Vinflunine: a new active drug for second-line treatment of advanced breast cancer. Results of a phase II and pharmacokinetic study in patients progressing after first-line anthracycline/taxane-based chemotherapy

Abstract

To evaluate the single agent activity, pharmacokinetics and tolerability of the novel tubulin targeted agent vinflunine (VFL) (320 mg m À2 q 21 days) as second-line chemotherapy in patients with metastatic breast carcinoma (MBC). All patients had disease progression after anthracycline/taxane (A/T) therapy. They could have received a nonanthracycline adjuvant treatment and subsequently received a first-line A/T combination for advanced/metastatic disease; or relapsed 46 months after completion of adjuvant A/T therapy and were subsequently treated with the alternative agent; or relapsed within 6 months from an adjuvant A/T combination. Objective response was documented in 18 of 60 patients enrolled (RR: 30% (95% confidence interval (CI): 18.9 -43.2%)). Among the responders, seven patients had relapsed during a period of o3 months from taxane-based regimen yielding a RR of 33.3%. The median duration of response was 4.8 months (95% CI: 4.2 -7.2), median progression-free survival was 3.7 months (95% CI: 2.8 -4.2) and median overall survival was 14.3 months (95% CI: 9.2 -19.6). The most frequent adverse event was neutropenia (grade 3 in 28.3% and grade 4 in 36.7% of patients). No febrile neutropenia was observed. Fatigue (grade 3 in 16.7% of patients) and constipation (grade 3 in 11.7% of patients) were also common; these were non-cumulative and manageable permitting achievement of a good relative dose intensity of 93.5%. Vinflunine is an active agent with acceptable tolerance in the management of MBC patients previously treated with (A/T)-based regimens. These encouraging phase II results warrant further investigation of this novel agent in combination with other active agents in this setting or in earlier stages of disease.

Microtubule inhibitors: Differentiating tubulin-inhibiting agents based on mechanisms of action, clinical activity, and resistance

“…Vinflunine-related adverse events were not cumulative and included mostly grade 3-4 neutropenia, fatigue, and constipation (69,71).…”

“…Recently completed clinical trials showed the activity of vinflunine in patients with advanced transitional cell carcinoma of the urothelium (TCCU; refs. 69,70), breast (71), NSCLC (72), and malignant pleural mesothelioma (73). In a recently reported phase 3 trial, the efficacy of vinflunine was equivalent to docetaxel in pretreated patients with NSCLC (74).…”

Resistance to Chemotherapy in Cancer: A Complex and Integrated Cellular Response

“…The high efficacy of vinflunine in a breast tumour xenograft model [176] prompted its evaluation in phase I studies for metastatic breast cancer, wherein it produced encouraging results [200] . A recent phase II trial supported the use of vinflunine in metastatic breast cancer, particularly as a second-line treatment following anthracycline/taxane chemotherapy [196] .…”

“…Vinflunine is a bifluorinated derivative of vinorelbine [196] and is the latest vinca alkaloid to reach the clinic. Although vinflunine initiates apoptosis by inhibiting mi-totic spindle formation [197] , its effects differ subtly from those of established vinca alkaloids [198,199] .…”

A phase I study of vinflunine in combination with capecitabine in patients with metastatic breast cancer previously treated with anthracyclines and taxanes

“…Overall median progression-free survival and median survival were 3.7 and 14.3 months, respectively [8].…”