TY - JOUR
T1 - Exposure–response relationship of ramucirumab in East Asian patients from RAINBOW
T2 - a randomized clinical trial in second-line treatment of gastric cancer
AU - Kim, Tae You
AU - Yen, Chia Jui
AU - Al-Batran, Salah Eddin
AU - Ferry, David
AU - Gao, Ling
AU - Hsu, Yanzhi
AU - Cheng, Rebecca
AU - Orlando, Mauro
AU - Ohtsu, Atsushi
N1 - Publisher Copyright:
© 2017, The International Gastric Cancer Association and The Japanese Gastric Cancer Association.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - Background: Ramucirumab is a recombinant human IgG1 neutralizing monoclonal antibody specific for vascular endothelial growth factor receptor-2. Second-line ramucirumab, in conjunction with paclitaxel (ramucirumab 8 mg/kg or placebo in combination with 80 mg/m2 paclitaxel), has been shown to be effective and safe in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma in RAINBOW, a global phase III randomized clinical trial. We conducted an exploratory exposure–response analysis of efficacy and safety of ramucirumab in East Asian patients from the RAINBOW trial. Methods: Using sparse pharmacokinetic samples collected in the RAINBOW trial, a population pharmacokinetic analysis was conducted to predict ramucirumab minimum trough concentration at steady state (Cmin,ss) using a nonlinear mixed-effect modeling approach. Kaplan–Meier and Cox proportional hazards analyses were conducted to evaluate ramucirumab exposure (Cmin,ss) and efficacy relationship by overall survival and progression-free survival. Exposure-safety relationships were assessed descriptively. Results: Two hundred and twenty-two East Asian patients were included in this exposure–response analysis. Higher ramucirumab Cmin,ss was associated with longer overall survival (p = 0.0115) and progression-free survival (p = 0.0179) in this patient cohort. Patients with higher ramucirumab Cmin,ss (≥56.87 ng/ml median) had higher incidences of grade ≥3 leukopenia and neutropenia, but not febrile neutropenia or hypertension. Conclusions: This exploratory analysis suggests a positive relationship between efficacy and ramucirumab exposure with manageable toxicities in East Asian patients from RAINBOW, consistent with the overall exposure–response analysis from this trial. A regimen with a higher dosage of ramucirumab warrants further consideration for East Asian patients with gastric/GEJ cancer.
AB - Background: Ramucirumab is a recombinant human IgG1 neutralizing monoclonal antibody specific for vascular endothelial growth factor receptor-2. Second-line ramucirumab, in conjunction with paclitaxel (ramucirumab 8 mg/kg or placebo in combination with 80 mg/m2 paclitaxel), has been shown to be effective and safe in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma in RAINBOW, a global phase III randomized clinical trial. We conducted an exploratory exposure–response analysis of efficacy and safety of ramucirumab in East Asian patients from the RAINBOW trial. Methods: Using sparse pharmacokinetic samples collected in the RAINBOW trial, a population pharmacokinetic analysis was conducted to predict ramucirumab minimum trough concentration at steady state (Cmin,ss) using a nonlinear mixed-effect modeling approach. Kaplan–Meier and Cox proportional hazards analyses were conducted to evaluate ramucirumab exposure (Cmin,ss) and efficacy relationship by overall survival and progression-free survival. Exposure-safety relationships were assessed descriptively. Results: Two hundred and twenty-two East Asian patients were included in this exposure–response analysis. Higher ramucirumab Cmin,ss was associated with longer overall survival (p = 0.0115) and progression-free survival (p = 0.0179) in this patient cohort. Patients with higher ramucirumab Cmin,ss (≥56.87 ng/ml median) had higher incidences of grade ≥3 leukopenia and neutropenia, but not febrile neutropenia or hypertension. Conclusions: This exploratory analysis suggests a positive relationship between efficacy and ramucirumab exposure with manageable toxicities in East Asian patients from RAINBOW, consistent with the overall exposure–response analysis from this trial. A regimen with a higher dosage of ramucirumab warrants further consideration for East Asian patients with gastric/GEJ cancer.
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U2 - 10.1007/s10120-017-0737-2
DO - 10.1007/s10120-017-0737-2
M3 - Article
C2 - 28634748
AN - SCOPUS:85021119897
SN - 1436-3291
VL - 21
SP - 276
EP - 284
JO - Gastric Cancer
JF - Gastric Cancer
IS - 2
ER -