The FDA recently licensed a biological approach
for the treatment of metastatic breast cancer. The intravenous
monoclonal antibody, trastuzumab (Herceptin), is approved for use
alone in certain patients who have tried chemotherapy with little
success, or as a first-line treatment for metastatic disease when
used in combination with paclitaxel (Taxol).
Trastuzumab is the second monoclonal antibody approved for the
treatment of cancer. (The first, rituximab [Rituxan], was approved in
November 1997 for patients with one type of non-Hodgkins
lymphoma.) Trastuzu-mab is a monoclonal antibody bioengineered from
part of a mouse antibody that is altered to closely resemble a human
antibody. It binds to a protein called HER-2, which is found on the
surface of some normal cells and plays a role in regulating cell
growth. In laboratory experiments, trastuzumab inhibited tumor cell
growth by this binding action.
In the case of metastatic breast cancer cells, approximately 30% of
tumors produce excess amounts of HER-2. When breast cancer tumors
produce excess HER-2, it appears that the cancer may be more
aggressive. Only patients who have tumors with this characteristic
have been studied and been shown to benefit from trastuzumab.
We now have a new weapon in our fight against breast
cancer, said HHS secretary, Donna E. Shalala. For certain
women with advanced disease, this new product can mean new hope.
As an oncologist myself, I know nothing is more important than
giving patients and their doctors new ways to fight serious and
life-threatening illnesses, said FDA acting commissioner,
Michael A. Friedman, MD. The increasing use of biological
products such as Herceptin to treat the underlying causes of diseases
is an exciting development in medicine. The FDA will continue to make
the review of products for serious and life-threatening diseases one
of our highest agency priorities.
Benefits Demonstrated in Two Clinical Trials
The benefits of trastuzumab were shown in two clinical trials. The
first was a randomized, controlled clinical trial, in which 469
patients with metastatic disease who overexpressed HER-2 were
assigned to receive chemotherapy alone or in combination with
trastuzumab. As a group, the women who received chemotherapy plus
trastuzumab had less rapid tumor growth, higher 1-year survival
rates, and a greater number of tumors that were reduced 50% or more
Specifically, the median time to disease progression was 7.2 months
for those receiving trastuzumab and chemotherapy and 4.5 months for
patients receiving chemotherapy alone. The overall tumor response was
44% in the trastuzumab group and 29% in the chemotherapy-alone group.
The 1-year survival rate for the trastuzumab combination treatment
was 79%, as compared with 68% for chemotherapy alone.
In the second trial, trastuzumab was used alone in a group of 222
breast cancer patients who had relapsed following previous
chemotherapy for metastatic disease. The overall tumor response rate
was 14%, with 3% of patients having their tumors completely
disappear. The duration of tumor responses ranged from 6 weeks to 18
months, with a median of 9 months.
In both clinical trials, the patients who responded best to
trastuzumab had the highest levels of HER-2 protein.
Testing of tumors from women with metastatic breast cancer is
critical in order to identify the 25% to 30% of patients who
overexpress HER-2 and who can potentially benefit from trastuzumab
treatment. A new test to measure HER-2 protein in tumors was approved
by the FDAs Center for Devices and Radiological Health (CDRH).
The new test, the DAKO HercepTest, is manufactured by Dako, a company
based in Denmark.
The selection of patients who are most likely to benefit from
trastuzumab therapy is important because along with the benefit for
certain patients comes possible serious risks. The use of
trastuzumab, either alone or in combination with chemotherapy, can
result in a weakening of the heart muscle, which can lead to
congestive heart failure. This potentially life-threatening side
effect was most common in patients who received trastuzumab in
combination with an anthracycline, Adriamycin, and cyclophosphamide
(AC). Because the benefit is not great enough to overcome this
serious risk, trastuzumab is not approved for use together with AC.
All patients treated with trastuzumab should have their heart
function assessed before starting treatment and be closely monitored
during treatment. If patients have heart problems, physicians must be
extremely cautious in deciding whether the potential benefit is worth
Other side effects that were more frequent with trastuzumab plus
chemotherapy as compared to chemotherapy alone included leukopenia,
anemia, diarrhea, abdominal pain, and infections. Side effects that
occurred in about half of the patients during the first infusion
included chills, fever, pain, weakness, nausea, vomiting and
headache. These were treatable and were much less likely to occur
with subsequent infusions.
Trastuzumab is administered as an intravenous infusion given weekly.
It can be administered in an outpatient setting.