FAIRFAX, VirginiaIn women with HER2/neu-positive advanced
breast cancer, augmenting trastuzu-mab (Herceptin)/paclitaxel with carboplatin
(Paraplatin) provides superior response and time to progression, results of a
randomized phase III trial suggest. The response rate was 52% for patients who
received trastuzu-mab/paclitaxel/carboplatin (TPC), significantly higher (P
= .04) than the 36% response rate for trastuzumab/paclitaxel (TP). Time to
progression was 11.2 months for TPC, vs 6.9 months for TP (P = .007).
Investigator Nicholas J. Robert, MD, chairman of the US Oncology Breast
Committee, Fairfax, Virginia, presented the results.
Toxicity of the regimen is "acceptable," with no increase in
incidence of febrile neutropenia vs trastuzumab/paclitaxel, according to Dr.
Robert. "Adverse event profiles are comparable between the two treatment
groups, except there is a greater incidence of neutropenia and thrombocytopenia
in the TPC group."
Builds on Pivotal Trial
Dr. Robert noted that this investigation builds on the pivotal
phase III trial showing TP is significantly superior to paclitaxel alone in
HER2/neu-positive breast cancer (N Engl J Med 344:783-92, 2001).
In that trial, response rate was 41% for TP, vs 17% for paclitaxel alone (P
< .001), while time to progression was 6.9 months for TP and 3.0 months for
paclitaxel alone (P < .001).
"In our trial vs the pivotal trial, there has been a stepwise
improvement in the case of patients with HER2/neu-positive disease. When
carboplatin is added to this combination, the response rate increases to 52%,
and time to progression is now 11.2 months," Dr. Robert said (see
Suspect Increased Synergism
A somewhat higher response rate was noted in patients with
immunohistochemistry (IHC) high-positive status (3+), a group in which
investigators "may suspect an increased synergism between trastuzumab,
paclitaxel, and carboplatin" due to overexpression of HER2/neu, Dr.
Robert said. Among IHC 3+ patients who received TPC, response rate was 57%, vs
37% for TP; time to progression was 13.6 months for TPC vs 7.2 months for TP.
The trial included 196 women (median age 55 years) with stage
IV breast cancer overexpressing HER2/neu (2+ or 3+ by
immunohistochemistry, approximately two-thirds IHC 3+ status) and Eastern
Cooperative Oncology Group (ECOG) performance status 0 to 2. Patients could not
have had prior chemotherapy for metastatic disease.
The TP regimen was similar to that used in the prior pivotal
trial and included paclitaxel 175 mg/m2 every 3 weeks and
trastuzumab until disease progression. The TPC arm included the same TP regimen
plus carboplatin at an area under the concentration-time curve (AUC) of 6 every
Upward Survival Trend
Although it was too early at this meeting to give a final
survival analysis, Dr. Robert said there was a trend toward improved survival (P
= .02) at 12 months, continuing to 24-month and 36-month evaluations.
Incidence of grade 4 neutropenia was 36% in the TPC arm and 12%
in the TP arm, while thrombocytopenia was seen in 9% of TPC patients vs 1% of
TP patients. "With the addition of carboplatin, one might expect more
myelosuppression, and that’s what we found," Dr. Robert said. "However, in
terms of complications, this did not translate into an increase in febrile
neutropenia (5% vs 4%)."
Likewise, incidence of neuropathy, nausea, arthralgias and
other adverse events were similar between groups. One patient developed
congestive heart failure on the TP arm.