Ramucirumab

Ramucirumab(^[5]), sold under the brand name Cyramza, is a fully human monoclonal antibody (IgG1) used for the treatment of cancer.^[3][4] Ramucirumab is a human vascular endothelial growth factor receptor 2 (VEGFR2) antagonist.^[3][4] Ramucirumab was developed by ImClone Systems.

Medical uses

Ramucirumab is indicated for the treatment of gastric cancer, colorectal cancer, non-small cell lung cancer, and hepatocellular carcinoma.^[3][4]

Contraindications

Under the European Union approval, NSCLC therapy with ramucirumab is contraindicated when there is tumor cavitation, or if major vessels are involved.^[6][7]

Side effects

The most common adverse effects in a study investigating ramucirumab monotherapy were diarrhea (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%).^[3][4]

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.^[3]

History

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.^[8] This trial has been criticised for its use of a placebo control arm, which does not reflect standard of care in most Western countries.^[9]

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.^[10]

In 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.^[11]

In April 2015, ramucirumab was approved by FDA for the treatment of people with metastatic colorectal cancer 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.^[12]

In May 2019, ramucirumab was approved by FDA as a single agent treatment for hepatocellular carcinoma (HCC) in people who have an alpha fetoprotein (AFP) of > 400 ng/mL and have been previously treated with sorafenib.^[13] The approval was based on REACH-2 (NCT02435433), a multinational, randomized, double-blind, placebo-controlled, multicenter study in participants 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 participants receiving ramucirumab and 7.3 months (5.4-9.1 months) for those receiving placebo.

Clinical trials

In September 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 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.^[17] It is being studied in the RANGE phase III trial for this indication.^[18]

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

References

1. ^ "Prescription medicines: registration of new chemical entities in Australia, 2015". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
2. ^ "Health Canada New Drug Authorizations: 2015 Highlights". Health Canada. 4 May 2016. Retrieved 7 April 2024.
3. ^ "Cyramza- ramucirumab solution". DailyMed. 27 November 2023. Retrieved 22 October 2024.
4. ^ "Cyramza EPAR". European Medicines Agency (EMA). 19 December 2014. Retrieved 22 October 2024.
5. ^ Statement On A Nonproprietary Name Adopted By The USAN Council - Ramucirumab, American Medical Association
6. ^ "Cyramza: EPAR – Product Information". European Medicines Agency. 21 January 2015. Archived from the original on 30 April 2018. Retrieved 6 May 2017.
7. ^ Haberfeld, H (ed.) (2017). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Cyramza 10 mg/ml Konzentrat zur Herstellung einer Infusionslösung.
8. ^ Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, Dos Santos LV, Aprile G, Ferry DR, Melichar B, Tehfe M, Topuzov E, Zalcberg JR, Chau I, Campbell W, Sivanandan C, Pikiel J, Koshiji M, Hsu Y, Liepa AM, Gao L, Schwartz JD, Tabernero J (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
9. ^ Gyawali B (2017). "Low-value practices in oncology contributing to financial toxicity". ecancermedicalscience. 11: 727. doi:10.3332/ecancer.2017.727. PMC 5365336. PMID 28386297
10. ^ Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A (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. PMID 25240821
11. ^ Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, Park K, Gorbunova V, Kowalyszyn RD, Pikiel J, Czyzewicz G, Orlov SV, Lewanski CR, Thomas M, Bidoli P, Dakhil S, Gans S, Kim JH, Grigorescu A, Karaseva N, Reck M, Cappuzzo F, Alexandris E, Sashegyi A, Yurasov S, Pérol M (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. PMID 24933332. S2CID 5078660
12. ^ Tabernero J, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Van Cutsem E, Grothey A, Prausová J, Garcia-Alfonso P (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 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
13. ^ "FDA approves ramucirumab for hepatocellular carcinoma". U.S. Food and Drug Administration (FDA). 10 May 2019.
14. ^
15. ^ Carroll, John (26 September 2013). "In another stinging setback, Eli Lilly's ramucirumab fails PhIII breast cancer study". Retrieved 27 September 2013.
16. ^ Philippidis, Alex. "Lilly's Cyramza Fails Phase III Trial in Liver Cancer". Genetic Engineering & Biotechnology News. Archived from the original on 9 April 2016. Retrieved 12 June 2014.
17. ^ Levitan, Dave (February 2016). "Added to Docetaxel Extends PFS in Urothelial Carcinoma". Cancer Network. Archived from the original on 2 March 2020. Retrieved 4 March 2016.
18. ^
19. ^ Pinto C, Zucali PA, Pagano M, Grosso F, Pasello G, Garassino MC, Tiseo M, Soto Parra H, Grossi F, Cappuzzo F, de Marinis F, Pedrazzoli P, Bonomi M, Gianoncelli L, Perrino M, Santoro A, Zanelli F, Bonelli C, Maconi A, Frega S, Gervasi E, Boni L, Ceresoli GL (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. PMID 34499874. S2CID 237471286