SABCS: Three-Drug Combo Shows Promise for First-Line Treatment of Advanced Breast Cancer

Charles Bankhead
SAN ANTONIO, Dec. 15 - Patients with locally advanced or metastatic breast cancer had high response rates to first-line treatment with trastuzumab (Herceptin) and docetaxel (Taxotere) with or without capecitabine (Xeloda).
Action Points --->
Explain to interested patients that a three-drug combination has shown promise for improving the response rate and survival in advanced breast cancer.
Note that the treatment regimen applies only to patients with HER2-positive breast cancer, which accounts for 20% to 30% of cases.
Note also that the study was published as an abstract and presented orally at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed publication.
Both the two- and three-drug regimens produced response rates exceeding 70%, Andrew Wardley, M.D., of Christie Hospital in Manchester, England, reported at the San Antonio Breast Cancer Symposium.
The addition of capecitabine, however, was associated with more complete responses, more stable disease, significantly longer progression-free survival (P=0.029), and a trend toward improved overall survival, he and his colleagues found.
"The significant improvement in time to progression and progression-free survival plus the higher rate of complete response suggest the three-drug combination has better efficacy, but that remains to be determined with a larger number of patients and longer follow-up," Dr. Wardley said.
Combination therapy with trastuzumab and a taxane has an established record as first-line therapy for HER2-positive advanced breast cancer. In a pivotal clinical trial of patients with anthracycline-treated metastatic breast cancer, adding capecitabine to docetaxel led to better survival compared with docetaxel alone (J Clin Oncol 2002; 20: 2812-2823).
"Consequently, a strong rationale existed for investigating the combination of all three agents in patients with HER2-positive advanced breast cancer," said Dr. Wardley.
The phase II randomized, open-label trial involved 222 patients with inoperable HER2-positive locally advanced or metastatic breast cancer. Baseline left ventricular ejection fraction exceeded 50% in all patients. None of the patients had prior exposure to trastuzumab, a taxane, or 5-fluorouracil, and none had received any chemotherapy for advanced or metastatic disease.
All patients received trastuzumab and docetaxel and were randomized to capecitabine or no third drug. Treatment continued until disease progression or unacceptable toxicity, and patients were followed until 18 months after enrollment of the final patient.
Investigators assumed a 50% response rate with the two-drug regimen and powered the study to detect a 40% improvement (20% absolute).
The two-drug regimen achieved an unexpectedly high 72.5% overall response, compared with 70.5% in the three-drug arm. However, substantially more patients had complete responses (23.2% versus 16.4%) and stable disease (25% versus 16.4%) with the addition of capecitabine.
Additionally, 3.6% of patients had disease progression as best response with the three-drug regimen compared with 9.1% of patients treated with trastuzumab and docetaxel.
Median progression-free survival and time to progression were 17.9 months and 18.6 months, respectively, in the capecitabine arm as compared with 12.8 months and 13.6 months with two drugs (P=0.0402, P=0.029).
Overall survival data have not matured sufficiently, but preliminary analyses suggested an advantage for the three-drug regimen. The one-year survival probability was 0.91 in the capecitabine arm and 0.85 with two drugs. Probability of survival at two years was 0.75 with capecitabine and 0.66 with trastuzumab and docetaxel.
The most common grade 3-4 hematologic toxicity was neutropenia, which occurred in 54% of the capecitabine group and 77% of the two-drug group. Febrile neutropenia occurred in 15% and 27% of patients in the capecitabine and two-drug treatment groups, respectively.
Most nonhematologic adverse events were grade 1-2 in severity. The most common grade 3-4 events were hand-foot syndrome and diarrhea, both of which occurred more often in the capecitabine group.
Two patients in each arm had declines in left ventricular ejection fraction to <40%, and two patients with prior anthracycline exposure (one in each arm) developed symptomatic congestive heart failure. Three of four treatment-related deaths occurred in the two-drug arm.
Follow-up will continue until survival data are mature, said Dr. Wardley. Other studies designed to evaluate the three-drug regimen have been planned.
Dr. Wardley reported no disclosures.
Primary source: Breast Cancer Research and TreatmentSource reference:Wardley A, et al "Evaluation of trastuzumab (Herceptin), docetaxel, and capecitabine as first-line therapy for HER2-positive locally advanced or metastatic breast cancer" Breast Cancer Res Treat 2007; 106 (Supp1): Abstract 309.