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

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 at investigating the exposure-response relationships of bevacizumab in mCRC patients while mitigating potential biases. Bevacizumab pharmacokinetics was described using target-mediated drug disposition (TMDD) modeling. Relationships between target kinetics, and progression-free (PFS) and overall (OS) survivals were assessed using joint pharmacokinetic and parametric hazard function models. Both potential biases due to prognostic-driven and response-driven of the concentration-effect relationship were mitigated. These models evaluated the impact of increased antigen target levels,clearance, and intensified dosing regimen on survival. Estimated target-mediated pharmacokinetic parameters in 130 assessed patients were baseline target levels (R =8.4 nM), steady-state dissociation constant (K =10 nM) and antibody-target complexes elimination constant (k =0.52 day ). The distribution of R was significantly associated with increased baseline concentrations of carcinoembryonic antigen, circulating Vascular Endothelial Growth Factor, and the presence of extra-hepatic 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. 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 target amount may be tumoral in mCRC. Future studies should provide a more in-depth description of this relationship.