Combination of Capecitabine and Ixabepilone Proves Effective in Resistant Triple-Negative Breast Cancer

The combination of capecitabine (Xeloda) and ixabepilone (Ixempra) appears to be robust in patients with the triple-negative breast cancer phenotype. In heavily pretreated metastatic breast cancer patients, the regimen yielded an overall response rate of 27% and median progression-free survival of 4.1 months, according to a subset analysis of 187 patients from a larger randomized phase III trial of capecitabine with and without ixabepilone.

Hope Rugo, MD
Photo Courtesy SABCS/Todd Buchanan 2007

"This study was an attempt to cull out this very resistant group of patients, which represented 25% of patients in our larger trial. These patients have limited treatment options, and this was quite an effective treatment for them," said principal investigator Hope Rugo, MD, of the University of California, San Francisco School of Medicine. Dr. Rugo pointed out that "triple-negative" breast cancers -- those that are estrogen receptor-negative, progesterone receptor-negative, and HER2-negative -- are associated with an aggressive phenotype and poor prognosis as a result of their increased mitotic index, central necrosis, proportion of apoptotic cells, and other high-risk pathological features. Patients with triple-negative tumors develop their disease at an earlier age, are more likely to relapse, and tend to develop visceral and brain metastases as well as bone metastases, compared with other breast cancer subtypes. "Such patients have worse survival compared with other subgroups and fewer effective treatment options, since they are not candidates for either hormonal or HER2-targeted therapy," she said. "We need new agents with novel mechanisms of action for this population that is so difficult to treat." The study population was part of a prospective multicenter phase III trial of 752 women with metastatic breast cancer resistant to taxanes and pretreated with or resistant to anthracyclines. Patients were randomized to capecitabine monotherapy 1250 mg/m² twice daily on days 1 to 14 of a 21-day cycle, or to capecitabine 1000 mg/m² twice daily on days 1 to 14 plus ixabepilone 40 mg/m² on day 1 of a 21-day cycle. For these triple-negative patients, progression-free survival was prolonged to 4.1 months with the combination, compared with 2.1 months with capecitabine alone, for a 32% reduction in risk. Overall response rates also increased with the combination, to 27% from 9% with monotherapy. The differences between the arms reflected those observed in the larger population, though outcomes were better overall in the non-triple-negative group. "Nearly half this patient group had received two or more lines of therapy. If you give this combination earlier, it is quite likely that you will get an even better response and, more important, a longer time to progression," Dr. Rugo said, noting that this has been shown in subset analyses. The combination was relatively well tolerated. The most common grade 3 or 4 adverse events were neutropenia (68%) and peripheral sensory neuropathy (21%). Both were manageable with dose adjustments. "Interestingly, the neuropathy that occurs with this regimen resolves very quickly when you stop the drug, unlike with taxanes. Within 6 weeks, patients return to baseline, and if you dose-reduce ixabepilone, it does not recur," she said.

Disclosures:

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.