Three-drug combo promising in metastatic breast cancer

February 1, 2008

Preliminary survival data are encouraging for the triple-drug combination of trastuzumab (Herceptin), docetaxel (Taxotere), and capecitabine (Xeloda) as first-line therapy for locally advanced or metastatic breast cancer

SAN ANTONIO—Preliminary survival data are encouraging for the triple-drug combination of trastuzumab (Herceptin), docetaxel (Taxotere), and capecitabine (Xeloda) as first-line therapy for locally advanced or metastatic breast cancer, according to an international study presented at the 2007 San Antonio Breast Cancer Symposium (abstract 309).

Andrew M. Wardley, MD, of Christie Hospital, Manchester, UK, reported the results of the Capecitabine, Herceptin and Taxotere (CHAT) study, a phase II randomized open-label trial in 225 patients with HER2+ breast cancer.

Patients with centrally confirmed HER2+ locally advanced or metastatic breast cancer were randomized to trastuzumab 8 mg/kg loading dose followed by 6 mg/kg every 3 weeks plus docetaxel 100 mg/m2 every 3 weeks (HT), or to trastuzumab plus docetaxel 75 mg/m2 every 3 weeks plus capecitabine 950 mg/m2 twice daily on days 1-14 every 3 weeks (HTX), and treated until disease progression.

Analysis on 222 patients was conducted 18 months after the last patient was enrolled, with a median follow-up of approximately 25 months.

The objective response rate was high in both treatment arms: 72.7% for HT and 70.5% for HTX (P = .717). However, the complete response rate was 7% higher in the HTX arm (23.2% vs 16.4%). The rate of stable disease was also higher (25.0% vs 16.4%), and fewer patients in the HTX arm had disease progression as the best response (3.6% vs 9.1%).

Progression-free survival

Median progression-free survival was 17.9 months for HTX and 12.8 months for HT, for a 28% reduction in risk (P = .0402). Median time to progression was 18.6 months and 13.6 months, respectively, for a 30% reduction (P = .029).

"The objective response rate in the HT arm was higher than expected, and both regimens showed response rates exceeding 70%," Dr. Wardley noted. "But significant improvements in time to progression and progression-free survival of approximately 5 months, and increased numbers of patients experiencing a complete response, suggest there is higher efficacy for the triple combination."

The overall survival data have not reached maturity, with 61% of patients alive at the time of this analysis. But at 1 year, the probability of survival was higher in the arm receiving capecitabine (0.91 vs 0.85 for the HT group). "This trend is maintained at 2 years," he added, "with a probability of survival of 0.75 in the HTX arm vs 0.66 in the HT arm."

Both treatments were well tolerated. The most frequent grade 3-4 adverse events were hand-foot syndrome and diarrhea, both more common with HTX than HT. The most common grade 3-4 hematological toxicity was neutropenia, which was lower with HTX (54%) than with HT (77%). The incidence of febrile neutropenia was also lower with HTX (15% vs 27%), likely due to the lower docetaxel dose. "This supports the concept of improved tolerability with a lower dose of capecitabine combined with docetaxel," Dr. Wardley suggested.

Fewer patients on HTX withdrew from treatment due to adverse events or laboratory abnormalities. Four deaths during treatment were considered to be treatment-related, one with HTX and three with HT.

Dr. Wardley said he is encouraged by the outcomes and tolerability of the experimental arm. "Although overall survival data are immature, 1- and 2-year data are promising and indicate improvements with three drugs vs standard two-drug therapy," he said.