NEW YORKResearchers at the Chemotherapy Foundation
Symposium XVIII presented findings from two phase II studies of trastuzumab
(Herceptin) in combination with chemotherapy agents with known synergistic
activity. Trastuzumab is a monoclonal antibody shown to be effective in
HER-2/neu-overexpressing breast cancer.
Trastuzumab and chemotherapy have been shown to be superior to
chemotherapy alone in women with HER-2-positive metastatic breast cancer.
"This has created a priority for finding the next generation of Herceptin
and chemotherapy combinations that are both active and safe regimens,"
said Harold J. Burstein, MD, PhD, of the Dana-Farber Cancer Center. He said the
focus was on chemotherapy agents that fit well with the documented toxicity
profile of trastuzumab, which has an excess of cardiotoxicity when paired
with anthracyclines such as doxorubicin.
Trastuzumab Plus Docetaxel
Brenda P. Nicholson, MD, director of the Clinical Breast Cancer
Program, Vanderbilt University Medical Center, reported on an ongoing pilot
study of weekly trastuzumab and docetaxel (Taxotere) as first- or second-line
therapy in patients with HER-2-overexpressing (2+ or 3+) metastatic breast
HER-2 is overexpressed in 25% to 30% of all breast cancers, Dr.
Nicholson said. These tumors are more resistant to standard chemotherapy and
are associated with decreased overall survival. She termed the HER-2 receptor
an "attractive target for antibody-based therapies" because
overexpression occurs not only in primary breast tumors but also at metastatic
sites, while remaining at low levels in normal tissue.
Patients receive an initial loading dose of 4 mg/kg, then 2
mg/kg IV weekly combined with weekly docetaxel (35 mg/m2 IV for 6 of 8 weeks).
To be eligible, participants must have received no prior taxane. Adjuvant
therapy is permitted, but subjects can have had no more than one previous
chemotherapy regimen for metastatic disease, and less than 250 mg/m2 of an
Dr. Nicholson presented preliminary results of the first 21
patients enrolled. The median age was 53 (range, 35 to 73). The median number
of disease sites was two, but ranged up to four. The majority of patients had
lung or liver metastases.
The regimen was well tolerated, with very few grade 3-4
hematologic toxicities. The most common side effects were edema, fatigue,
alopecia, and GI symptoms. There were no congestive heart failure symptoms,
though two patients had a decline from their baseline left ventricular ejection
Response data were based on 19 patients. The overall response
rate was 63%, with 2 complete responses and 10 partial responses. The response
was greater in the tumors with 3+ HER-2 overexpression73% vs 25% in the 2+
tumors. Median time to progression was 12 months and median survival, 18.3
months. The median duration of response has not yet been reached.
Dr. Nicholson acknowledged that the response rate for 2+ tumors
was lower than expected, but said that the small sample size may be
responsible, and the data require further analysis before a definitive
conclusion can be drawn. Currently, 25 patients are enrolled in the multicenter
study, with planned accrual of 34 patients, Dr. Nicholson said.
Trastzumab Plus Vinorelbine
Dr. Burstein presented the final results of a phase II study of
40 patients at Dana-Farber who received trastuzumab plus vinorelbine
(Navelbine), a vinca alkaloid with activity in a variety of solid tumors. As
first-line therapy in breast cancer, vinorelbine has a response rate of 30% to
50%, Dr. Burstein said, and as second-line therapy, the response rate ranges
from 15% to 30%.
It has a favorable side effect profile for use with
trastuzumab. The main toxicities are neutropenia, constipation, neuropathy, and
phlebitis, but it has no significant cardiotoxicity or major GI side effects.
Neither agent causes alopecia.
Study participants had metastatic disease with HER-2-positive
(2+ or 3+) tumors. Prior adjuvant or second-line chemotherapy was permissible,
but patients who had previously received trastuzumab or vinorelbine were
excluded. All had to have an LVEF of at least 50%. Restaging and cardiac
assessment were performed every 8 weeks.
Patients received trastuzumab at the standard dose of 2 mg/kg
weekly after a loading dose of 4 mg/kg. Vinorelbine was given as an initial 25
mg/m2 IV push. Thereafter, the weekly dose was adjusted according to neutrophil
count on the day of treatment. Some patients received an intermediate dose of
15 mg/m2 and those whose neutrophil count was less than 750 got no vinorelbine
Full-dose vinorelbine was given in 80% of all weeks; the
intermediate dose was given in 13% of weeks, and in only 7% of weeks were
patients not treated at all. The median dose was 21 mg/m2/wk.
"As we move forward in an era of combining biological
therapy with chemotherapy, it’s clear that if you want to achieve synergy by
giving both agents together, you’ve got to give both agents together,"
he said. "One of the nice things about this study is that in more than 90%
of the treatment weeks, we were able to give both at the same time."
Toxicity was mild. There was only one episode of grade 4
febrile neutropenia. One third of patients had infusion reactions to
trastuzumab, but these did not preclude receiving the drug. There was some mild
neuropathy, most of which was pre-existing, Dr. Burstein said.
Importantly, there was no symptomatic congestive heart failure
and no significant decline in LVEF over time. A correlation between LVEF and
prior anthracycline therapy was seen.
Patients who had received less than 240 mg/m2 cumulative
doxorubicin and those whose ejection fraction was greater than 60% had no
cardiotoxicity. Among those who had received more doxorubicin and had
borderline ejection fractions at baseline (50% to 60%), three of five had grade
The overall response rate was 75%, with 3 complete responses
and 27 partial responses. Two other patients had stable disease for 6 months or
more. The best response (84%) was seen in patients with no prior therapy. For
second-line therapy, the response was 64%, and for third-line therapy, 71%.
These results "lend themselves to other trials that may answer some
important questions about how to optimally administer Herceptin," Dr.
Burstein said, citing a multicenter validation study currently underway.
Areas to be explored in further study, he said, include how
long to treat with trastuzumab, its use up front, whether chemotherapy needs to
be added for some patients, and its use in adjuvant and neoadjuvant settings. A
multicenter randomized study has been proposed comparing trastuzumab and a
taxane vs trastuzumab and vinorelbine.