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

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.

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

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.