Impact of trough concentrations of regorafenib and its major metabolites M-2 and M-5 on overall survival of chemorefractory metastatic colorectal cancer patients: Results from a multicentre GERCOR TEXCAN phase II study

Cmin公司 四分位间距 瑞戈非尼 医学 结直肠癌 内科学 不利影响 泌尿科 胃肠病学 药代动力学 肿瘤科 癌症 最大值
作者
Benoit Rousseau,Arezki Khaled Boukerma,Julie Henriques,Romain Cohen,Olivier Lucidarme,Christophe Borg,Christophe Tournigand,Stefano Kim,Jean-Baptiste Bachet,Thibault Mazard,Christophe Louvet,Benoist Chibaudel,Dewi Vernerey,Thierry André,Anne Hulin
出处
期刊:European Journal of Cancer [Elsevier]
卷期号:168: 99-107 被引量:1
标识
DOI:10.1016/j.ejca.2022.03.009
摘要

This prospective pharmacokinetic (PK) ancillary study of the TEXCAN phase II GERCOR trial of patients with chemorefractory metastatic colorectal cancer and treated with regorafenib (REGO) investigated correlations between overall survival (OS) and concentrations (C) of REGO and its active metabolites, M-2 and M-5.55 patients received REGO 160 mg/day for 21 days of a 28-day cycle (NCT02699073). REGO, M-2, M-5 were measured by liquid chromatography-mass spectrometry assay on day 15 of cycle 1 (C1) and 2 (C2). We studied the association between OS and Cmin of REGO, M-2 and M-5 at C1 and their accumulations between C1 and C2.Medians of C2/C1 M-2 and M-5 ratios were 0.82 (interquartile range 0.50-1.78) and 0.75 (interquartile range 0.41-1.93), respectively. Patients with C2/C1 M-2 ratio ≥ median had improved survival compared to those < median (12.6 versus 4.0 months, P = 0.023), corresponding to a 66% mortality risk reduction in multivariate analysis. The C2/C1 M-2 ratio correlated with C1 REGO+M-2+M-5 (Csum; P = 0.006). Restricted cubic spline analysis showed an increased OS benefit as the C2/C1 M-2 ratio raises and when C1 Csum ranged between 2.5 and 5.5 mg/L. Patients within the Csum range had a reduced incidence of serious adverse events and improved OS.We identified PK parameters associated with a survival benefit in patients with metastatic colorectal cancer treated by REGO. OS and safety were favourable when C1 REGO+M-2+M-5 Csum ranged between 2.5 and 5.5 mg/L. These results pave the way for individual REGO dose modification strategies based on PK monitoring.NCT02699073.
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