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Cohn, Allen Lee; Yoshino, Takayuki; Heinemann, Volker; Obermannova, Radka; Bodoky, Gyorgy; Prausova, Jana; Garcia-Carbonero, Rocio; Ciuleanu, Tudor; Garcia-Alfonso, Pilar; Portnoy, David C.; Cutsem, Eric van; Yamazaki, Kentaro; Clingan, Philip R.; Polikoff, Jonathon; Lonardi, Sara; O'Brien, Lisa M.; Gao, Ling; Yang, Ling; Ferry, David; Nasroulah, Federico; Tabernero, Josep (2017): Exposure-response relationship of ramucirumab in patients with advanced second-line colorectal cancer: exploratory analysis of the RAISE trial. In: Cancer Chemotherapy and Pharmacology, Vol. 80, No. 3: pp. 599-608
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To characterize ramucirumab exposure-response relationships for efficacy and safety in patients with metastatic colorectal cancer (mCRC) using data from the RAISE study. 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. 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 ae<yen>3 neutropenia was associated with an increase in ramucirumab exposure. 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.