Chemo Combo for Metastatic Breast Cancer May Help Previously Treated Patients

A 33-patient Phase 1/2 study in Europe published in the European Journal of Cancer (doi:10.1016/j.ejca.2011.01.001) has shown that a new chemotherapy combo of a novel taxoid, cabazitaxel, and capectiabine shows promise in previously treated metastatic breast cancer patients. The combination also had a good safety profile, which means that it warrants more extensive clinical trials.

Chemical structure of cabazitaxel (TXD 258)

The authors stated that “There is an urgent need to find new active agents in the metastatic setting, as most patients with metastatic breast cancer (MBC) develop chemotherapy-resistant tumours.” Currently, several chemotherapy combinations are approved for metastatic breast cancer. Most of them include anthracycline or a taxane for the first-line therapy.

Higher-grade toxicites (grade 3-4) included asthenia, hand-foot-syndrome, neutropenic infection, and neutropenic colitis. The highest-frequency high grade toxicitiy was neutropenia, which developed in 21 patients. 

Anti-tumor activity was demonstrated at all doses. Five patients had a partial response, 20 had stable disease, and 2 had complete responses. Additionally, there were 7 unconfirmed partial responses. The overall response was 23.8% and the median response duration was 3.1 months. Median time to progression was 4.9 months. These statistics were evaluated among 21 of the 33 patients that received the maximum tolerated dose. 

Anthracyclines, derived from a class of bacteria, are some of the more effective chemotherapies. They work by inhibiting DNA and RNA synthesis as well as topoisomerase II, which inhibits replication and transcription. The chemotherapy also creates iron-mediated free radicals that damage DNA.  However, anthracycline-resistance is a major issue for patients, and taxanes may provide a potential clinical benefit in this setting. 

Taxanes distrupt cell division by preventing microtubule function. Cabazitaxel (XRP6258) is a new taxoid compound that appears to be a potent microtubule stabilizer. It is being developed by Sanofi Aventis and has shown efficacy in a broad range of tumor models that are sensitive or resistant to docetaxel, another type of taxane. Currently, capcitabine monotherapy is approved as an option for MBC after failure of a first-line taxane regime, based on a large-scale phase 2 trial that showed anti-tumor activity in MBC refractory to paclitaxel. 

The current trial was designed based on evidence from preclinical studies of cabazitaxel that showed activity in taxane and anthracycline-pretreated MBC, a synergistic activity of capcitabine and docetaxel, and a lack of overlapping toxicities between the two therapies.