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

Cohn, Allen; Yoshino, Takayuki; Heinemann, Volker; Obermannova, Radka; Bodoky, György; Prausová, Jana; Garcia-Carbonero, Rocio; Ciuleanu, Tudor; Garcia-Alfonso, Pilar; Portnoy, David; Van Cutsem, Eric; Yamazaki, Kentaro; Clingan, Philip; Polikoff, Jonathon; Lonardi, Sara; O'Brien, Lisa; Gao, Ling; Yang, Ling; Ferry, David; Nasroulah, Federico

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 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.

COLON cancer treatment; DRUG therapy; DRUG efficacy; PHARMACOKINETICS; FOLINIC acid; THERAPEUTIC use of monoclonal antibodies; ANTINEOPLASTIC agents; CLINICAL trials; COLON tumors; MONOCLONAL antibodies; PROGNOSIS; RECTUM tumors; PHARMACODYNAMICS

Cancer Chemotherapy & Pharmacology, 2017, Vol 80, Issue 3, p599

0344-5704

Academic Journal

10.1007/s00280-017-3380-z