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Relationship Between Cetuximab Target-Mediated Pharmacokinetics and Progression-Free Survival in Metastatic Colorectal Cancer Patients

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Abstract

Background and Objective

Cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal immunoglobulin (Ig)G1 antibody, has been approved for the treatment of metastatic colorectal cancer (mCRC). The influence of target-antigen on cetuximab pharmacokinetics has never been investigated using target-mediated drug disposition (TMDD) modelling. This study aimed to investigate the relationship between cetuximab concentrations, target kinetics and progression-free survival (PFS).

Methods

In this ancillary study (NCT00559741), 91 patients with mCRC treated with cetuximab were assessed. Influence of target levels on cetuximab pharmacokinetics was described using TMDD modelling. The relationship between cetuximab concentrations, target kinetics and time-to-progression (TTP) was described using a joint pharmacokinetic-TTP model, where unbound target levels were assumed to influence hazard of progression by an Emax model. Mitigation strategies of concentration-response relationship, i.e., time-varying endogenous clearance and mutual influences of clearance and time-to-progression were investigated.

Results

Cetuximab concentration-time data were satisfactorily described using the TMDD model with quasi-steady-state approximation and time-varying endogenous clearance. Estimated target parameters were baseline target levels (R0 = 43 nM), and complex elimination rate constant (kint = 0.95 day−1). Estimated time-varying clearance parameters were time-invariant component of CL (CL0= 0.38 L/day−1), time-variant component of CL (CL1= 0.058 L/day−1) and first-order rate of CL1 decreasing over time (kdes = 0.049 day−1). Part of concentration-TTP was TTP-driven, where clearance and TTP were inversely correlated. In addition, increased target occupancy was associated with increased TTP.

Conclusion

This is the first study describing the complex relationship between cetuximab target-mediated pharmacokinetics and PFS in mCRC patients using a joint PK-time-to-progression model. Further studies are needed to provide a more in-depth description of this relationship.

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Acknowledgements

The authors thank the investigators who included the patients in this study, Jean-Philippe Metges, Antoine Adenis, Jean-Luc Raoul, You Heng Lam, Roger Faroux, Claude Masliah, Virginie Berger and Erick Gamelin; Anne-Claire Duveau and Caroline Guerineau-Brochon for technical assistance with cetuximab assays, And Jean-Christophe Pages for his logistical help with the samples.

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Authors and Affiliations

  1. Inserm UMR 1069, Nutrition Croissance et Cancer (N2C), Tours University, Tours, France

    Sarah Lobet, Romain Chautard & Thierry Lecomte

  2. EA4245 Transplantation, Immunologie, Inflammation (T2i), Tours University, Tours, France

    Gilles Paintaud, Céline Desvignes & David Ternant

  3. Centre Pilote de suivi Biologique des traitements par Anticorps (CePiBAc), Tours University Hospital, Tours, France

    Gilles Paintaud, Céline Desvignes & David Ternant

  4. Pharmacology-Toxicology Department, Tours University Hospital, Tours, France

    Gilles Paintaud & David Ternant

  5. PRC, INRAe UMR85, CNRS UMR7247, Tours University, Nouzilly, France

    Nicolas Azzopardi

  6. Oncopharmacology-Pharmacogenetics Department INSERM U892, Institut de Cancérologie de l’Ouest site Paul Papin, Angers, France

    Christophe Passot & Olivier Capitain

  7. Gastroenterology and Digestive oncology Department, Tours University Hospital, Tours, France

    Morgane Caulet, Romain Chautard & Thierry Lecomte

  8. Gastroenterology Department, Poitiers University Hospital, Poitiers, France

    David Tougeron

  9. PRoDiCeT, Poitiers University, Poitiers, France

    David Tougeron

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  1. Sarah Lobet
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Corresponding author

Correspondence to David Ternant.

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Funding

This study was partly supported by the Higher Education and Research Ministry under the programme ‘Investissements d’avenir’ Grant Agreement: LabEx MAbImprove ANR-10-LABX-53-01.

Conflict of interest

Gilles Paintaud has received grants for his research team from Cytosorbents, Lilly, Novartis, Merck, Shire (Takeda) and Lundbeck. Morgane Caulet acted as a consultant for Lilly, Sanofi, Servier, Bayer, Amgen and Novartis. David Tougeron acted as a consultant for Pierre Fabre, Boehringer-Ingelheim, Novartis, Bristol Myers Squibb, Merck Sharp and Dohme, Roche, Merck Serono, Servier and Astra-Zeneca. Olivier Capitain acted as a consultant for Merck, MSD and BMS. Thierry Lecomte acted as a consultant for Novartis, Sanofi, Amgen, Servier, Merck Serono, Lilly, Ipsen Pharma, Pierre Fabre and Chugai Pharma. David Ternant acted as a consultant and has given lectures on behalf of his institution for Amgen, Boehringer Ingelheim, Novartis, Lundbeck and Astra-Zeneca. Sarah Lobet, Nicolas Azzopardi, Christophe Passot, Céline Desvignes, Romain Chautard have no conflict of interest to declare regarding the study.

Ethics approval and consent to participate

This study was registered in ClinicalTrials.gov database (NCT00559741) and was approved by the local ethics committee. Written informed consent was obtained from all patients.

Availability of data, material and code

Data, material and code are available on request to the corresponding author.

Author contributions

Sarah Lobet managed and analysed the data, interpreted the results and wrote the manuscript. David Ternant designed the research, analyzed the data, interpreted the results and reviewed the manuscript. Gilles Paintaud and Thierry Lecomte participated to data acquisition, interpreted the results and reviewed the manuscript. Nicolas Azzopardi and Morgane Caulet interpreted the results and reviewed the manuscript. Romain Chautard, Céline Desvignes, Christophe Passot, Olivier Capitain, and David Tougeron participated to data acquisition and reviewed the manuscript.

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Lobet, S., Paintaud, G., Azzopardi, N. et al. Relationship Between Cetuximab Target-Mediated Pharmacokinetics and Progression-Free Survival in Metastatic Colorectal Cancer Patients. Clin Pharmacokinet 62, 1263–1274 (2023). https://doi.org/10.1007/s40262-023-01270-2

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