Revisiting Bevacizumab + Cytotoxics Scheduling Using Mathematical Modeling: Proof of Concept Study in Experimental Non‐Small Cell Lung Carcinoma

Imbs, D; Cheikh, Raouf El; Boyer, Arnaud; Ciccolini, Joseph; Mascaux, Céline; Lacarelle, Bruno; Barbolosi, Dominique; Benzekry, Sébastien

doi:10.1002/psp4.12265

Cited by 19 publications

(39 citation statements)

References 47 publications

(95 reference statements)

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“…During structural model building, we confirmed the validity of the model previously published in Imbs et al . We also reconfirmed the efficacy improvement of BEV‐PEM/CIS dosing over PEM/CIS or control.…”

Section: Discussionsupporting

confidence: 91%

“…After a period of manual exploration, k was set to the value of 0.3. This choice is consistent with the parameterization made in Imbs et al . This choice also limits the total transition time from the tumor mass compartment to cellular death to the order of a day, which is consistent with the upper limits of cellular death clearance …”

Section: Resultssupporting

confidence: 78%

“…The next stage of this study consisted of determining whether the semimechanistic model of tumor dynamics in response to BEV‐PEM/CIS developed in Imbs et al . best fit the unfit fluorescence data from the same study.…”

Section: Discussionmentioning

confidence: 99%

“…Comprehensive details on the animals and the experimental procedure are available in Imbs et al . Briefly, on day 0 of the experiment, tumors (ca.…”

Section: Methodsmentioning

confidence: 99%

“…16 Previous studies on BEV-PEM/CIS suggest that the sequential administration of BEV-PEM/CIS (i.e., BEV before PEM/CIS) outperforms concomitant scheduling of BEV-PEM/CIS in treating NSCLC. 11,[17][18][19] This makes BEV-PEM/CIS an attractive target for scheduling optimization via modeling and simulation, as a range of practical predictions-such as optimal scheduling in humans-can be made without the considerable time and resource investment required to conduct in vivo experiments. These predictions can be used to guide future studies, greatly accelerating drug development.…”

Section: Study Highlightsmentioning

confidence: 99%

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

Schneider

Boyer

Ciccolini

et al. 2019

CPT Pharmacom & Syst Pharma

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Bevacizumab‐pemetrexed/cisplatin ( BEV ‐ PEM / CIS ) is a first‐line therapeutic for advanced nonsquamous non‐small cell lung cancer. Bevacizumab potentiates PEM / CIS cytotoxicity by inducing transient tumor vasculature normalization. BEV ‐ PEM / CIS has a narrow therapeutic window. Therefore, it is an attractive target for administration schedule optimization. The present study leverages our previous work on BEV ‐ PEM / CIS pharmacodynamic modeling in non‐small cell lung cancer–bearing mice to estimate the optimal gap in the scheduling of sequential BEV ‐ PEM / CIS . We predicted the optimal gap in BEV ‐ PEM / CIS dosing to be 2.0 days in mice and 1.2 days in humans. Our simulations suggest that the efficacy loss in scheduling BEV ‐ PEM / CIS at too great of a gap is much less than the efficacy loss in scheduling BEV ‐ PEM / CIS at too short of a gap.

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Section: Discussionsupporting

confidence: 91%

Section: Resultssupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

“…Comprehensive details on the animals and the experimental procedure are available in Imbs et al . Briefly, on day 0 of the experiment, tumors (ca.…”

Section: Methodsmentioning

confidence: 99%

Section: Study Highlightsmentioning

confidence: 99%

See 3 more Smart Citations

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

Schneider

Boyer

Ciccolini

et al. 2019

CPT Pharmacom & Syst Pharma

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Whole-Brain Radiotherapy Alone vs Preceded by Bevacizumab, Etoposide, and Cisplatin for Untreated Brain Metastases From Breast Cancer

