127P Personalizing treatment in colorectal cancer by monitoring bevacizumab blood levels and ICAM-1 polymorphisms

Bevacizumab treatment presents large interpatient variability in efficacy. We have previously reported that trough bevacizumab levels ³ 87.9 mg/L and mutations in ICAM-1 rs1799969 are associated with longer survival in metastatic colorectal cancer (mCRC). The aim of the present study was to investigate correlations between bevacizumab levels and ICAM-1 polymorphisms in order to develop a better-informed personalized treatment approach. 46 patients (61% male, median age 64.5 years) with mCRC, who received bevacizumab-based treatment were studied. A pharmacokinetic model was developed in order to identify potential sources of variability. ICAM-1 rs1799969 polymorphisms and bevacizumab levels were determined in whole blood. Data were analyzed using nonlinear mixed-effects modeling. 22% of the patients were carriers of mutant ICAM-1 rs1799969. The two-compartment PK model showed that clearance was significantly decreased with mutant ICAM-1 rs1799969 (p<0.0001) and increased with weight (p<0.0001). Trough levels were significantly higher in carriers of mutant ICAM-1 rs1799969 (99.1 vs. 57.2 mg/L, p=0.00004). ICAM-1 rs1799969 polymorphisms and weight found to be significantly correlated with bevacizumab clearance. Moreover, trough levels are associated with survival and found to be significantly higher in carriers of mutant ICAM-1 rs1799969. Nowadays, bevacizumab dose is normalized to weight but not to adjust based on genetics. Herein, we present the mechanistic underline to support the development of an individualized treatment approach. Genetic and pharmacokinetic data should be combined at baseline and throughout the treatment to improve treatment outcomes in all patients with mCRC.