OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 29 May 2017

Abbreviations used: NSCLC, non-small cell lung cancer; HCC, hepatocellular carcinoma; HER, human epidermal growth factor.

• Zimmerman HJ. Hepatotoxic effects of oncotherapeutic and immunosuppressive agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 673-708.

  (Expert review of hepatotoxicity published in 1999, well before the availability of most monoclonal antibody therapies).
• Reuben A. Hepatotoxicity of immunosuppressive drugs. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 569-91.

  (Review of hepatotoxicity of immunosuppressive drugs; mentions that "the biological immunosuppressants are largely free from hepatotoxicity, with the exception of the TNF alpha antagonists").
• Chabner BA, Barnes J, Neal J, Olson E, Mujagiv H, Sequist L, Wilson W, et al. Targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies, and cytokines. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1731-53.

  (Textbook of pharmacology and therapeutics).
• Fuchs CS, Tomasek J, Yong CJ, Dumitru F, Passalacqua R, Goswami C, Safran H, et al.; REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014; 383 (9911): 31-9. [PubMed: 24094768]

  (Among 355 patients with previously treated, refractory, advanced gastric cancer treated with ramucirumab [8 mg/kg] or placebo intravenously every 2 weeks, median overall survival was improved by therapy [5.2 vs 3.8 months] while rates of adverse events were similar except for a higher rate of hypertension [16% vs 8%]; no mention of ALT elevations or hepatotoxicity).
• Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, et al.; RAINBOW Study Group. 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. Lancet Oncol 2014; 15: 1224-35. [PubMed: 25240821]

  (Among 665 patients with previously treated advanced gastric cancer treated with paclitaxel, overall survival was improved by addition of ramucirumab [median 9.6 vs 7.4 months] and side effects that were more frequent with ramucirumab included hypertension, neutropenia, fatigue and anemia; "liver injury or failure" occurred in 16.5% vs 12.5%, but no details given).
• Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, Park K, et al. 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 2014; 384 (9944): 665-73. [PubMed: 24933332]

  (Among 1253 patients with NSCLC treated with docetaxel with or without ramucirumab, overall survival improved with addition of ramucirumab [median 10.5 vs 9.1 months], while rates of adverse and serious adverse events were similar, although hypertension, neutropenia and hemorrhage were more frequent with ramucirumab; no mention of ALT elevations or hepatotoxicity).
• Mackey JR, Ramos-Vazquez M, Lipatov O, McCarthy N, Krasnozhon D, Semiglazov V, Manikhas A, et al. Primary results of ROSE/TRIO-12, a randomized placebo-controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer. J Clin Oncol 2015; 33: 141-8. [PubMed: 25185099]

  (Among 1144 patients with metastatic HER-2 negative breast cancer treated with docetaxel, addition of ramucirumab did not increase median overall survival [27.3 vs 27.2 months] and adverse and serious adverse event rates were similar, but more patients on ramucirumab had fatigue, hypertension, febrile neutropenia, hand-foot syndrome and stomatitis; no mention of ALT elevations or hepatotoxicity).
• Zhu AX, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, Blanc JF, et al; REACH Trial Investigators. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib(REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 2015; 16: 859-70. [PubMed: 26095784]

  (Among 565 patients with advanced hepatocellular carcinoma [HCC] who were treated with ramucirumab [8 mg/kg every 2 weeks] vs placebo, overall survival was not significantly better with ramucirumab [9.2 vs 7.6 months], while adverse events were more frequent with more edema, ascites, hypertension, proteinuria and liver injury [51% vs 37%], but no details provided).
• Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, et al.; RAISE Study Investigators. 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 2015; 16: 499-508. [PubMed: 25877855]

  (Among 1072 patients with refractory, metastatic colorectal cancer treated with ramucirumab [8 mg/kg] or placebo, median overall survival was greater with ramucirumab therapy [13.3 vs 11.7 months] as were serious adverse events including neutropenia [38% vs 23%], hypertension [11% vs 3%], and fatigue [12% vs 8%], but not liver injury [12% vs 10%]).
• Larkins E, Scepura B, Blumenthal GM, Bloomquist E, Tang S, Biable M, Kluetz P, et al. U.S. Food and Drug Administration approval summary: ramucirumab for the treatment of metastatic non-small cell lung cancer following disease progression on or after platinum-based chemotherapy. Oncologist 2015; 20: 1320-5. [PMC free article: PMC4718430] [PubMed: 26446239]

  (Summary of the clinical results of registration trials of ramucirumab for NSCLC that led to its FDA approval; no mention of ALT elevations or hepatotoxicity).
• Ramucirumab (Cyramza) for gastric and GEJ cancer. Med Let Drugs Ther 2015; 57: e74-5 (on line only: not in PubMed)

  (Concise review of the mechanism of action, efficacy, safety and costs of ramucirumab shortly after its approval in the United States; mentions that new onset or worsening of encephalopathy, ascites, or hepatorenal syndrome has occurred in patients with Child-Pugh B or C cirrhosis during ramucirumab therapy).
• Vahdat LT, Layman R, Yardley DA, Gradishar W, Salkeni MA, Abraham Joy A, Garcia AA, et al. Randomized phase II study of ramucirumab or icrucumab in combination with capecitabine in patients with previously treated locally advanced or metastatic breast cancer. Oncologist 2017; 22: 245-54. [PMC free article: PMC5344637] [PubMed: 28220020]

  (Among 153 patients with previously treated, advanced or metastatic breast cancer treated with capecitabine with icrucumab, ramucirumab or placebo, overall survival was similar in all 3 groups, while side effects were more frequent with the monoclonal antibody treated groups; ALT elevations occurred in 9.6% on ramucirumab vs 10.2% on capecitabine alone, and none had elevations above 5 times ULN).