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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 3/2017

Open Access 01-09-2017 | Original Article

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

Authors: 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 Nasroulah, Josep Tabernero

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2017

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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 (C min,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 C min,ss quartiles (Q). An ordered categorical model analyzed the relationship between C min,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 C min,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 C min,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 C min,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.
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Metadata
Title
Exposure–response relationship of ramucirumab in patients with advanced second-line colorectal cancer: exploratory analysis of the RAISE trial
Authors
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 Nasroulah
Josep Tabernero
Publication date
01-09-2017
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 3/2017
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-017-3380-z

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