SAN ANTONIOIn a trial of first-line, single-agent therapy for metastatic breast cancers that overexpress the HER-2 breast cancer gene, Herceptin (trastuzu-mab) resulted in major objective responses in 20% to 25% of patients. The monoclonal antibody is approved for use as first-line therapy in combination with paclitaxel(Drug information on paclitaxel) (Taxol) and as a single agent in second- and third-line therapy.
The therapeutic antibody resulted in noteworthy response rates in patients who had a history of adjuvant anthracycline therapy or bone marrow transplantation, said Charles Vogel, MD, an oncologist at Aventura Hospital, Aven-tura, Florida. Response rates were similar with a 2 or 4 mg/kg/wk dose. Because toxicity was greater with 4 mg/kg, the lower dose should be used, he said at the San Antonio Breast Cancer Symposium.
Herceptin is active as a single agent in patients who have had no previous therapy for metastatic breast cancer, Dr. Vogel said. The therapy is well tolerated and has a favorable safety profile. Severe adverse events are infrequent. The adverse events common with cytotoxic chemotherapy are rarely seen.
The trial involved 112 women with metastatic breast cancers that overex-pressed HER-2 by immunohistochemistry staining (either 2-plus or 3-plus overexpression). The trial protocol excluded patients who had received prior therapy for metastatic disease, but prior adjuvant therapy was allowed. Two-thirds of the patients had received prior adjuvant chemotherapy, and 55% had prior anthracycline therapy. Dr. Vogel said that 12% had received bone marrow transplants. About half had a history of radiation therapy, and 37% had prior hormonal treatment.
The patients had a mean age of 54. More than half were estrogen receptor-negative. Three-fourths overexpressed HER-2 at the 3-plus level.
Patients were randomized to one of two doses of Herceptin: a 4 mg/kg loading dose, followed by 2 mg/kg weekly, or an 8 mg/kg loading dose and 4 mg/kg weekly. Efficacy assessment occurred at 8, 12, and 24 weeks, and then every 12 weeks thereafter.
At a median follow-up of 11 months, 37 patients have died, 20 in the high-dose Herceptin arm and 17 in the low-dose arm. None of the deaths occurred on study, Dr. Vogel said. All the deaths occurred secondary to metastatic breast cancer. We had no discontinuations for adverse events.
Six patients achieved a complete response, and 20 had a partial response, resulting in an overall response rate of 23%. An additional 8% had disease stabilization for more than 6 months. The overall response rate was 24% in the low-dose group and 22% in the high-dose group.
The treatment resulted in durable responses, with several persisting beyond 2 years. The median time to progression has been 8.4 months in responders and 10.8 months in patients who had prolonged disease stabilization. These patients had clinically significant stabiliza-tions that persisted beyond the median for responders, Dr. Vogel commented.
Herceptin led to responses in 25% of patients who had liver metastases, 31% of patients who overexpressed HER-2 at the 3-plus level, 25% of patients who had a history of doxorubicin(Drug information on doxorubicin) treatment, and 38% of patients who had received bone marrow transplants. Because of the brief follow-up period, survival cannot yet be assessed, he said.
Toxicity was generally mild and infrequent. Leukopenia occurred in 1% of patients, thrombocytopenia in none, anemia in 3% (2% severe), stomatitis in 1%, and alopecia in 4% (1% severe). The most common adverse events (occurring in 20% or more of patients) were asthenia, nausea/vomiting, fever, chills, rash, headache, and diarrhea.
These adverse events were almost certainly due to Herceptin, but they were generally mild and easily managed, Dr. Vogel said.
Although the overall incidence of adverse events was low, the incidence was higher in the 4 mg/kg patient group. Given the fact that there is more toxicity with the 4 mg/kg dose, the recommended dose of 2 mg/kg should be adhered to, he said.
There have been three cases of cardiac dysfunction, defined as any recognized symptoms of cardiac dysfunction or an asymptomatic absolute decrease in ejection fraction of greater than 10%. An independent review committee ruled that one case was secondary to pericardial tamponade in a patient who had a history of pericardial malignant effusion. The two other cases remain under review. Both involved elderly patients with a history of heart disease, Dr. Vogel said.