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Cancer Therapy: Cyramza by Eli Lilly and Company

Cyramza (ramucirumab), manufactured by Eli Lilly and Company, is an angiogenesis inhibitor indicated for the treatment of patients with advanced (unresectable) or metastatic gastric cancer or gastroesophageal junction adenocarcinoma with disease progression on or after treatment with prior fluoropyrimidine- or platinum-containing chemotherapy. The FDA recently approved Cyramza under its priority review program, which is reserved for drugs that have the potential to be a “significant improvement in safety or effectiveness in the treatment of a serious condition.” In addition to an expedited review process, Cyramza was granted orphan product designation, as it is intended to treat a rare disease or condition. (It is the first and only approved second-line treatment for gastric cancer.)

Cyramza is a vascular endothelial growth factor (VEGF) receptor 2 antagonist that blocks binding of ligands VEGF-A, VEGF-C, and VEGF-D, resulting in inhibition of ligand-induced proliferation and migration of human endothelial cells. Pharmacokinetic data of Cyramza have not been fully characterized.

The recommended dose of Cyramza is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes. Once the required volume of drug is withdrawn from the vial, it should be further diluted with normal saline to a final volume of 250 mL. The container should then be gently inverted to ensure adequate mixing. Prior to each infusion, all patients should be premedicated with an IV H1 antagonist (eg, diphenhydramine). Patients who have experienced a grade 1 or 2 infusion reaction should also be premedicated with dexamethasone (or equivalent) and acetaminophen prior to each Cyramza dose. Continue Cyramza until disease progression or unacceptable toxicity occurs.

Cyramza obtained FDA approval based on the REGARD trial performed by Fuchs and colleagues. This multicenter, double-blind, phase III trial sought to assess the safety and efficacy of Cyramza in patients with advanced gastric or gastroesophageal junction adenocarcinoma. At a ratio of 2:1, 355 patients between the ages of 24 and 87 years, whose disease progressed after receiving first-line platinum-containing or fluoropyrimidine- containing chemotherapy, were assigned to receive either ramucirumab 8 mg/kg (n = 238) or placebo (n = 117) intravenously once every 2 weeks. All patients, regardless of assigned treatment, also received best supportive care. Median treatment duration was 8 weeks (4 doses) for the Cyramza group and 6 weeks (3 doses) for the placebo group. Radiological and symptomatic disease progression was the most common reason for treatment discontinuation, followed by adverse events (AEs).

In assessing overall survival (primary end point), investigators found that patients in the Cyramza group lived a median of 5.2 months (95% CI, 4.4-5.7) compared with 3.8 months (95% CI, 2.8-4.7) for patients in the placebo group, a statistically significant difference (P = .047). When assessing progression-free survival (secondary end point), investigators found that patients in the Cyramza group lived a median of 2.1 months (95% CI, 1.5-2.7) compared with 1.3 months (95% CI, 1.3-1.4) for patients in the placebo group, also a statistically significant difference (P <.001).

Cyramza carries a black box warning concerning the increased risk of hemorrhage, which can sometimes be fatal, as demonstrated in the REGARD trial. The most common AEs observed in patients treated with Cyramza in clinical trials were hypertension and diarrhea at a rate of >10% and >2% higher than placebo, respectively. The most common serious adverse events seen were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of Cyramza-treated patients versus 8.7% of patients who received placebo. Approximately 2% of patients who received Cyramza in clinical trials experienced serious and sometimes fatal arterial thromboembolic events, such as myocardial infarction and stroke. Gastrointestinal perforation and infusion-related reactions occurred in less than 1% of patients. Proteinuria also occurred in 8% of Cyramza-treated patients compared with 3% of placebo-treated patients. No formal drug interaction studies between Cyramza and other drugs have been conducted. Cyramza is a pregnancy category C drug.

Cyramza is supplied in 100-mg/10- mL and 500-mg/50-mL (both at 10-mg/mL concentration) single-dose vials. Vials should be stored in a refrigerator at 2°C to 8°C (36°F to 46°F), and should be kept in the outer carton to protect from light. Do not freeze or shake the vials. The wholesale acquisition cost of the 100-mg/10-mL vial is $1020, and the 500-mg/50-mL vial is $5100. More information is available at www.cyramza.com.

Ashley L. Pappas, PharmD, BCPS, is a drug information specialist at University of North Carolina (UNC) Hospitals and an adjunct assistant professor at the UNC Eshelman School of Pharmacy.

Sandra Hanna, PharmD candidate, is a third-year pharmacy student at the UNC Eshelman School of Pharmacy and an intern at the UNC Hospital Drug Information Center in Chapel Hill, North Carolina.

  1. Cyramza [package insert]. Indianapolis, IN: Eli Lilly and Company; April 2014.
  2. Cyramza. Micromedex [online database]. Greenwood Village, CO: Thomson Healthcare; May 2014.
  3. Fuchs CS, Tomasek J, Yong CJ, et al. 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):31-39.
  4. Pricing obtained from AmerisourceBergen database.
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