Exposure-response analyses of ramucirumab from two randomized, phase III trials of second-line treatment for advanced gastric or gastroesophageal junction cancer

Josep Tabernero, Atsushi Ohtsu, Kei Muro, Eric Van Cutsem, Sang Cheul Oh, György Bodoky, Yasuhiro Shimada, Shuichi Hironaka, Jaffer A. Ajani, Jiri Tomasek, Howard Safran, Kumari Chandrawansa, Yanzhi Hsu, Michael Heathman, Azhar Khan, Lan Ni, Allen S. Melemed, Ling Gao, David Ferry, Charles S. Fuchs

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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 minimum trough concentration at steady state (Cmin,ss). Kaplan–Meier methods and Cox proportional hazards models were used to evaluate the ramucirumab exposure (Cmin,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 Cmin,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.

Original languageEnglish
Pages (from-to)2215-2222
Number of pages8
JournalMolecular Cancer Therapeutics
Volume16
Issue number10
DOIs
Publication statusPublished - 2017 Oct 1

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Tabernero, J., Ohtsu, A., Muro, K., Van Cutsem, E., Oh, S. C., Bodoky, G., Shimada, Y., Hironaka, S., Ajani, J. A., Tomasek, J., Safran, H., Chandrawansa, K., Hsu, Y., Heathman, M., Khan, A., Ni, L., Melemed, A. S., Gao, L., Ferry, D., & Fuchs, C. S. (2017). Exposure-response analyses of ramucirumab from two randomized, phase III trials of second-line treatment for advanced gastric or gastroesophageal junction cancer. Molecular Cancer Therapeutics, 16(10), 2215-2222. https://doi.org/10.1158/1535-7163.MCT-16-0895