The CetuxIMAX protocol: a non-interventional, uncontrolled, and non-comparative multicentric study for exploring the pharmacokinetics/pharmacodynamics relationships of cetuximab in head and neck cancer patients
DOI:
https://doi.org/10.18203/2349-3259.ijct20233175Keywords:
Cetuximab, Pharmacokinetics, Head and neck cancer, ModellingAbstract
Background: In a previous pilot-study, a link between Cetuximab exposure levels (i.e., trough levels above 34 mg/ml) and clinical outcome in head and neck cancer patients was found. Considering the high inter-individual variability in Cetuximab plasma levels, lack of efficacy could thus be linked to inadequate exposure levels, rather than issues with signalling pathways at the tumor level.
Methods: The CetuxIMAX study is a non-interventional, uncontrolled, and non-comparative multicentric study in patients with recurrent or metastatic head and neck squamous cell carcinoma, and treated by any Cetuximab-based regimen. A total of 122 patients will be enrolled in this study. The primary endpoint is the estimation of receiver operating characteristic (ROC) and area under the ROC curve (AUROC) of Cetuximab trough plasma level for the disease control rate (DCR). Pharmacokinetics samples will be collected at first cycle, when steady-state is reached, and during maintenance phase to monitor the Cetuximab levels throughout time. Standard PK modelling using population-approach will be performed to identify individual PK parameters and enable further simulations of exposure levels throughout the different cycles. Univariate and multivariable statistical analysis aiming at exploring any association between Cetuximab exposure levels and clinical outcome will be performed.
Conclusions: Should the target therapeutic window associated with efficacy be confirmed with Cetuximab in head/neck cancer patients, this could pave the way for PK-guided dosing next. Based upon single point PK sampling, pop-PK modelling could help personalizing dosing or scheduling, to ensure an optimal toxicity-efficacy ratio with Cetuximab.
Trial Registration: Trial registration number is NCT 04218136.
References
Azzopardi N, Lecomte T, Ternant D, Boisdron-Celle M, Piller F, Morel A, et al. Cetuximab pharmacokinetics influences progression-free survival of metastatic colorectal cancer patients. Clin Cancer Res. 2011;17(19):6329-37.
Pointreau Y, Azzopardi N, Ternant D, Calais G, Paintaud G. Cetuximab Pharmacokinetics Influences Overall Survival in Patients With Head and Neck Cancer. Ther Drug Monit. 2016;38(5):567-72.
Becher F, Ciccolini J, Imbs DC, Marin C, Fournel C, Dupuis C, 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. Sci Rep. 2017;7(1):2714.
Zech HB, Laban S, Schafhausen P, Bussmann L, Betz C, Busch CJ. Treatment of head and neck squamous cell carcinoma recurrences and distant metastases: Highlights of the 2019 ASCO Meeting. HNO. 2019;67(12):898-904.
Guigay J, Aupérin A, Fayette J, Saada-Bouzid E, Lafond C, Taberna M, et al. Cetuximab, docetaxel, and cisplatin versus platinum, fluorouracil, and cetuximab as first-line treatment in patients with recurrent or metastatic head and neck squamous-cell carcinoma (GORTEC 2014-01 TPExtreme): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2021;22(4):463-75.
Marin C, Khoudour N, Millet A, Lebert D, Bros P, Thomas F, et al. Cross-Validation of a Multiplex LC-MS/MS Method for Assaying mAbs Plasma Levels in Patients with Cancer: A GPCO-UNICANCER Study. Pharmaceuticals (Basel). 2021;14(8):796.
European Medicines Agency. Bioanalytical method validation. European Medicines Agency. 2018. Available at: https://www.ema.europa.eu/en/ bioanalytical-method-validation. Accessed on 30 November 2020.
Posch D, Fuchs H, Kornek G, Grah A, Pammer J, Aretin MB, et al. Docetaxel plus cetuximab biweekly is an active regimen for the first-line treatment of patients with recurrent/metastatic head and neck cancer. Sci Rep. 2016;6:32946.
Lai CL, Chen TH, Chang PMH, Tai SK, Chu PY, Yang MH. Efficacy of cetuximab-containing regimens in the treatment of recurrent/metastatic head and neck cancer after progression to immune checkpoint inhibitors. J Chin Med Assoc. 2022;85(6):687-92.
Baselga J, Trigo JM, Bourhis J, Tortochaux J, Cortés-Funes H, Hitt R, et al. Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol. 2005;23(24):5568-77.
Knoedler M, Gauler TC, Gruenwald V, Matzdorff A, Schroeder M, Dietz A, et al. Phase II study of cetuximab in combination with docetaxel in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck after platinum-containing therapy: a multicenter study of the Arbeitsgemeinschaft Internistische Onkologie. Oncology. 2013;84(5):284-9.
Zhou XH, McClich DK, Obuchowski NA. Statistical Methods in Diagnostic Medecine. Second Edition. John Wiley & Sons, Inc. 2011.
Hanley JA, BMcNeil BJ. The meaning and Use of the Area under a Receiver Operating Characteristic (ROC) Curve. Radiology. 1982;143(1):29-36.
Heagerty PJ, Lumley T, Pepe MS. Time-dependent ROC curves for censored survival data and a diagnostic marker. Biometrics. 2000;56(2):337-44.
Ferrer F, Fanciullino R, Milano G, Ciccolini J. Towards Rational Cancer Therapeutics: Optimizing Dosing, Delivery, Scheduling, and Combinations. Clin Pharmacol Ther. 2020;108(3):458-70.
Vermorken JB, Herbst RS, Leon X, Amellal N, Baselga J. Overview of the efficacy of cetuximab in recurrent and/or metastatic squamous cell carcinoma of the head and neck in patients who previously failed platinum-based therapies. Cancer. 2008;112(12):2710-9.
Jin Z, Zhang B, Zhang L, Huang W, Mo X, Chen Q, et al. Immune-checkpoint inhibitor plus chemotherapy versus conventional chemotherapy for treatment of recurrent or metastatic head and neck squamous cell carcinoma: a systematic review and network meta-analysis. Ther Adv Med Oncol. 2020;12:1758835920983717.
Cézé N, Ternant D, Piller F, Degenne D, Azzopardi N, Dorval E, et al. An Enzyme-Linked Immunosorbent Assay for Therapeutic Drug Monitoring of Cetuximab. Therapeutic Drug Monitoring. 2009;31(5):597-601.
Maeda H, Hazama S, Iwamoto S, Oba K, Tsunedomi R, Okayama N, et al. Association between polymorphisms in EGFR and tumor response during cetuximab and oxaliplatin-based combination therapy in metastatic colorectal cancer: Analysis of data from two clinical trials. Oncol Lett. 2019;18(5):4555-62.
