Xeloda/Ixempra Effective in Resistant Triple-Negative Ca

January 1, 2008

The combination of capecitabine (Xeloda) and ixabepilone (Ixempra) appears to be robust in patients with the so-called triple-negative breast cancer phenotype

SAN ANTONIO-The combination of capecitabine (Xeloda) and ixabepilone (Ixempra) appears to be robust in patients with the so-called triple-negative breast cancer phenotype, according to an analysis of a predefined subset of the larger 752-patient phase III trial of the combination vs capecitabine alone.

In 187 heavily pretreated metastatic breast cancer patients with the triple-negative subtype, the regimen yielded an overall response rate of 27% and median progression-free survival (PFS) of 4.1 months, Hope Rugo, MD, of the University of California, San Francisco, reported at the 2007 San Antonio Breast Cancer Symposium (abstract 6069).

"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," Dr. Rugo commented.

An aggressive phenotype

Triple-negative breast cancer is characterized by tumors that are estrogen-receptor (ER) negative, progesterone-receptor (PR) negative, and HER2 negative. This is an aggressive phenotype with poor prognosis as a result of its 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, Dr. Rugo noted.

"Most importantly, such patients have worse survival, compared with other subgroups, and have fewer effective treatment options, since they are not candidates for either hormonal or HER2-targeted therapy," she said.

Prolonged PFS

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 capecita-bine monotherapy 1,250 mg/m2 twice daily on days 1 to 14 of a 21-day cycle, or to capecitabine 1,000 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 (see Table).

"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 importantly, a longer time to progression," Dr. Rugo predicted, noting that this has been shown in other subset analyses.

Lack of resistance a factor

Dr. Rugo maintained that the benefit of the combination may be due to the lack of resistance seen to ixabepilone. The drug is a semisynthetic analog of epothilone B that stabilizes microtubules and that has shown low susceptibility to multiple- drug-resistance mechanisms.

Taxanes work by binding to tubulin proteins and making spindle complexes associated with cell division, but upon resistance to the drug, the taxane can no longer bind. Ixabepilone also binds to tubulin but to a slightly different site.

"Ixabepilone can overcome some of the mechanisms of resistance to the taxanes, and it is less susceptible to multidrug resistance phenotypes for which there is drug efflux out of the cells," she said. "In cell lines known to have tubulin mutations that result in resistance, ixabepilone has shown good anti-tumor activity."

This appears to be true in the clinical setting as well, Dr. Rugo said. "Ixabepilone produces a good response in patients with very strictly defined anthracycline and taxane resistance, as well as patients resistant to these agents plus capecita-bine," she said.

Well tolerated

The combination was relatively well tolerated. The most common grade 3-4 adverse events were neutropenia (68%) and peripheral sensory neuropathy (21%), both manageable with dose adjustments. "Interestingly, the neuropathy seen 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," Dr. Rugo said.

New studies on the horizon

Dr. Rugo and her colleagues are evaluating ixabepilone in the first-line metastatic setting in a randomized phase II trial comparing ixabepilone, weekly or every 3 weeks, plus bevacizumab (Avastin) against weekly paclitaxel/bevacizumab.

This will be a precursor to a 900-patient phase III cooperative group trial in the first-line metastatic setting, led by Dr. Rugo. Weekly ixabepilone will be compared with weekly nab-paclitaxel (Abraxane) and weekly paclitaxel, all with bevacizumab. "We believe that weekly dosing may be very effective, with a better toxicity profile," she said.

'A reasonable option'

Andrew Seidman, MD, professor of medicine, Weill Medical College of Cornell University and attending physician, Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, commented on the difficulty of treating triple-negative breast cancer.

Triple-negative breast cancers themselves represent a subset of tumors that do exhibit heterogeneity, even within this category, he said. A subset of triple-negatives appears to have a particularly aggressive biology-one characterized by relative resistance to "the usual suspects," ie, taxanes and anthracyclines, he said.

"The observation of differentially enhanced activity in these patients treated with ixabepilone/capecitabine is encouraging," Dr. Seidman said. "The combination certainly represents a reasonable noninvestigational option for such patients. Entry of patients with triple-negative metastatic breast cancer into clinical trials examining novel treatment strategies such as this one remains a priority."