Study was stopped before progressive disease or death of alive subjects.

The combination of vinflunine and gemcitabine in advanced breast cancer in comparison to paclitaxel and gemcitabine is based on the following points: the significant antitumour activity of vinflunine in metastatic breast cancer (MBC) as single agent after anthracycline-taxane exposure and recent phase I study results of the vinflunine plus gemcitabine is at least additive and both drugs have a distinct mechanism of action; since taxanes have been approved in the adjuvant setting and are widely used in the treatment of early breast cancer it is worthwhile to assess new combination chemotherapy regimens as first line therapy for metastatic breast cancer.

This is a randomised, multicentre, open-label phase III study comparing antitumour efficacy of vinflunine plus gemcitabine versus paclitaxel plus gemcitabine, as first line treatment for patients with unresectable, locally recurrent or metastatic breast cancer after prior anthracycline-based adjuvant chemotherapy.

Patients with metastatic breast cancer are incurable using conventional therapy with antitumoural hormonal drugs or cytostatic agents. The median survival from diagnosis of metastatic disease to death is reported to be approximately 3 years. While newer chemotherapeutic agents have been able to achieve tumour shrinkage, no significant increases in overall survival have been demonstrated so far. One reason for this result may be that breast cancer has a longer disease time span than NSCLC, allowing for administration of multiple therapies with different modalities. These therapies confound overall survival regardless of whether the treatment is a first-line or a subsequent treatment. The combination of gemcitabine plus paclitaxel has demonstrated improvement in overall survival over paclitaxel alone as first line therapy in patients with locally recurrent or metastatic breast cancer, however, this study compared single agent versus combination chemotherapy.

Using overall survival as a primary endpoint in a trial Using overall survival as a primary endpoint in a trial comparing 2 different cytostatic combinations in the treatment of metastatic breast cancer requires a large phase III study to detect a clinically significant difference. The advantages with such an endpoint are that it is technically easy to monitor and it is not dependent on monitoring tumour status. However, since patients with breast cancer typically receive 3 or more lines of chemotherapy, it becomes difficult to assess the impact of a first-line therapy on overall survival (as proposed herein) due to the potential for confounding effects from later treatments. A more specific instrument -if closely monitored- is progression-free survival. This endpoint reflects the impact of a specific treatment modality on the disease at a given time period and is probably confounded neither by prior treatments nor by subsequent therapies. Progression-free survival also represents an important clinical achievement for patients with metastatic breast cancer.

Inclusion Criteria:

• female patients
• 18 years or older but less than 75 years old
• histologically/cytologically confirmed breast cancer
• documented locally recurrent or metastatic breast cancer
• HER-2 negative or unknown
• prior neo- and/or adjuvant anthracycline-based chemotherapy
• measurable or non-measurable disease according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.0
• adequate haematological, hepatic and renal functions
• ECG without any clinically relevant abnormality

Exclusion Criteria:

• known or clinical evidence of brain metastases or leptomeningeal involvement
• history of second primary malignancy
• patients having as sole tumour lesion: malignant effusion, lymphangitis, cystic lesion, bone lesion, and any other lesion not assessed by imaging techniques or colour photography
• pre-existing motor/sensory grade > 1 peripheral neuropathy
• prior therapy with vinca alkaloids and/or gemcitabine
• history of severe hypersensitivity to vinca alkaloids and/or gemcitabine or contraindication to any of these drugs
• pregnancy or breast feeding

Each subject was assessed for occurrence of Adverse Events throughout the study period (treatment period and follow-up period), up to 8 years.

Safety data are presented for the global safety population which include the safety data of the 13 patients ongoing treatment (up to the premature termination date 18 February 2015). Safety population is defined as all treated patients analysed in the treatment arm they received (n=495 subjects in the Vinflunine Plus Gemcitabine arm and n=496 in the Paclitaxel Plus Gemcitabine arm)

None reported