Metronomics Global Health Initiative

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Revisiting metronomic vinorelbine with mathematical modelling:

We are delighted to share our latest publication entitled : Revisiting metronomic vinorelbine with mathematical modelling: a Phase I trial in lung cancer that as just been published in Cancer Chemotherapy and Pharmacology by Barlesi and al. from Marseille Early Phases Cancer Trials Center CLIP2, the SMARTc Unit Centre de Recherche en Cancérologie de Marseille Inserm U1068, Aix Marseille University, Marseille, , Gustave Roussy Cancer Campus, Villejuif, France and Metronomics Global Health Initiative, Marseille, France

It report on a phase Ia/Ib trial of metronomic oral vinorelbine (MOV) driven by a mathematical model was performed in heavily pretreated metastatic Non-Small Cell Lung Cancer or Pleural Mesothelioma patients. Disease Control Rate, progression free survival, toxicity and PK/PD were the main endpoints.

The best MOV scheduling was selected using a simplifed phenomenological, semi-mechanistic model with a total weekly dose of 150-mg vinorelbine. Computation of individual PK parameters was performed using population approach.

The mathematical model proposed the following metronomic schedule for a 150-mg weekly dose of vinorelbine: 60 mg D1, 30 mg D2, 60 mg D4. A total of 37 heavily pre-treated patients (30 evaluable) were enrolled. Grade III/IV neutropenia was observed in 30% patients. Median PFS was 11 weeks. Disease Control Rate was 73% (i.e.; 13% partial response and 60% stable disease). A large variability in drug exposure (AUC0-24 h: 53%) and PK parameters (Cl: 83%) were observed among patients. Simulated trough levels after D2 and D4 showed similarly 56–73% variability among patients. Drug exposure was not associated with efcacy, but neutropenia was more frequent in patients with AUC>250 ng/ml.h. Tumor burden, performance status and neutrophils-to-lymphocyte ratio (NLR) were associated with PFS, suggesting that MOV would be indicated in selected patients. We built a composite score to predict efcacy, mixing baseline tumor size and NLR showing 84% selectivity and 75% specifcity. Conclusions : MOV was characterized by important variability in drug exposure among patients. However, and despite being all heavily pre-treated, 73% of disease control rate and 11 weeks PFS were achieved with manageable toxicities. PK/PD relationships yielded conficting results depending on the initial tumor burden and BSA, suggesting that patients should be carefully selected prior to be scheduled for metronomic regimen. Possible role NLR could play as a predictive marker suggests immunomodulating features with MOV.