Efficacy and Safety of Ixabepilone and Capecitabine in Patients With Advanced Triple-negative Breast Cancer: a Pooled Analysis From Two Large Phase III, Randomized Clinical Trials.

INTRODUCTION: The purpose of this study was to evaluate the safety and efficacy of ixabepilone plus capecitabine in patients with metastatic or locally advanced triple-negative breast cancer (TNBC). PATIENTS AND METHODS: We conducted a pooled analysis of patients with TNBC enrolled in 2 phase III trials (NCT00080301 and NCT00082433), pretreated or resistant to an anthracycline and a taxane. In each study, patients were randomized to receive ixabepilone 40 mg/m2 (3-hour intravenous infusion, day 1), plus oral capecitabine 1000 mg/m2 twice daily (days 1-14), or capecitabine alone 1250 mg/m2 twice daily (days 1-14), every 3 weeks. Treatment was continued until disease progression or unacceptable toxicity. RESULTS: In the subset of patients with TNBC (N = 443), the addition of ixabepilone to capecitabine compared with capecitabine alone prolonged median progression-free survival from 1.7 months to 4.2 months (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.52-0.78; P < .0001), and doubled the objective response rate from 15% (95% CI, 10.4%-20.5%) to 31% (95% CI, 24.4%-38.0%). The median overall survival was similar (9.0 vs. 10.4 months; HR, 0.88; 95% CI, 0.72-1.08; P = .1802). A similar pattern of efficacy between arms was observed in the overall pooled population (N = 1973). The safety profile was comparable between the pooled TNBC subset and the overall pooled population. Adverse events observed with combination therapy were generally manageable and consistent with the safety profiles of the individual agents. CONCLUSION: Adding ixabepilone to capecitabine is effective in prolonging progression-free survival and improving objective response rate compared with capecitabine alone in patients with advanced TNBC previously treated with anthracyclines and taxanes.

Analysis of overall survival from a phase III study of ixabepilone plus capecitabine versus capecitabine in patients with MBC resistant to anthracyclines and taxanes.

Limited proven treatment options exist for patients with metastatic breast cancer (MBC) resistant to anthracycline and taxane treatment. Ixabepilone, a novel semisynthetic analog of epothilone B, has demonstrated single-agent activity in MBC resistant to anthracyclines and taxanes. In combination with capecitabine in a phase III trial (CA163-046) in this setting, ixabepilone prolonged progression-free survival and increased objective response rate relative to capecitabine (Thomas et al. J Clin Oncol 25:5210-5217, 2007). Here, we report the results of overall survival (OS), a secondary efficacy endpoint from the CA163-046 trial. Seven hundred fifty-two patients with MBC resistant to anthracyclines and taxanes were randomized to ixabepilone (40 mg/m(2) intravenously on day 1 of a 21-day cycle) plus capecitabine (2,000 mg/m(2) orally on days 1 through 14 of a 21-day cycle) or capecitabine alone (2,500 mg/m(2) on the same schedule). Patients receiving ixabepilone plus capecitabine treatment had a median survival of 12.9 months compared to 11.1 months for patients receiving capecitabine alone (HR = 0.9; 95%CI: 077-1.05; P = 0.19). This observed increase in median OS favored the combination; however, the difference was not statistically significant. Predefined subset analyses showed a clinically meaningful increase in OS in KPS 70-80 patients receiving ixabepilone plus capecitabine (HR = 0.75; 95% CI: 0.58-0.98). Ixabepilone plus capecitabine did not show a significant improvement in survival compared to capecitabine alone in patients with MBC resistant to anthracyclines and taxanes. The observed differences in survival favored the combination arm. A clinical benefit was also seen in patients in the KPS 70-80 subgroup.

Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment.

PURPOSE: Effective treatment options for patients with metastatic breast cancer resistant to anthracyclines and taxanes are limited. Ixabepilone has single-agent activity in these patients and has demonstrated synergy with capecitabine in this setting. This study was designed to compare ixabepilone plus capecitabine versus capecitabine alone in anthracycline-pretreated or -resistant and taxane-resistant locally advanced or metastatic breast cancer. PATIENTS AND METHODS: Seven hundred fifty-two patients were randomly assigned to ixabepilone 40 mg/m(2) intravenously on day 1 of a 21-day cycle plus capecitabine 2,000 mg/m(2) orally on days 1 through 14 of a 21-day cycle, or capecitabine alone 2,500 mg/m(2) on the same schedule, in this international phase III study. The primary end point was progression-free survival evaluated by blinded independent review. RESULTS: Ixabepilone plus capecitabine prolonged progression-free survival relative to capecitabine (median, 5.8 v 4.2 months), with a 25% reduction in the estimated risk of disease progression (hazard ratio, 0.75; 95% CI, 0.64 to 0.88; P = .0003). Objective response rate was also increased (35% v 14%; P < .0001). Grade 3/4 treatment-related sensory neuropathy (21% v 0%), fatigue (9% v 3%), and neutropenia (68% v 11%) were more frequent with combination therapy, as was the rate of death as a result of toxicity (3% v 1%, with patients with liver dysfunction [>/= grade 2 liver function tests] at greater risk). Capecitabine-related toxicities were similar for both treatment groups. CONCLUSION: Ixabepilone plus capecitabine demonstrates superior efficacy to capecitabine alone in patients with metastatic breast cancer pretreated or resistant to anthracyclines and resistant to taxanes.