Pharmacogenomic determinants of cetuximab and oxaliplatin pharmacokinetics during combined intravenous cetuximab (IV-Cet) and triplet hepatic artery chronomodulated infusion in patients (pts) with initially unresectable liver metastases from colorectal cancer (uLM-CRC) (EU OPTILIV trial).

Abstract

e14082 Background: Triplet HAI with IV-Cet achieved 29.7% complete uLM-CRC resections (R0+R1) and an overall median survival (OS) of 25.7 months in previously treated pts. While the high antitumour efficacy of this new regimen involved direct exposure of LM to the HAI drugs and their potentiation by cetuximab, haematological and intestinal toxicities mostly related to systemic exposure (Lévi, Ann Oncol 2016; Clin Pharmacokin 2016). Methods: To identify potential pharmacogenomics (PG) determinants of toxicity-related systemic exposure to the HAI drugs, 207 single nucleotide polymorphisms (SNPs) from 34 pharmacology genes were analysed in blood mononuclear cells (ADME PGx, MassArray platform, Sequenom, USA) from 11 pts undergoing a first course of chronomodulated triplet HAI and iv-CET (Levi et al. Clin Pharmacokinet 2016). Relations between SNPs and main pharmacokinetics parameters and toxicities were determined using ANOVA or Fisher Exact test. Results: Nine toxicity-related polymorphic genes were identified in the 52 pts of the PG study (ASCO, submitted). Here we investigated whether any of these polymorphic genes modified PK in 4F and 7M (33-72 yo) with WHO performance status 0-1. ABCB1 (rs1045642) was the only polymorphic gene that was significantly associated with both pharmacokinetics and toxicity in this study population. Conclusions: ABCB1 polymorphisms might contribute to the systemic hematologic toxicity of the combined IV-HAI regimen through altering cetuximab and oxaliplatin disposition, yet without affecting efficacy. Consideration of ABCB1 polymorphism could help optimize OPTILIV delivery in individual patients. Clinical trial information: NCT00852228. [Table: see text]