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Mechanism Of Action
Ramucirumab is a vascular endothelial growth factor receptor 2 (VEGFR2) antagonist that specifically binds VEGF Receptor 2 and blocks binding of VEGFR ligands, VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand-stimulated activation of VEGF Receptor 2, thereby inhibiting ligand-induced proliferation, and migration of human endothelial cells. Ramucirumab inhibited angiogenesis in an in vivo animal model.
With the dosing regimen of 8 mg/kg every 2 weeks in patients with advanced gastric or gastroesophageal cancer, the geometric means of the minimum ramucirumab concentrations (Cmin) were 50 μg/mL (6-228 μg/mL) after the third dose and 74 μg/mL (14-234 μg/mL) after the sixth dose.
Animal Toxicology And/Or Pharmacology
Adverse effects in the kidney (glomerulonephritis) occurred with doses of 16-50 mg/kg (0.7-5.5 times the exposure in humans at the recommended dose of ramucirumab as a single-agent).
A single dose of ramucirumab resulting in an exposure approximately 10 times the exposure in humans at the recommended dose of ramucirumab as a single-agent did not significantly impair wound healing in monkeys using a fullthickness incisional model.
Study 1 was a multinational, randomized, double-blind, multicenter study of CYRAMZA plus best supportive care (BSC) versus placebo plus BSC that randomized (2:1) 355 patients with locally advanced or metastatic gastric cancer (including adenocarcinoma of the gastro-esophageal junction [GEJ]) who previously received platinum- or fluoropyrimidine-containing chemotherapy. The major efficacy outcome measure was overall survival and the supportive efficacy outcome measure was progression-free survival. Patients were required to have experienced disease progression either within 4 months after the last dose of first-line therapy for locally advanced or metastatic disease or within 6 months after the last dose of adjuvant therapy. Patients were also required to have Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Patients received either an intravenous infusion of CYRAMZA 8 mg/kg (n=238) or placebo solution (n=117) every 2 weeks. Randomization was stratified by weight loss over the prior 3 months ( ≥ 10% versus < 10%), geographic region, and location of the primary tumor (gastric versus GEJ).
Demographic and baseline characteristics were similar between treatment arms. Median age was 60 years; 70% of patients were men; 77% were White, 16% Asian; the ECOG PS was 0 for 28% of patients and 1 for 72% of patients; 91% of patients had measurable disease; 75% of patients had gastric cancer; and 25% had adenocarcinoma of the GEJ. The majority of patients (85%) experienced disease progression during or following first-line therapy for metastatic disease. Prior chemotherapy for gastric cancer consisted of platinum/fluoropyrimidine combination therapy (81%), fluoropyrimidine-containing regimens without platinum (15%), and platinum-containing regimens without fluoropyrimidine (4%). In Study 1, patients received a median of 4 doses (range 1-34) of CYRAMZA or a median of 3 doses (range 1-30) of placebo.
Overall survival and progression-free survival were statistically significantly improved in patients randomized to receive CYRAMZA as compared to patients randomized to receive placebo. Efficacy results are shown in Table 2 and Figure 1.
Table 2: Efficacy Results
|Number of deaths (%)||179 (75%)||99 (85%)|
|Median - months (95% CI)||5.2 (4.4, 5.7)||3.8 (2.8, 4.7)|
|Hazard Ratio (95% CI)||0.78 (0.60, 0.998)|
|Stratified Log-rank p-value||0.047|
|Number of events (%)||199 (84%)||108 (92%)|
|Median - months (95% CI)||2.1 (1.5, 2.7)||1.3 (1.3, 1.4)|
|Hazard Ratio (95% CI)||0.48 (0.38, 0.62)|
|Stratified Log-rank p-value||< 0.001|
|Abbreviations: CI = confidence interval|
Figure 1: Kaplan-Meier Curves of Overall Survival
Last reviewed on RxList: 5/1/2014
This monograph has been modified to include the generic and brand name in many instances.
Additional Cyramza Information
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