SAN ANTONIOWomen with metastatic breast cancer who
experience disease progression on trastuzumab (Herceptin) may benefit from
continued treatment with the antibody, according to results of a crossover
study presented by Debu Tripathy, MD, associate clinical professor of medicine,
University of California, San Francisco, School of Medicine. Moreover,
trastuzumab cardiotox-icity was only 2.2% among long-term users.
The study involved a subset of the 469 women enrolled in the
randomized Trastuzumab Pivotal Combination Chemotherapy Trial, which compared
chemotherapy alone to chemotherapy plus trastuzumab. The crossover study was
incorporated into the original trial after trastuzumab’s activity as a single
agent became apparent from other studiesand at the urging of the scientific
and advocacy communities.
"The other important factor was that we really have no
safety or outcome data on patients who are continued on trastuzumab after
progressing on tras-tuzumab-containing therapy," Dr. Tripathy noted.
"This presents a dilemma for the practicing oncologist who wants to take
advantage of some of the synergistic interactions that may exist with other
chemotherapy agents, even after progression."
Patients who progressed in the randomized trial were given the
option to join the crossover study. Participants were then given, at the
discretion of the treating physician, trastuzumab alone or trastuzumab in
combination with chemotherapeutic or hormonal agents that would be considered
standard of care for metastatic breast cancer.
The chemotherapeutic agents used in the original trial were
doxorubicin or epirubicin (Ellence) plus cyclophosphamide or, for patients who
had received anthracycline therapy in the adjuvant setting, paclitaxel (Taxol).
A total of 247 patients from the randomized trial opted to
participate in the crossover study154 patients from the control
(chemotherapy alone) arm and 93 patients from the chemotherapy plus trastuzumab
A significant portion of patients in the crossover study
received trastuzumab alone, Dr. Tripathy said. The remaining patients received
trastuzumab plus chemotherapeutic agents representative of the community
standard for refractory breast cancer. Paclitaxel, vinorelbine (Navelbine), and
docetaxel (Taxotere) were the most commonly used agents.
Patients continued on therapy until withdrawn by their
physician or through their own choice. Tumor assessments were undertaken when
clinically indicated, and responses were judged by the investigators.
Among patients originally given chemotherapy alone in the
randomized trial, the crossover to trastuzumab (alone or in combination)
yielded a response rate of 14%. The clinical benefit rate (complete response,
partial response, or disease stabilization for more than 6 months) in this
group was 32%. Response duration was 7.4 months.
In the group of patients who originally received trastuzumab in
the randomized trial, the response rate was 11%. In this group, 22% received a
clinical benefit from the extended therapy, and response duration was 6.7
"Responses were seen with single-agent Herceptin,
including patients who may have received hormonal therapy, and with Herceptin
plus paclitaxel, vinorel-bine, andto a lesser extentcisplatin [Platinol],
docetaxel, and doxorubicin," Dr. Tripathy said.
No clear predictive factors emerged, other than HER-2-neu 3+
overexpression in the group originally assigned to chemotherapy alone, he said.
Performance status and the site or number of metastases had no effect. There
was, however, a trend toward a greater likelihood of response among patients
who had responded in the randomized trial.
"No clear safety signals emerged, which is an important
observation here," Dr. Tripathy added. "When you look at severe
adverse events, all are less than 15%, and many reflect side effects
attributable to chemotherapy or to progression of carcinomaasthenia, pain,
Among events possibly or probably related to trastuzumab,
cardiac events surfaced as a significant factor. The cardiac event rate was
6.5%, half of which were New York Heart Association class III or IV. Among
patients already receiving the antibody, however, cardiotoxicity was low2
out of 93 patients. "Other events, such as infusion reactions, were seen
at a very low frequency," Dr. Tripathy said.
The researchers concluded that trastu-zumab may be active in
patients who have progressed on a trastuzumab-based therapy and that long-term
treatment with the antibody does not seem to increase the risk of
cardiotoxicity. The individual contribution of trastuzumab, however, could not
be determined from this trial and will need to be addressed in future