PD-038 Exposure-Response relationship of second-line ramucirumab in East Asian patients with advanced gastric cancer from RAINBOW, a global, randomized, double-blind, phase 3 study

Abstract

Introduction: RAINBOW showed that adding 8 mg/kg ramucirumab to weekly paclitaxel (80 mg/m2) led to significant improvements in progression‐free survival (PFS), overall survival (OS), and response rate. The exposure‐response relationship of ramucirumab in East Asian patients from the RAINBOW trial was evaluated. Methods: Patients received ramucirumab 8 mg/kg or placebo every two weeks (q2w) + paclitaxel 80 mg/m2 on days 1, 8, and 15 (28‐day cycle). Pharmacokinetic samples were collected in the overall trial; a population pharmacokinetic analysis was conducted. A model‐predicted minimum concentration after first ramucirumab dose (Cmin,1) was used to assess the relationships between ramucirumab exposure and measures of efficacy (OS and PFS) and selected safety variables. Kaplan‐Meier method and Cox regression analyses evaluated the exposure‐efficacy relationship. Exposure‐safety relationship was assessed descriptively. Results: Pharmacokinetic data were available from 108 ramucirumab patients. Ramucirumab patients were divided into Cmin,1 High and Low (n = 54 each) by median Cmin,1 (28.5 μg/mL) and compared to placebo patients (n = 114). As compared to patients with Low Cmin,1, patients with High Cmin,1 showed longer survival and smaller hazard ratio (HR). Cmin,1 Low ramucirumab patients had a median OS of 9.0 months. Cmin,1 High ramucirumab patients had a median OS of 14.2 months. Placebo patients had a median OS of 10.5 months. Cmin,1 Low ramucirumab patients had a median PFS of 4.2 months. Cmin,1 High ramucirumab patients had a median PFS of 7.0 months. Placebo patients had a median PFS of 2.8 months. Exposure‐response relationship was also seen in multivariate models after adjustment for prognostic factors. Higher ramucirumab exposure was associated with higher incidence of grade ≥3 neutropenia (Cmin,1 Low: 44.4% vs. Cmin,1 High: 77.8%) and leukopenia (25.9% vs. 42.6%). Incidence of febrile neutropenia was identical (3.7%) in both Cmin,1 High and Low groups. Conclusion: Exposure‐response analysis of the RAINBOWEast Asian subgroup indicated that higher exposure to ramucirumab was associated with improvements in efficacy and increased toxicity; these results are consistent with those of the RAINBOW ITT exposure‐response analysis. A clinical trial comparing second‐line ramucirumab 8 versus 12 mg/kg q2w plus paclitaxel in gastric/gastroesophageal junction cancer is underway (NCT02514551).