Exposure-response relationship of ramucirumab in East Asian patients from RAINBOW: a randomized clinical trial in second-line treatment of gastric cancer

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/m(2) 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 (C-min,C-ss) using a nonlinear mixed-effect modeling approach. Kaplan-Meier and Cox proportional hazards analyses were conducted to evaluate ramucirumab exposure (C-min,C-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 C-min,C-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 C (min,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.