A simple and rapid LC-MS/MS method for therapeutic drug monitoring of cetuximab: a GPCO-UNICANCER proof of concept study in head-and-neck cancer patients

Francois Becher (1, 2, 3, 4) , Joseph Ciccolini (5, 6, 7, 1) , Diane-Charlotte Imbs (1, 5, 6, 7) , Clemence Marin (1, 5, 6, 7) , Claire Fournel (8, 7) , Charlotte Dupuis (7) , Nicolas Fakhry (9) , Bertrand Pourroy (10) , Aurelie Ghettas (2, 3, 4) , Alain Pruvost (2, 3, 4) , Christophe Junot (2, 11) , Florence Duffaud (7) , Bruno Lacarelle (1, 5, 6, 7) , Sebastien Salas (7)

1 Groupe de Pharmacologie Clinique & Oncologique (GPCO)
2 LERI - Laboratoire d'Etudes et de Recherches en Immunoanalyses
3 CEA - Commissariat à l'énergie atomique et aux énergies alternatives
4 INRA - Institut National de la Recherche Agronomique
5 SMARTc unit - Simulation & Modelling : Adaptive Response for Therapeutics in Cancer
6 INSERM - Institut National de la Santé et de la Recherche Médicale
7 Medical Oncology Unit
8 TIMONE - Hôpital de la Timone [CHU - APHM]
9 LA CONCEPTION - Hôpital de la Conception [CHU - APHM]
10 Oncopharma
11 Université Paris-Saclay

Administration of first-in-class anti-EGFR monoclonal antibody cetuximab is contingent upon extensive pharmacogenomic testing. However in addition to tumor genomics, drug exposure levels could play a critical, yet largely underestimated role, because several reports have demonstrated that cetuximab pharmacokinetic parameters, in particular clearance values, were associated with survival in patients. Here, we have developed an original bioanalytical method based upon the use of LC-MS/MS technology and a simplified sample preparation procedure to assay cetuximab in plasma samples from patients, thus meeting the requirements of standard Therapeutic Drug Monitoring in routine clinical practice. When tested prospectively in a pilot study in 25 head-and-neck cancer patients, this method showed that patients with clinical benefit had cetixumab residual concentrations higher than non-responding patients (i.e., 49 +/- 16.3 mu g/ml VS. 25.8 +/- 17 mu g/ml, p < 0.01 t test). Further ROC analysis showed that 33.8 mu g/ml was the Cmin threshold predictive of response with an acceptable sensitivity (87%) and specificity (78%). Mass spectrometry-based therapeutic drug monitoring of cetuximab in head-and-neck cancer patients could therefore help to rapidly predict cetuximab efficacy and to adapt dosing if required.

Mots clés: oral cancer; translational research

Domaines: Sciences du Vivant [q-bio]

Francois Becher, Joseph Ciccolini, Diane-Charlotte Imbs, Clemence Marin, Claire Fournel, et al.. A simple and rapid LC-MS/MS method for therapeutic drug monitoring of cetuximab: a GPCO-UNICANCER proof of concept study in head-and-neck cancer patients. Scientific Reports, 2017, 7, ⟨10.1038/s41598-017-02821-x⟩. ⟨hal-01606760⟩