Optimal Scheduling of Bevacizumab and Pemetrexed/Cisplatin Dosing in Non‐Small Cell Lung Cancer

Schneider, Benjamin; Boyer, Arnaud; Ciccolini, Joseph; Wang, Kenneth; Benzekry, Sébastien; Mochel, Jonathan P.

doi:10.1002/psp4.12415

Cited by 8 publications

(9 citation statements)

References 45 publications

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“…Tumor growth dynamics of two cell lines of breast cancer (HER2+ and Triple Negative) were modelled in the absence (unperturbed) or presence (perturbed) of MBQ-167 using the model proposed by Simeoni et al [ 10 ]. There is vast scientific evidence regarding the ability of the model to quantitatively characterize the time-course of tumor dynamics in xenograft experiments and evaluate the efficacy of anticancer drugs early in discovery and development [ 15 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. The mathematical framework allowed for an adequate prediction of the tumor dynamics under the different groups considered.…”

Section: Discussionmentioning

confidence: 99%

Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice

et al. 2020

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MBQ-167 is a dual inhibitor of the Rho GTPases Rac and Cdc42 that has shown promising results as an anti-cancer therapeutic at the preclinical stage. This drug has been tested in vitro and in vivo in metastatic breast cancer mouse models. The aim of this study is to develop a physiologically based pharmacokinetic/pharmacodynamic (PBPK-PD) model of MBQ-167 to predict tumor growth inhibition following intraperitoneal (IP) administration in mice bearing Triple Negative and HER2+ mammary tumors. PBPK and Simeoni tumor growth inhibition (TGI) models were developed using the Simcyp V19 Animal Simulator. Our developed PBPK framework adequately describes the time course of MBQ-167 in each of the mouse tissues (e.g., lungs, heart, liver, kidneys, spleen, plasma) and tumor, since the predicted results were consistent with the experimental data. The developed PBPK-PD model successfully predicts tumor shrinkage in HER2+ and triple-negative breast tumors after the intraperitoneal administration of 1 and 10 mg/kg body weight (BW) dose level of MBQ-167 three times a week. The findings from this study suggest that MBQ-167 has a higher net effect and potency inhibiting Triple Negative mammary tumor growth compared to HER2+ and that liver metabolism is the major route of elimination of this drug.

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Section: Discussionmentioning

confidence: 99%

Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice

et al. 2020

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“…We are also aware that balancing out unmeasurable differences in patient outcome through randomization is not always achieved with confidence in trials with a relatively small sample size, as in our study. In addition, we cannot definitively rule out that a different interval between bevacizumab and chemotherapy could improve the efficacy of combination treatment …”

Section: Discussionmentioning

confidence: 99%

Effect of Bevacizumab in Combination With Standard Oxaliplatin-Based Regimens in Patients With Metastatic Colorectal Cancer

et al. 2021

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IMPORTANCE Although bevacizumab is a standard of care in combination treatments for metastatic colorectal cancer (mCRC), its clinical benefit has been limited. OBJECTIVE To determine whether sequential scheduling of bevacizumab administration in combination with chemotherapy improves treatment efficacy in patients with mCRC, in keeping with the tumor vascular normalization hypothesis. DESIGN, SETTING, AND PARTICIPANTS This open-label, randomized clinical phase 3 trial was

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“…Mathematical modeling has been used to define the normalization window for increased perfusion after bevacizumab administration, a period in which the release of a cytotoxic drug could be increased. In this way, the optimal schedule for sequential administration of bevacizumab and pemetrexed-cisplatin in human NSCLC xenograft model has been defined [88] and scaled for use in humans [89]. A mathematical model has also been used to assess the value of metronomic therapy in a vascular normalization strategy [90].…”

Section: Cellular Components Of Thementioning

confidence: 99%

Metronomic Anti-Cancer Therapy: A Multimodal Therapy Governed by the Tumor Microenvironment

Muñoz

Girotti

Hileeto

et al. 2021

Cancers

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The concept of cancer as a systemic disease, and the therapeutic implications of this, has gained special relevance. This concept encompasses the interactions between tumor and stromal cells and their microenvironment in the complex setting of primary tumors and metastases. These factors determine cellular co-evolution in time and space, contribute to tumor progression, and could counteract therapeutic effects. Additionally, cancer therapies can induce cellular and molecular responses in the tumor and host that allow them to escape therapy and promote tumor progression. In this study, we describe the vascular network, tumor-infiltrated immune cells, and cancer-associated fibroblasts as sources of heterogeneity and plasticity in the tumor microenvironment, and their influence on cancer progression. We also discuss tumor and host responses to the chemotherapy regimen, at the maximum tolerated dose, mainly targeting cancer cells, and a multimodal metronomic chemotherapy approach targeting both cancer cells and their microenvironment. In a combination therapy context, metronomic chemotherapy exhibits antimetastatic efficacy with low toxicity but is not exempt from resistance mechanisms. As such, a better understanding of the interactions between the components of the tumor microenvironment could improve the selection of drug combinations and schedules, as well as the use of nano-therapeutic agents against certain malignancies.

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Optimal Scheduling of Bevacizumab and Pemetrexed/Cisplatin Dosing in Non‐Small Cell Lung Cancer

Cited by 8 publications

References 45 publications

Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice

Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice

Effect of Bevacizumab in Combination With Standard Oxaliplatin-Based Regimens in Patients With Metastatic Colorectal Cancer

Metronomic Anti-Cancer Therapy: A Multimodal Therapy Governed by the Tumor Microenvironment

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