Metronomic treatment of advanced non-small-cell lung cancer with daily oral vinorelbine – a Phase I trial

Abstract

Micro-abstractIn a Phase I dose-finding study of metronomic daily oral vinorelbine in advanced non-small-cell lung cancer, a recommended dose was established for this therapeutic approach. In addition, this trial revealed promising efficacy data and an acceptable tolerability profile. The observed vinorelbine blood concentrations suggest continuous anti-angiogenic coverage.IntroductionWe present a Phase I dose-finding study investigating metronomic daily oral vinorelbine (Navelbine® Oral, NVBo) in advanced non-small-cell lung cancer (NSCLC).Patients and methodsPatients with stage III/IV NSCLC received daily NVBo at fixed dose levels of 20–50 mg/d for 21 days of each 4-week cycle. Primary end point was the maximum tolerated dose. Secondary end points included tumor response, time to progression (TTP), overall survival (OS) and tolerability.ResultsTwenty-seven patients with advanced NSCLC were enrolled. Most of them were extensively pretreated. Daily NVBo was well tolerated up to 30 mg/d. At 40 mg/d, two of five patients experienced dose-limiting toxicities (DLTs). Three of six patients had DLTs at the 50 mg/d level. The recommended dose was established at 30 mg/d in cycle 1, with escalation to 40 mg/d in cycle 2, if tolerated. Pharmacokinetic analyses showed continuous blood exposure over 21 days and only marginal accumulation. The tolerability profile was acceptable (all dose levels – all grades: decreased appetite 33%, diarrhea 33%, leukopenia 33%, nausea 30%, vomiting 26%; ≥grade 3: leukopenia 30%, lymphopenia 19%, neutropenia 19%, febrile neutropenia 15%). Disease control rate, OS and TTP signaled a treatment effect.ConclusionDaily metronomic NVBo therapy in extensively pretreated patients with advanced NSCLC is feasible and safe at the recommended dose of 30 mg/d. Escalation to 40 mg/d in the second cycle is possible. The blood concentrations of vinorelbine after daily metronomic dosing reached lower peaks than intravenous or oral conventional dosing. Blood concentrations were consistent with anti-angiogenic or immune modulating pharmacologic properties of vinorelbine. Further studies are warranted to evaluate the safety and efficacy of this novel approach in specific patient populations.

An individual patient-data meta-analysis of metronomic oral vinorelbine in metastatic non-small cell lung cancer

“…The first step of the selection process identified fourteen studies that matched the selected MeSH terms (Fig 1). After careful analysis of each publication, four studies were found to be ineligible: the study by Elharrar X et al [14] investigated a mathematical model in a phase I study with various malignant diseases (pharmacological evaluation as primary endpoint); two studies (Rajdev L. et al 2011 and Guetz et al 2017) [15,16] used a daily administration of oral vinorelbine with a “week-on, week-off“schedule; one study was a redundant publication with fewer accrued patients in the first publication 17 than in the final publication (Briasoulis E. et al 2009 [17], n = 14; Briasoulis E. et al 2013, n = 31); finally, one study analyzing 26 patients, and published in mandarin seemed eligible according to the English abstract, albeit retrospective [18]. The authors were contacted in order to test feasibility of including their study in this individual patient-data metaanalysis but could not be reached despite repeated attempts.…”

Metronomic oral vinorelbine in previously untreated advanced non-small-cell lung cancer patients unfit for platinum-based chemotherapy: results of the randomized phase II Tempo Lung trial

“…The potential of metronomic chemotherapy has been assessed in various advanced cancer in preclinical and clinical studies. 8 , 12 , 13 , 22 , 23 In metastatic breast cancer, metronomic chemotherapy with vinorelbine is a treatment option. 24 Despite the availability of immunotherapy or targeted therapy agents as first-line treatment in advanced NSCLC, there are still NSCLC patients with advanced disease who may not be eligible for these treatments.…”

“…Therefore, it may be important in this challenging population composed of unfit advanced NSCLC patients to explore the use of oral metronomic chemotherapy over standard oral chemotherapy. 22 …”

Phase II study of metronomic treatment with daily oral vinorelbine as first-line chemotherapy in patients with advanced/metastatic HR+/HER2− breast cancer resistant to endocrine therapy: VinoMetro—AGO-B-046

“…The ease of oral VRL administration allows for flexible treatment schedules including a more frequent and metronomic dose application. Various schedules have been evaluated including a fractionated regimen (day 1, 3, 5) and daily intake (Adamo et al 2019;Addeo et al 2010;Guetz et al 2017). In patients with non-small-cell lung cancer, the daily administration of VRL up to 40 mg per day was welltolerated (Banna et al 2018;Guetz et al 2017).…”

“…Various schedules have been evaluated including a fractionated regimen (day 1, 3, 5) and daily intake (Adamo et al 2019;Addeo et al 2010;Guetz et al 2017). In patients with non-small-cell lung cancer, the daily administration of VRL up to 40 mg per day was welltolerated (Banna et al 2018;Guetz et al 2017). For these reasons, VinoMetro aimed to investigate a truly metronomic schedule with daily oral VRL in HR+/HER2− MBC patients following endocrine resistance, by assessing efficacy and safety of doses well below the maximum tolerated dose in advanced breast cancer patients with visceral metastases.…”