©2017 AACR. Ramucirumab is an IgG 1 monoclonal antibody specific for the vascular endothelial growth factor receptor-2. Ramucirumab, 8 mg/kg every 2 weeks, administered as monotherapy (REGARD) or in combination with paclitaxel (RAINBOW), was safe and effective in patients with previously treated advanced gastric or gastroesophageal junction (GEJ) cancer. We evaluated exposure–efficacy and exposure–safety relationships of ramucirumab from two randomized, placebo-controlled phase III trials. Sparse pharmacokinetic samples were collected, and a population pharmacokinetic analysis was conducted to predict ramucirumab minimum trough concentration at steady state (C min,ss ). Kaplan–Meier methods and Cox proportional hazards models were used to evaluate the ramucirumab exposure (C min,ss )–efficacy relationship to overall survival (OS) and progression-free survival (PFS). Logistic regression analyses were used to evaluate exposure–safety relationships. Analyses included 321 ramucirumab þ paclitaxel and 335 placebo þ paclitaxel patients from RAINBOW and 72 ramucirumab and 35 placebo patients from REGARD. Exposure–efficacy analysis showed ramucirumab C min,ss was a significant predictor of OS and PFS in both trials. Higher ramucirumab exposure was associated with longer OS and PFS. In RAINBOW, grade ≥3 hypertension, leukopenia, and neutropenia, but not febrile neutropenia, significantly correlated with C min,ss , with increased exposure leading to increased incidence. Exploratory exposure–response analyses suggest a positive relationship between efficacy and ramucirumab exposure with manageable toxicities at exposures generated from a dose of 8 mg/kg ramucirumab given every 2 weeks for patients with advanced gastric/GEJ cancer. These findings suggest an opportunity to further optimize benefit versus risk profiles of ramucirumab treatment in patients with gastric/GEJ cancer.