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 (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 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.