Chen,

Dai,

Tseng

et al. 2024

JAMA Oncol

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ImportanceThe incidence of brain metastasis is increasing in patients with metastatic breast cancer. Treatments to extend the control of brain metastasis are urgently required.ObjectiveTo investigate whether the addition of an induction treatment of bevacizumab, etoposide, and cisplatin (BEEP) improves brain-specific progression-free survival (PFS) after whole-brain radiotherapy (WBRT).Design, Setting, and ParticipantsThis open-label, randomized, multicenter clinical trial assessed patients with brain metastases from breast cancer (BMBC) in Taiwan from September 9, 2014, to December 24, 2018, with survival follow-up until December 31, 2021. Key inclusion criteria included metastatic brain tumors not suitable for focal treatment, WBRT naivety, age 20 to 75 years, and at least 1 measurable brain metastatic lesion. The primary end point was brain-specific PFS, with an expected hazard ratio of 0.60, a 2-sided α ≤ .20, and power of 0.8.InterventionsEligible patients were randomly assigned at a ratio of 2:1 to the experimental arm, which involved 3 cycles of BEEP followed by WBRT, or the control arm, which involved WBRT alone.Main Outcomes and MeasuresThe primary end point was the determination of brain-specific PFS by local investigators according to the Response Evaluation Criteria in Solid Tumors, version 1.1, the initiation of other brain-directed treatment after WBRT, or death. Other key end points included brain-specific objective response rate after 8 weeks of BEEP treatment or WBRT and 8-month brain-specific PFS rate, PFS, and overall survival.ResultsA total of 118 patients with BMBC were randomized, with the intention-to-treat cohort comprising 112 patients. The median age was 56 years (range, 34-71 years), and 61 patients (54.5%) had ERBB2 (formerly HER2 or HER2/neu)-positive disease. The median (range) brain-specific PFS was 8.1 (0.3-29.5) vs 6.5 (0.9-25.5) months in the experimental and control arms, respectively (hazard ratio, 0.71; 95% CI, 0.44-1.13; P = .15; significant at predefined α ≤ .20). The brain-specific objective response rate at 2 months was not significantly different (BEEP treatment vs WBRT, 41.9% vs 52.6%), but the 8-month brain-specific PFS rate was significantly higher in the experimental group (48.7% vs 26.3%; P = .03). Adverse events were generally manageable with prophylactic granulocyte colony-stimulating factor treatment.Conclusions and RelevanceThe findings show that induction BEEP before WBRT may improve the control of BMBC compared with using upfront WBRT, which could address an unmet need for an effective systemic treatment for intractable brain and extracranial metastases from metastatic breast cancer.Trial RegistrationClinicalTrials.gov Identifier: NCT02185352

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Angiogenic inhibitor pre‐administration improves the therapeutic effects of immunotherapy

et al. 2023

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In lung cancer, immune checkpoint inhibitors (ICIs) are often inadequate for tumor growth inhibition. Angiogenic inhibitors (AIs) are required to normalize tumor vasculature for improved immune cell infiltration. However, in clinical practice, ICIs and cytotoxic antineoplastic agents are simultaneously administered with an AI when tumor vessels are abnormal. Therefore, we examined the effects of pre‐administering an AI for lung cancer immunotherapy in a mouse lung cancer model. Using DC101, an anti‐vascular endothelial growth factor receptor 2 (VEGFR2) monoclonal antibody, a murine subcutaneous Lewis lung cancer (LLC) model was used to determine the timing of vascular normalization. Microvessel density (MVD), pericyte coverage, tissue hypoxia, and CD8‐positive cell infiltration were analyzed. The effects of an ICI and paclitaxel after DC101 pre‐administration were investigated. On Day 3, increased pericyte coverage and alleviated tumor hypoxia represented the highest vascular normalization. CD8+ T‐cell infiltration was also highest on Day 3. When combined with an ICI, DC101 pre‐administration significantly reduced PD‐L1 expression. When combined with an ICI and paclitaxel, only DC101 pre‐administration significantly inhibited tumor growth, but simultaneous administration did not. AI pre‐administration, and not simultaneous administration, may increase the therapeutic effects of ICIs due to improved immune cell infiltration.

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Revisiting Bevacizumab + Cytotoxics Scheduling Using Mathematical Modeling: Proof of Concept Study in Experimental Non‐Small Cell Lung Carcinoma

Cited by 19 publications

References 47 publications

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

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

Whole-Brain Radiotherapy Alone vs Preceded by Bevacizumab, Etoposide, and Cisplatin for Untreated Brain Metastases From Breast Cancer

Angiogenic inhibitor pre‐administration improves the therapeutic effects of immunotherapy

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