TY - JOUR
T1 - Revisiting metronomic vinorelbine with mathematical modelling
T2 - a Phase I trial in lung cancer
AU - Barlesi, Fabrice
AU - Deyme, Laure
AU - Imbs, Diane Charlotte
AU - Cousin, Elissa
AU - Barbolosi, Mathieu
AU - Bonnet, Sylvanie
AU - Tomasini, Pascale
AU - Greillier, Laurent
AU - Galloux, Melissa
AU - Testot-Ferry, Albane
AU - Pelletier, Annick
AU - André, Nicolas
AU - Ciccolini, Joseph
AU - Barbolosi, Dominique
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2022/8/1
Y1 - 2022/8/1
N2 - 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.
AB - 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.
KW - Lung cancer
KW - Mathematical modelling
KW - Mesothelioma
KW - Metronomic
KW - Vinorelbine
UR - http://www.scopus.com/inward/record.url?scp=85134540592&partnerID=8YFLogxK
U2 - 10.1007/s00280-022-04455-x
DO - 10.1007/s00280-022-04455-x
M3 - Article
C2 - 35867144
AN - SCOPUS:85134540592
SN - 0344-5704
VL - 90
SP - 149
EP - 160
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 2
ER -