PMID25240821.
^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): 665–673. doi:10.1016/S0140-6736(14)60845-X. PMID24933332. S2CID5078660.
^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.
^Clinical trial number NCT02426125 for "A Study of Ramucirumab (LY3009806) Plus Docetaxel in Participants With Urothelial Cancer (RANGE)" at ClinicalTrials.gov
^Pinto C, Zucali PA, Pagano M, Grosso F, Pasello G, Garassino MC, et al. (October 2021). "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. PMID34499874. S2CID237471286.
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