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

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.

Clinical Impact of High Throughput Sequencing on Liquid Biopsy in Advanced Solid Cancer.

BACKGROUND: Cancer therapies targeting actionable molecular alterations (AMA) have developed, but the clinical routine impact of high-throughput molecular profiling remains unclear. We present a monocentric experience of molecular profiling based on liquid biopsy in patients with cancer. METHODS: Patients included had solid cancer and underwent cfDNA genomic profiling with FoudationOne Liquid CDx (F1LCDx) test, analyzing 324 genes. Primary endpoint was to describe patients with an AMA for whom clinical decisions were impacted by F1LCDx test results. RESULTS: 191 patients were included, mostly with lung cancer (46%). An AMA was found in 52%. The most common molecular alterations were: TP53 (52%), KRAS (14%) and DNMT3 (11%). The most common AMA were: CHEK2 (10%), PIK3CA (9%), ATM (7%). There was no difference in progression-free survival (2.66 months vs. 3.81 months, p = 0.17), overall survival (5.3 months vs. 7.1 months, p = 0.64), or PFS2/PFS1 ratio ≥ 1.3 (20% vs. 24%, p = 0.72) between patients receiving a molecularly matched therapy (MMT) or a non-MMT, respectively. Patients with a MMT had an overall response rate of 19% and a disease control of 32%. CONCLUSIONS: Routine cfDNA molecular profiling is feasible and can lead to the access of targeted therapies. However, no notable benefit in patient's outcomes was shown in this unselected pan-cancer study.

Mathematical modeling for Phase I cancer trials: A study of metronomic vinorelbine for advanced non-small cell lung cancer (NSCLC) and mesothelioma patients.

INTRODUCTION: Using mathematical modelling allows to select a treatment's regimen across infinite possibilities. Here, we report the phase I assessment of a new schedule for metronomic vinorelbine in treating refractory advanced NSCLC and mesothelioma patients. RESULTS: Overall, 13 patients were screened and 12 were treated (50% male, median age: 68yrs), including 9 NSCLC patients. All patients received at least one week (3 doses) of treatment. At data cut-off, the median length of treatment was 6.5 weeks (1-32+). All the patients presented with at least one adverse event (AE) and six patients with a severe AE (SAE). One partial response and 5 stable diseases were observed. The median OS was 6.4 months (95% CI, 4.8 to 12 months). The median and mean vinorelbine's AUC were 122 ng/ml*h and 159 ng/ml*h, respectively, with the higher plasmatic vinorelbine exposure associated with the best ORR (difference of AUC comparison between responders and non-responders, p-value 0.017). MATERIALS AND METHODS: The mathematical modelling determined the administration of vinorelbine, 60 mg on Day 1, 30 mg on Day 2 and 60 mg on Day 4 weekly until progression, as the best schedule. Advanced NSCLC or mesothelioma patients progressing after standard treatment were eligible for the trial. NCT02555007. CONCLUSIONS: Responses with acceptable safety profile were observed in heavily pretreated NSCLC and mesothelioma patients using oral vinorelbine at this metronomic dosage based on a mathematic modeling. This study demonstrates the feasibility of this new type of approach, as mathematical modeling may help to rationally decide the better regimen to be clinically tested across infinite possibilities.