Oral vinorelbine in metastatic breast cancer

Introduction

A new oral formulation of vinorelbine has been introduced in clinical studies since 1994, following increasing interest in the development of oral chemotherapy, driven by pharmacoeconomic issues, patient convenience and the potential for improved quality of life. A dose-finding study [1] established that 100 mg/m² was the MTD dose, limiting toxicities being neutropenia, nausea and vomiting, and neuroconstipation; the recommended dose was then defined at 80 mg/m² per week. The first phase II studies conducted in chemotherapy-naive NSCLC and as first-line chemotherapy in advanced breast cancer (ABC) showed an excessive rate of complicated neutropenia. This led to the formulation of a new schedule in which a lower dose of 60 mg/m² per week was administered for the first three courses with escalation to 80 mg/m², with a safety profile qualitatively comparable to that of intravenous vinorelbine at standard doses [2]. Equivalent blood concentrations were demonstrated between 80 mg/m² oral and 30 mg/m² intravenous, and between 60 mg/m² oral and 25 mg/m² intravenous [3].

Studies in metastatic breast cancer (MBC): single agent

A multicenter phase II trial assessed the activity, safety and pharmacokinetic profile of oral navelbine in ABC. Sixty-four patients were entered to receive oral NVB on a weekly basis for a total of 8 weeks unless progression or toxicity occurred. Oral vinorelbine was given at 60 mg/m² weekly for the first three administrations and was increased to 80 mg/m² for the subsequent administrations if there was no grade 4 neutropenia or no more than one episode of grade 3 neutropenia. Patients with objective response or stable disease continued treatment up to a total of 12 weeks or more. Fifty-eight evaluable patients were included. Four patients (6.9%) had complete responses and 14 (24.1%) had partial responses, for an overall response rate of 31% (95% confidence interval 19–43%). The median progression-free survival was 17.4 weeks, and the median overall survival was 22.9 months. There were no treatment-related deaths. The main toxicity was neutropenia: grade 4 in 17.2% of the patients, and 1.8% of administrations and associated clinical serious events in four patients (6.2%). Grade 3 and 4 nausea and/or vomiting were noted in 3.1% and 4.6% of the patients, respectively. Only one patient developed grade 3 neuroconstipation. An analysis of Quality of Life Questionnaire C30 forms revealed no significant alteration between baseline and weeks 8 and 16 in global quality of life. Oral navelbine as single agent in first-line MBC has the same efficacy of intravenous vinorelbine in phase II studies in terms of OR, duration of response, progression-free survival and overall survival, and is well tolerated with a manageable gastrointestinal toxicity (8% of G3-4 N/V without prophylactic antiemetic treatment) [5].

A second phase II trial is still ongoing. An interim analysis on the first 72 patients (median age 63 years) showed a similar toxicity profile with a RR of 30%, a median progression free-survival of 4.6 months and a median survival of 20.7 months.

Studies in MBC: combinations

The increasing prevalence of antracycline and taxane treatment in adjuvant setting led to an exploration of new combinations of non-cross-resistant therapies, in particular for those patients for which a polychemotherapy might offer greater benefits than single agents. In this setting the results of intravenous navelbine in combination with other drugs suggested new models in which to introduce the oral formulation.

Several phase II studies had investigated intravenous vinorelbine in association with capecitabine with a RR in second line >50% and with a mild toxicity. Only one phase II trial with this combination has been conducted as first-line chemotherapy, and it confirmed a good toxicity profile. The availability of oral formulations of both of these drugs led to investigation of their attractive combination, and preliminary results are now available from an ongoing phase II trial of vinorelbine oral plus capecitabine ± trastuzumab in MBC as first-line chemotherapy. Capecitabine is administered at the dose of 2000 mg/m² per day given days 1 to 14, and vinorelbine at the dose of 60 mg/m² on days 1 and 8 every 3 weeks for the first course, then escalated to 80 mg/m² from the second course. After 81 courses the incidence of G3 nausea/vomiting was 2.5%, G3 diarrhea 3.7%, grade 3 HFS 1.2%, and G3/4 neutropenia 13.5%. After 2 cycles the combination has revealed 4/16 CR-PR, 10/16 SD and 1/16 PD; and after 4 cycles 7/15 CR-PR and 7/15 SD. From these preliminary results this combination seems to be effective in the treatment of MBC previously treated with an anthracycline and/or a taxane with low toxicity.

Several studies have investigated the combination of intravenous navelbine and trastuzumab with an OR of 61–75%, demonstrating that this can be an effective and well tolerated option for HER2⁺ MBC. It is an important regimen, given the increasing prevalence of antracycline and taxane treatment in adjuvant setting.

Other sequential combinations of oral vinorelbine with paclitaxel or docetaxel or epirubicin are being explored, suggesting a possible role for the oral formulation in a sequential prolonged treatment in MBC.