Revisiting metronomic vinorelbine with mathematical modelling: a Phase I trial in lung cancer.

Abstract

BACKGROUND:

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.

METHODS:

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

RESULTS:

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 efficacy, 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 efficacy, mixing baseline tumor size and NLR showing 84% selectivity and 75% specificity.

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 conflicting 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.

• Authors: Fabrice Barlesi, Laure Deyme, Diane-Charlotte Imbs, Elissa Cousin, Mathieu Barbolosi, Sylvanie Bonnet, Pascale Tomasini, Laurent Greillier, Melissa Galloux, Albane Testot-Ferry, Annick Pelletier, Nicolas André, Joseph Ciccolini, Dominique Barbolosi
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 90 Issue 2 Pg. 149-160 (08 2022) ISSN: 1432-0843 [Electronic] Germany
• PMID: 35867144 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Chemical References

• Vinblastine
• Vinorelbine

Topics

• Administration, Metronomic
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Carcinoma, Non-Small-Cell Lung (pathology)
• Humans
• Lung Neoplasms (pathology)
• Models, Theoretical
• Neutropenia (chemically induced, drug therapy)
• Vinblastine (therapeutic use)
• Vinorelbine (adverse effects)