PLANTATION, FloridaThe humanized anti-HER2 antibody trastuzumab
(Herceptin) produced an overall response rate of 26% when used as
first-line therapy in women with metastatic breast cancer whose
tumors overexpress HER2.
Charles Vogel, MD, clinical professor at the Sylvester Cancer Center
of the University of Miami, reported data from a trial comparing
standard-dose and high-dose trastuzumab regimens at the ASCO annual
Trastuzumab alone is an effective and safe treatment for
patients with recently diagnosed metastatic breast cancer, Dr.
Vogel summarized. Survivals in this study were similar to those
reported with first-line trastuzumab plus chemotherapy. Response
rates are similar at the 2-mg/kg and 4-mg/kg maintenance dose, and
trastuzumab is well tolerated and has a favorable safety profile.
The incidence of cardiac dysfunction in this trial was much lower
than that in other trials with patients who had more prior
anthracycline exposure, Dr. Vogel noted. He said that the only
cardiac events were in two patients with extensive preexisting
Single-agent trastuzumab is an important new option for
first-line treatment of women with metastatic breast cancer whose
tumors demonstrate evidence of HER2 gene amplification or 3+ HER2
gene overexpression by immunohistochemistry, he stated.
Trastuzumab as a Single Agent
Previous studies had shown a benefit from trastuzumab used with
chemotherapy as first-line treatment for metastatic breast cancer, or
used as a single agent for metastatic breast cancer progressing after
initial chemotherapy. This study examined the usefulness of
trastuzumab alone in lieu of chemotherapy in women with metastatic
Patients enrolled were women who did not wish to receive
chemotherapy for metastatic breast cancer. They had progressive,
metastatic disease with HER2 overexpression at 2+ or 3+ according to
the clinical trials assay. They had to have no prior chemotherapy for
stage IV disease. They had to have measurable disease; bone-only
disease was excluded, Dr. Vogel said.
The trial included 114 women, with a mean age of 54 years: 50% were
postmenopausal, 76% had tumors expressing HER2 at the 3+ level, 44%
had lung metastases, and 39% had liver metastases. The median
disease-free interval had been 17 months. Fifty-one percent of
patients had received adjuvant anthracyclines, and 13% had undergone
adjuvant high-dose therapy with transplantation.
Patients were randomized to a standard lower-dose regimen of
trastuzumab (4 mg/kg IV loading and 2 mg/kg IV weekly maintenance
until progression) or to a higher-dose regimen (8 mg/kg IV loading
and 4 mg/kg IV weekly until progression).
The primary endpoints were overall response rate and safety.
Secondary endpoints were duration of response, time to progression,
The mean duration of follow-up was 19 months. Only three patients
One Unexpected Result
The response rate for the entire group was 26%. Response rates in the
two dosage groups were similar: 25% for standard dose and 27% for
There were 7 complete responses and 23 partial responses, for
an overall response rate of 26% in the intent-to-treat analysis,
Dr. Vogel reported. Thirteen patients had stable disease for
more than 6 months, for an overall clinical benefit rate of 38%.
All responders had tumors that overexpressed HER2 at the 3+ level.
This was unexpected, Dr. Vogel said.
The median times to disease progression were similar: 3.5 months for
standard-dose treatment and 3.8 months for high-dose treatment.
However, most striking was a clinical benefit rate of 47% in 3+ overexpressors.
Median time to progression was 19 months in the subgroup of patients
who were responders and 15 months in the patients who derived
clinical benefit. The median time to progression was only 2 months
for those not deriving clinical benefit.
It is worth remembering that the average response duration to
first-line chemotherapy in patients with metastatic breast cancer is
8 to 10 months, Dr. Vogel said.
Similar Overall Survival
Overall survival times were also similar: 22.9 months for the
standard-dose group and 25.8 months for the high-dose group. The
estimated median duration of survival was 24 months. Please recall
that there is a 20-month median survival for chemotherapy alone in
prior Herceptin pivotal-trials, Dr. Vogel said.
Forty-three percent of the patients who had prior transplant derived
clinical benefit from single-agent trastuzumab, he added.
Most adverse effects were mild to moderate in severity. The most
common were pain, asthenia, fever, and chills. Dr. Vogel said that
these typically occurred with the first dose of therapy and tended
not to recur with subsequent infusions. The incidence of adverse
events typically associated with chemotherapy, such as neutropenia
and alopecia, was low.
Reports of serious cardiac events in other trials prompted a
retrospective analysis of cardiac events by an independent review
committee, Dr. Vogel noted.
Cardiac dysfunction was defined as congestive failure or at least a
10% decrease in left ventricular ejection fraction. The incidence of
cardiac dysfunction was 2.8%.
This event rate appears lower than was seen in other studies
where patients had greater previous exposure to anthracyclines. There
were no drug-related deaths in this study. Both treatment
discontinuations were due to cardiac events, he said. Both
patients who developed cardiac dysfunction had significant underlying
ischemic cardiac disease.