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Cyramza

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Cyramza

CLINICAL PHARMACOLOGY

Mechanism Of Action

Ramucirumab is a vascular endothelial growth factor receptor 2 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.

Pharmacokinetics

With the dosing regimen of 8 mg/kg every 2 weeks in patients with advanced gastric or gastro-esophageal junction 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. Similar Cmin values of ramucirumab were observed when ramucirumab was administered with paclitaxel.

Based on a population PK analysis, the mean (% coefficient of variation [CV%]) volume of distribution at steady state for ramucirumab was 5.5 L (14%), the mean clearance was 0.014 L/hour (30%), and the mean elimination half-life was 15 days (24%).

Specific Populations

Age, sex and race had no clinically meaningful effect on the PK of ramucirumab based on a population PK analysis.

Renal Impairment: The effect of renal impairment on the average concentration of ramucirumab at steady state (Css) was evaluated in patients with mild (calculated creatinine clearance [CLcr] 60-89 mL/min, n=204), moderate (CLcr 30-59 mL/min, n=91) or severe (CLcr 15 -29 mL/min, n=3) renal impairment compared to patients with normal renal function (CLcr ≥ 90 mL/min, n=198) in a population PK analysis. No clinically meaningful differences in the average Css of ramucirumab were observed between patients with renal impairment and patients with normal renal function.

Hepatic Impairment: The effect of hepatic impairment on the average Css of ramucirumab was evaluated in patients with mild (total bilirubin > 1.0-1.5 times upper limit of normal [ULN] and any AST, n=107) or moderate hepatic impairment (total bilirubin > 1.5-3.0 times ULN and any AST, n=3) compared to patients with normal hepatic function (total bilirubin and AST ≤ ULN, n=386) in a population PK analysis. No clinically meaningful differences in the average Css of ramucirumab were found between patients with mild or moderate hepatic impairment and patients with normal hepatic function. No PK data were available from patients with severe hepatic dysfunction (total bilirubin > 3.0 times ULN and any AST).

Drug Interaction Studies

No clinically meaningful changes in paclitaxel exposure or ramucirumab exposure were observed when CYRAMZA 8 mg/kg and paclitaxel 80 mg/m² were co-administered in patients with solid tumors.

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.

Clinical Studies

Gastric Cancer

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 W hite, 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 3 and Figure 1.

Table 3: Efficacy Results

  CYRAMZA
N=238
Placebo
N=117
Overall Survival
  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
Progression-free Survival
  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 in Study 1

Kaplan-Meier Curves of Overall Survival in Study 1 - Illustration

Study 2 was a multinational, randomized, double-blind study of CYRAMZA plus paclitaxel versus placebo plus paclitaxel that randomized (1:1) 665 patients with locally advanced or metastatic gastric cancer (including adenocarcinoma of the gastro-esophageal junction) who previously received platinum-and fluoropyrimidine-containing chemotherapy. Patients were required to have experienced disease progression during, or within 4 months after the last dose of first-line therapy. Patients were also required to have ECOG PS of 0 or 1. Randomization was stratified by geographic region, time to progression from the start of first-line therapy ( < 6 months versus ≥ 6 months) and disease measurability.

Patients were randomized to receive either CYRAMZA 8 mg/kg (n=330) or placebo (n=335) as an intravenous infusion every 2 weeks (on days 1 and 15) of each 28-day cycle. Patients in both arms received paclitaxel 80 mg/m² by intravenous infusion on days 1, 8, and 15 of each 28-day cycle. Prior to administration of each dose of paclitaxel, patients were required to have adequate hematopoietic and hepatic function. The paclitaxel dose was permanently reduced in increments of 10 mg/m² for a maximum of two dose reductions for Grade 4 hematologic toxicity or Grade 3 paclitaxel-related non-hematologic toxicity. The major efficacy outcome measure was overall survival and the supportive efficacy outcome measures were progression-free survival and objective response rate.

Demographics and baseline characteristics were similar between treatment arms including the following: Median age was 61 years; 71% of patients were men; 61% were W hite, 35% Asian; the ECOG PS was 0 for 39% of patients, 1 for 61% of patients; 78% of patients had measurable disease; 79% of patients had gastric cancer; and 21% had adenocarcinoma of the GEJ. Two-thirds of the patients experienced disease progression while on first-line therapy (67%) and 25% of patients received an anthracycline in combination with platinum/fluoropyrimidine combination therapy.

Overall survival, progression-free survival, and objective response rate were statistically significantly improved in patients randomized to receive CYRAMZA plus paclitaxel compared to patients randomized to receive placebo plus paclitaxel. Efficacy results are shown in Table 4 and Figure 2.

Table 4: Summary of Efficacy Data – Intent to Treat (ITT) Population

  CYRAMZA + paclitaxel
N=330
Placebo + paclitaxel
N=335
Overall Survival
  Number of deaths (%) 256 (78%) 260 (78%)
  Median - months (95% CI) 9.6 (8.5, 10.8) 7.4 (6.3, 8.4)
  Hazard Ratio (95% CI) 0.81 (0.68, 0.96)
  Stratified Log-rank p-value 0.017
Progression-free Survival
  Number of events (%) 279 (85%) 296 (88%)
  Median - months (95% CI) 4.4 (4.2, 5.3) 2.9 (2.8, 3.0)
  Hazard Ratio (95% CI) 0.64 (0.54, 0.75)
  Stratified Log-rank p-value < 0.001
Objective Response Rate (CR + PR)
  Rate - percent (95% CI) 28 (23, 33) 16 (13, 20)
  Stratified CMH p-value < 0.001
Abbreviations: CI = confidence interval, CR = complete response, PR = partial response, CMH = Cochran-Mantel-Haenszel

Figure 2: Kaplan-Meier Curves of Overall Survival in Study 2

Kaplan-Meier Curves of Overall Survival in Study 2 - Illustration

Last reviewed on RxList: 11/12/2014
This monograph has been modified to include the generic and brand name in many instances.

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