Cetuximab pharmacokinetic/pharmacodynamics relationships in advanced head and neck carcinoma patients
Open Access
- 27 February 2019
- journal article
- research article
- Published by Wiley in British Journal of Clinical Pharmacology
- Vol. 85 (6), 1357-1366
- https://doi.org/10.1111/bcp.13907
Abstract
Aims Cetuximab associated with cisplatin and 5‐fluorouracil is used to treat patients with inoperable or metastatic head and neck squamous cell carcinomas (HNSCC) up until disease progression or unacceptable toxicities. To date, no biomarkers of efficacy are available to select patients who will benefit from treatment. Methods An ancillary pharmacokinetics (PK) exploration was performed in the context of a prospective study investigating circulating‐tumour cells vs progression‐free survival (PFS). Cetuximab plasma concentrations were analysed according to a population PK model. Individual exposure parameters were confronted with soluble epidermal growth factor receptor (sEGFR) concentrations, tumour response and PFS. Results PK data (28 patients, 203 observations) were best described by a two‐compartment model with linear elimination. Performance status (PS) significantly correlated to both cetuximab clearance and central volume of distribution with both parameters increasing by 33.3% (95% CI 1–65.6) for each 1‐point increase of PS compared to PS = 0. Univariate analysis showed that patients with higher trough cetuximab concentrations at Day 7 (Cmin,D7) had better tumour response (P = 0.03) and longer PFS (P = 0.035). However, multivariate analysis revealed that only PS and tumour size at baseline remained significantly associated with PFS. Levels of sEGFR increased during cetuximab treatment but were not associated with PFS in the multivariate analysis. Conclusions Our study prospectively indicates that PS is likely a confounding factor in the relationship between cetuximab PK and PFS, patients with a poor PS having lower cetuximab plasma exposure and lower PFS.Keywords
Funding Information
- Fondation ARC pour la Recherche sur le Cancer (PAIR VADS 2011)
- Institut National Du Cancer
This publication has 27 references indexed in Scilit:
- Pathology of Head and Neck Cancer I: Epithelial and Related TumorsPublished by Springer Science and Business Media LLC ,2013
- Cancer incidence and mortality patterns in Europe: Estimates for 40 countries in 2012European Journal Of Cancer, 2013
- Cetuximab Pharmacokinetics Influences Progression-Free Survival of Metastatic Colorectal Cancer PatientsClinical Cancer Research, 2011
- Analysis of the Prognostic Value of Soluble Epidermal Growth Factor Receptor Plasma Concentration in Advanced Non–Small-Cell Lung Cancer PatientsClinical Lung Cancer, 2011
- Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck: EXTREME studyAnnals of Oncology, 2010
- Platinum-Based Chemotherapy plus Cetuximab in Head and Neck CancerNew England Journal of Medicine, 2008
- Population Pharmacokinetics of Cetuximab in Patients With Squamous Cell Carcinoma of the Head and NeckThe Journal of Clinical Pharmacology, 2008
- Serum epidermal growth factor receptor and HER2 expression in primary and metastatic breast cancer patientsBreast Cancer Research, 2007
- Alteration of the serum levels of the epidermal growth factor receptor and its ligands in patients with non-small cell lung cancer and head and neck carcinomaBritish Journal of Cancer, 2007
- A Phase 1 Escalating Single-Dose and Weekly Fixed-Dose Study of Cetuximab: Pharmacokinetic and Pharmacodynamic Rationale for DosingClinical Cancer Research, 2007