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. 2024 Apr;90(4):976-986.
doi: 10.1111/bcp.15983. Epub 2023 Dec 29.

Confounding mitigation for the exposure-response relationship of bevacizumab in colorectal cancer patients

Sarah Lobet  1 , Morgane Caulet  2 , Gilles Paintaud  3   4 , Nicolas Azzopardi  5 , Céline Desvignes  3   4 , Romain Chautard  1   2 , Christophe Borg  6 , Olivier Capitain  7 , Aurélie Ferru  8 , Olivier Bouché  9 , Thierry Lecomte  1   2 , David Ternant  3   4
Affiliations
Free article

Confounding mitigation for the exposure-response relationship of bevacizumab in colorectal cancer patients

Sarah Lobet et al. Br J Clin Pharmacol. 2024 Apr.
Free article

Abstract

Aims: The exposure-response relationship of bevacizumab may be confounded by various factors, including baseline characteristics, time-dependent target engagement and recursive relationships between exposure and response, requiring effective mitigation. This study aimed to investigate the exposure-response relationships of bevacizumab in metastatic colorectal cancer (mCRC) patients while mitigating potential biases.

Methods: Bevacizumab pharmacokinetics was described using target-mediated drug disposition modelling. Relationships between target kinetics, progression-free (PFS) and overall (OS) survivals were assessed using joint pharmacokinetic and parametric hazard function models. Both prognostic-driven and response-driven potential biases were mitigated. These models evaluated the impact of increased antigen target levels, clearance and intensified dosing regimen on survival.

Results: Estimated target-mediated pharmacokinetic parameters in 130 assessed patients were baseline target levels (R0 = 8.4 nM), steady-state dissociation constant (KSS = 10 nM) and antibody-target complexes elimination constant (kint = 0.52 day-1). The distribution of R0 was significantly associated with increased baseline concentrations of carcinoembryonic antigen, circulating vascular endothelial growth factor and the presence of extrahepatic metastases. Unbound target levels (R) significantly influenced both progression and death hazard functions. Increasing baseline target levels and/or clearance values led to decreased bevacizumab unbound concentrations, increased R levels and shortened PFS and OS, while increasing bevacizumab dose led to decreased R and longer survival.

Conclusion: This study is the first to demonstrate the relationship between bevacizumab concentrations, target involvement and clinical efficacy by effectively mitigating potential sources of bias. Most of the target amount may be tumoural in mCRC. Future studies should provide a more in-depth description of this relationship.

Trial registration: ClinicalTrials.gov NCT00489697.

Keywords: bevacizumab; exposure‐response relationship; metastatic colorectal cancer; pharmacokineticstarget‐mediated drug disposition.

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Conflict of interest statement

Morgane Caulet acted as a consultant for Lilly, Sanofi, Servier, Bayer, Amgen and Novartis. Gilles Paintaud has received grants for his research team from Roche Pharma, Chugai, Pfizer, Novartis and Sanofi-Genzyme. 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 Astra-Zeneca, Amgen, Boehringer-Ingelheim and Novartis. Christophe Borg acted as a consultant for and received fees from Bayer, Daichi Sankyo, Janssen-Cilag, MSD, Pierre Fabre, Sanofi-Aventis and Servier. Aurélie Ferru acted as a consultant and received fees from Amgen, Ipsen, Merck Serono, Novartis, Roche, Sanofi-Aventis and Servier. Olivier Bouché acted as a consultant and has given lectures for Amgen, Apmomia Therapeutics, Bayer, Pierre Fabre, Servier, Merck Sereno and MSD outside the submitted work. Sarah Lobet, Nicolas Azzopardi, Céline Desvignes, Romain Chautard have no conflict of interest to declare regarding the study.

References

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