Abstract 425P
Background
Cetuximab (ERBITUX®), an anti-EGFR monoclonal antibody, has been approved for the treatment of metastatic colorectal cancer (mCRC). The pharmacokinetics (PK) of cetuximab has a nonlinear elimination due to the turnover of EGFR. (1) Target-mediated drug disposition (TMDD) models (2,3) have been commonly used to describe target-mediated pharmacokinetics (TMPK) of monoclonal antibodies.
This study aimed at investigating TMPK of cetuximab, the relationship between the target occupancy (TO) of EGFR and progression free survival (PFS), and the impact of dosage adjustments.
Methods
Ninety-one patients with mCRC were enrolled in a retrospective multicenter phase II study evaluating FOLFIRI-cetuximab regimens (4). Patients received cetuximab as an infusion with a loading dose of 400 mg/m2 followed by weekly infusions of 250 mg/m2. Concentration-time data were analysed using a population target-mediated drug disposition (TMDD) model. The association between TO and PFS was investigated by using Kaplan-Meier methods and Cox proportionnal-hazards models (5). Several dosing strategies based on increased injection schedule were simulated.
Results
Cetuximab PK data were satisfactorily described using TMDD model. Median PFS of included patients (n=91) was 6,4 months (95% CI : 4,1-7,4 months). A relationship between EGFR concentration (R) and PFS was significant after the first administration (p=0.019) and at steady state (p=0.0012). The target occupancy reached at 250mg/m2 QW and 500mg/m2 Q2W was similar (99.96% vs 99.98%).
Conclusions
This is the first study describing TMPK of cetuximab using a QSS TMDD model. Our model allowed quantifying EGFR kinetics over time, which was associated to PFS. Our simulations suggested that a 500mg/m2 Q2W regimen could be used instead of 250mg/m2 QW in some patients. This dosing regimen would lead to the same efficacy with fewer constraints in terms of administration for patients.
Clinical trial identification
NCT00559741.
Editorial acknowledgement
Legal entity responsible for the study
Université de Tours.
Funding
Labex MabImprove, région Centre-Val de Loire.
Disclosure
T. Lecomte: Financial Interests, Institutional, Principal Investigator: Ipsen; Astellas; Erythec Pharma; AstraZeneca; Financial Interests, Personal, Advisory Board: Ipsen; Amgen; Servier; Sanofi; Merck Serono. All other authors have declared no conflicts of interest.