Exposure-Response Analyses of Ramucirumab from Two Randomized, Phase III Trials of Second-line Treatment for Advanced Gastric or Gastroesophageal Junction Cancer
- Authors
- Tabernero, Josep; Ohtsu, Atsushi; Muro, Kei; Van Cutsem, Eric; Oh, Sang Cheul; Bodoky, Gyorgy; Shimada, Yasuhiro; Hironaka, Shuichi; Ajani, Jaffer A.; Tomasek, Jiri; Safran, Howard; Chandrawansa, Kumari; Hsu, Yanzhi; Heathman, Michael; Khan, Azhar; Ni, Lan; Melemed, Allen S.; Gao, Ling; Ferry, David; Fuchs, Charles S.
- Issue Date
- 10월-2017
- Publisher
- AMER ASSOC CANCER RESEARCH
- Citation
- MOLECULAR CANCER THERAPEUTICS, v.16, no.10, pp.2215 - 2222
- Indexed
- SCIE
SCOPUS
- Journal Title
- MOLECULAR CANCER THERAPEUTICS
- Volume
- 16
- Number
- 10
- Start Page
- 2215
- End Page
- 2222
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/82152
- DOI
- 10.1158/1535-7163.MCT-16-0895
- ISSN
- 1535-7163
- Abstract
- Ramucirumab is an IgG1 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 minimumtrough concentration at steady state (C-min,C-ss). Kaplan-Meier methods and Cox proportional hazards models were used to evaluate the ramucirumab exposure (C-min,C-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 + paclitaxel and 335 placebo + paclitaxel patients from RAINBOW and 72 ramucirumab and 35 placebo patients from REGARD. Exposure-efficacy analysis showed ramucirumab C-min,C-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 Cmin, 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. (C) 2017 AACR.
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