Exposure–response relationship of ramucirumab in patients with advanced second-line colorectal cancer: exploratory analysis of the RAISE trial

Allen Lee Cohn, Takayuki Yoshino, Volker Heinemann, Radka Obermannova, György Bodoky, Jana Prausová, Rocio Garcia-Carbonero, Tudor Ciuleanu, Pilar Garcia-Alfonso, David C. Portnoy, Eric Van Cutsem, Kentaro Yamazaki, Philip R. Clingan, Jonathon Polikoff, Sara Lonardi, Lisa M. O’Brien, Ling Gao, Ling Yang, David Ferry, Federico NasroulahJosep Tabernero

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Purpose: To characterize ramucirumab exposure–response relationships for efficacy and safety in patients with metastatic colorectal cancer (mCRC) using data from the RAISE study. Methods: Sparse pharmacokinetic samples were collected; a population pharmacokinetic analysis was conducted. Univariate and multivariate Cox proportional hazards models analyzed the relationship between predicted ramucirumab minimum trough concentration at steady state (Cmin,ss) and survival. Kaplan–Meier analysis was used to evaluate survival from patients in the ramucirumab plus folinic acid, 5-fluorouracil, and irinotecan (FOLFIRI) treatment arm stratified by Cmin,ss quartiles (Q). An ordered categorical model analyzed the relationship between Cmin,ss and safety outcomes. Results: Pharmacokinetic samples from 906 patients were included in exposure–efficacy analyses; samples from 905 patients were included in exposure–safety analyses. A significant association was identified between Cmin,ss and overall survival (OS) and progression-free survival (PFS) (p < 0.0001 for both). This association remained significant after adjusting for baseline factors associated with OS or PFS (p < 0.0001 for both). Median OS was 11.5, 12.9, 16.4, and 16.7, and 12.4 months for ramucirumab Cmin,ss Q1, Q2, Q3, Q4, and placebo group, respectively. Median PFS was 5.4, 4.6, 6.8, 8.5, and 5.2 months for ramucirumab Cmin,ss Q1, Q2, Q3, Q4, and placebo group, respectively. The risk of Grade ≥3 neutropenia was associated with an increase in ramucirumab exposure. Conclusions: Exploratory exposure–response analyses suggested a positive relationship between efficacy and ramucirumab exposure with manageable toxicities in patients from the RAISE study with mCRC over the ranges of exposures achieved by a dose of 8 mg/kg every 2 weeks in combination with FOLFIRI.

Original languageEnglish
Pages (from-to)599-608
Number of pages10
JournalCancer Chemotherapy And Pharmacology
Volume80
Issue number3
DOIs
Publication statusPublished - Sep 1 2017

Keywords

  • Colorectal cancer
  • Exposure–response
  • FOLFIRI
  • Ramucirumab
  • Second line

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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    Cohn, A. L., Yoshino, T., Heinemann, V., Obermannova, R., Bodoky, G., Prausová, J., Garcia-Carbonero, R., Ciuleanu, T., Garcia-Alfonso, P., Portnoy, D. C., Van Cutsem, E., Yamazaki, K., Clingan, P. R., Polikoff, J., Lonardi, S., O’Brien, L. M., Gao, L., Yang, L., Ferry, D., ... Tabernero, J. (2017). Exposure–response relationship of ramucirumab in patients with advanced second-line colorectal cancer: exploratory analysis of the RAISE trial. Cancer Chemotherapy And Pharmacology, 80(3), 599-608. https://doi.org/10.1007/s00280-017-3380-z