The trough levels of bevacizumab significantly affect the outcome of the treatment in patients with metastatic colorectal cancer: A Turkish Oncology Group study.

Akbulut, Hakan; Ocal, Muge; Sonugur, Fatma Gizem; Abgarmi, Samira Abdi; Babahan, Cansu; Akay, B.; Arslan, Ulku Yalcintas; Artaç, Mehmet; Şendur, Mehmet Ali Nahit; Demirkazık, Ahmet

doi:10.1200/jco.2018.36.15_suppl.e15553

Cited by 4 publications

(3 citation statements)

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“…The total plasma or serum VEGF concentration is used as an in vivo marker, and to date, its true association with the efficacy of bevacizumab for treating cancer in humans is uncertain, as the results of studies assessing the predictive value of serum VEGF levels for treatment outcomes have been not consistent ( Presta et al, 1997 ; Bernaards et al, 2010 ; Tang et al, 2016 ). Aiming to find biomarkers, several studies have investigated the exposure–response relationship of bevacizumab, exploring trough concentrations associated with a threshold for treatment efficacy ( Nugue et al, 2013 ; Caulet et al, 2016 ; Akbulut et al, 2018 ; Papachristos et al, 2020 ), and most of the research has focused on metastatic colorectal cancer, with little to no published data from investigations of bevacizumab’s exposure–response relationship in the treatment of advanced NSCLC.…”

Section: Introductionmentioning

confidence: 99%

Exposure–response analysis using time-to-event data for bevacizumab biosimilar SB8 and the reference bevacizumab

Park,

Jung,

et al. 2024

Front. Pharmacol.

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Purpose: This analysis aimed to characterize the exposure–response relationship of bevacizumab in non-small-cell lung cancer (NSCLC) and evaluate the efficacy of SB8, a bevacizumab biosimilar, and Avastin®, the reference bevacizumab sourced from the European Union (EU), based on the exposure reported in a comparative phase III efficacy and safety study (EudraCT, 2015-004026-34; NCT 02754882).Materials and methods: The overall survival (OS) and progression-free survival (PFS) data from 224 patients with steady-state trough concentrations (Css,trough) were analyzed. A parametric time-to-event (TTE) model was developed using NONMEM®, and the effects of treatments (SB8 and bevacizumab-EU) and patient demographic and clinical covariates on OS and PFS were evaluated. Simulations of median OS and PFS by bevacizumab Css,trough were conducted, and concentrations required to achieve 50% and 90% of the maximum median TTE were computed.Results: A log-logistics model with Css,trough best described the OS and PFS data. Treatment was not a predictor of the hazard for OS or PFS. Simulations revealed steep exposure–response curves with a phase of rapid rise before saturating to a plateau. The median Css,trough values of SB8 and bevacizumab-EU reported from the clinical study were on the plateaus of the exposure–response curves. The concentrations required to achieve 50% and 90% of the maximum effect were 82.4 and 92.2 μg/mL, respectively, for OS and 79.7 and 89.1 μg/mL, respectively, for PFS.Conclusion: Simulations based on the constructed TTE models for OS and PFS have well described the exposure–response relationship of bevacizumab in advanced NSCLC. The analysis demonstrated comparable efficacy between SB8 and bevacizumab-EU in terms of OS and PFS based on their exposure levels.

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Section: Introductionmentioning

confidence: 99%

Exposure–response analysis using time-to-event data for bevacizumab biosimilar SB8 and the reference bevacizumab

Park,

Jung,

et al. 2024

Front. Pharmacol.

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“…Therefore, a positive exposure-response relationship suggests that longer overall (OS) and/or progression-free (PFS) survivals are associated with higher exposure, as identified for the bevacizumab in several studies. [3][4][5][6] However, recent studies have shown that the actual relationship is more complex, [7][8][9] which might challenge the usual strategies of description and interpretation of exposure-response analysis for mAbs in oncology. 2 The mAb exposure-response relationship may be confounded by various factors, 1,10,11 notably baseline disease status 3 and time-varying phenomena such as target engagement 12 and disease improvement 13 (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…In general, it is assumed that the exposure‐response relationship is a one‐way connection wherein clinical response is driven by exposure. Therefore, a positive exposure‐response relationship suggests that longer overall (OS) and/or progression‐free (PFS) survivals are associated with higher exposure, as identified for the bevacizumab in several studies 3–6 . However, recent studies have shown that the actual relationship is more complex, 7–9 which might challenge the usual strategies of description and interpretation of exposure‐response analysis for mAbs in oncology 2 …”

Section: Introductionmentioning

confidence: 99%

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

Lobet,

Caulet,

Paintaud

et al. 2023

Brit J Clinical Pharma

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AimsThe 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.MethodsBevacizumab 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.ResultsEstimated 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.ConclusionThis 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.

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Assessment of exposure-response relationship for bevacizumab in patients with metastatic colorectal cancer

Peña-Cabia

Vicente

Díaz³

et al. 2021

Biomedicine & Pharmacotherapy

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The trough levels of bevacizumab significantly affect the outcome of the treatment in patients with metastatic colorectal cancer: A Turkish Oncology Group study.

Cited by 4 publications

References 0 publications

Exposure–response analysis using time-to-event data for bevacizumab biosimilar SB8 and the reference bevacizumab

Exposure–response analysis using time-to-event data for bevacizumab biosimilar SB8 and the reference bevacizumab

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

Assessment of exposure-response relationship for bevacizumab in patients with metastatic colorectal cancer

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