SAN ANTONIOAdding weekly paclitaxel (Taxol) and
carboplatin (Paraplatin) to trastuzumab (Herceptin) improves disease control
among women with advanced breast cancer, according to results of an ongoing
phase II trial reported by Howard A. Burris III, MD, director of drug
development, Sarah Cannon Cancer Center, Nashville.
The rationale for the study, Dr. Burris said, was the
documented activity of trastuzumab and paclitaxel in randomized clinical
trials, the established efficacy of a paclitaxel/carboplatin combination, and
preclinical work suggesting a synergistic effect between trastuzumab, the
taxanes, and the platinums.
The overall aim of the study was to develop a combination
chemotherapy regimen that might avoid the cardiotox-icity seen when trastuzumab
is combined with anthracyclines.
The researchers enrolled 52 patients with metastatic disease
(mean age, 52). Eligibility requirements included 2+ or 3+ overexpression of
HER-2-neu, normal organ function, no previous chemotherapy for metastatic
disease, and no prior trastuzumab therapy or weekly taxane treatment.
Prior adjuvant chemotherapy was permitted if completed at least
3 months before the study began. Previous treatment with paclitaxel on a 3-weekbut
not weeklyschedule also was allowed.
Thirty of the women were hormone-receptor positive; 35 were
HER-2-neu 3+ overexpressers; 28 had undergone prior adjuvant chemotherapy (20
with doxorubicin and 12 with 3-week paclitaxel), and one had received a stem
cell transplant. Performance status was 0-1 for 50 patients and 2 for 2
All patients were placed on an 8-week induction regimen of
trastuzumab, with a loading dose of 8 mg/kg followed by 4 mg/kg each week. At
the end of 8 weeks, patients were evaluated and assigned to one of three
Patients who had achieved at least a minor response to
the antibody (25% or greater reduction in their disease) continued on
trastuzumab for another 8 weeks and then converted to a weekly regimen of
lower-dose trastuzumab (2
mg/kg), paclitaxel (70 mg/m2), and carboplatin (AUC 2.0).
Patients whose disease remained stable during the 8-week
trastuzumab induction (25% or less change in their disease) went straight to
the lower-dose trastuzumab plus paclitaxel and carbo-platin regimen.
Patients whose breast cancer progressed during
single-agent trastuzumab therapy were taken off the monoclonal antibody and
placed on the weekly paclitaxel/carboplatin regimen.
Therapy was given in 8-week cycles6 weeks on, followed by a
2-week rest period.
Among 46 patients who completed induction therapy and could be
evaluated for response, single-agent trastuzumab produced 1 complete remission,
9 partial remissions, and 2 minor responses. Fourteen patients had stable
disease, 14 progressed, and 6 were too early to evaluate. The overall response
rate to trastuzumab alone was 25%, and two thirds of the patients experienced
disease stabilization or better, Dr. Burris reported.
Among the 20 patients who ultimately received the three-drug
regimen (including some patients who received 16 weeks of trastuzumab), there
were 3 complete remissions, 6 partial remissions, 1 minor response, 1
stabilization, 5 progressions, and 4 patients who were too early to evaluate.
The overall response rate of this group (complete and partial
remissions) was 56%, with nearly 70% of patients achieving stabilization or
Many of the 14 patients who progressed on the trastuzumab
induction therapy benefited from paclitaxel/carboplatin therapy. "One
complete remission and six partial remissions have been documented in this
group, for a response ratealbeit small numbersof 58%," Dr. Burris
said. "Certainly this is encouraging activity for a group of patients
believed to be refractory to Herceptin."
The regimens were very well tolerated overall, he said. Brief
and reversible myelosuppression was the primary toxicity: Seven patients
experienced grade 3 and one patient grade 4 neutropenia. Nonhematologic
toxicities were minimal, with only a few patients reporting myalgia, fatigue,
Cardiotoxicity data were available for 34 patients who had
sequential evaluations on MUGA (multigated angiogram) or echocardiogram, Dr.
Three of these patients had asymptomatic ejection fraction
declines. One patient had a drop from 55% to 36% after 6 months. That patient
was taken off trial, and her ejection fraction returned to 55%. Two patients
experienced declines from 45% to 29% and 63% to 38% at 8 and 5 months,
respectively. Both were treated medically and had no symptoms of congestive
Concerning the overall activity of the regimens tested, Dr.
Burris noted that the best overall response, whether with trastuzumab or the
combination, was 63%, including four complete remissions. The median time to
progression was 12 months.
Although longer follow-up is required on many patients, Dr.
Burris noted, the actuarial progression-free survival at 1 year was 47%;
overall survival was 78% at 1 year and 64% at 2 years.
The study results also suggest that the durability of response
may be better in HER-2-neu 3+ overexpressers. "If you look at the
the 2+ overexpressers, there is a trend for the 3+ overexpressers to do better
with this regimen," he added. "Again, there are too few patients to
reach statistical significance, but the curve is still nicely separated at the
12- to 18-month mark."