ASCO Interim findings from two phase III studies, one a
North American joint analysis and the other a large international trial, have
changed the standard of care for women with early invasive HER2-positive breast
cancer. Trastuzumab (Herceptin) used in addition to standard adjuvant
chemotherapy yielded dramatic responses in these patients, cutting the risk of
both locoregional and distant recurrence in half, and significantly improving
overall survival time. Both studies were reported in a late-breaking scientific
symposium at the 41st Annual Meeting of the American Society of Clinical
Oncology (ASCO), "Advances in Monoclonal Antibody Therapy for Breast Cancer."
The joint analysis combined data from 3,351 patients in two
National Cancer Institute-sponsored trials, NSABP (National Surgical Adjuvant
Breast and Bowel Project)-B31 and NCCTG (North Central Cancer Treatment
Group)-N9831. Each study evaluated a combination of doxorubicin (Adriamycin)
and cyclophosphamide (AC), followed by paclitaxel , with or without trastuzumab,
using different schedules of paclitaxel. The international trial, HERA (HERceptin
Adjuvant), is a 39-country, 5,090-patient study of Herceptin vs observation
following a wide range of primary chemotherapy options.
Efficacy results of the NSABP-B31/NCCTG-N9831 joint analysis
and of the HERA trial were first made public in late April, shortly after they
became available to the investigators, and both trials were stopped early, with
about 2 years and 1 year of median follow-up, respectively, because they had
met their efficacy endpoints (see Table).
Commenting on the "strikingly positive" findings in the two
trials, discussant George W. Sledge, Jr., of the Indiana University Cancer
Center, told a packed ASCO audience: "Ladies and gentlemen, biology has
spokenand we should listen." In particular, he noted, the extraordinarily high
disease-free-survival (DFS) response seen with trastuzumab in the joint
analysis "is certainly the most stunning result that I have seen in an adjuvant
trial during my entire professional career . . . with a P value
astonishing beyond belief."
Joint Analysis Permitted
Because NSABP-B31 and NCCTG-N9831 were so similar in design,
FDA permitted a joint analysis, said NSABP study chair Edward Romond, MD. Dr.
Romond, associate professor of medicine, University of Kentucky, Lexington,
presented the findings from the joint analysis. NCCTG chair Edith Perez, MD,
presented further analysis of NCCTG-N9831, and in a poster presentation she
discussed interim cardiac safety data from that trial (abstract 556). Dr. Perez
is professor of medicine, Mayo Medical School; director, Clinical
Investigations; and director of the Breast Cancer Program, in the Division of
Hematology/Oncology, Mayo Clinic, Jacksonville, Florida.
Women with operable breast cancer whose tumors overexpressed
HER2 were enrolled in NSABP-B31 and NCCTG-N9831 in early 2000. The joint
analysis is on data from 3,351 patients: 1,736 women in NSABP-B31 and 1,615
women in NCCTG-N9831. Half of the women in all arms had 1 to 3 positive nodes,
and about 25% had 4 to 9 positive nodes. Half were ER+ and 40% were PR+. Tumor
size was less than 4 cm in about 80% and less than 2 cm in about 40% of
patients; 15% of patients had tumors larger than 4 cm.
In both trials, Dr. Romond said, AC was given as 60 mg/m2
doxorubicin every 3 weeks and 600 mg/m2 cyclophosphamide every 3
weeks, for four cycles, followed by paclitaxel. In NSABP-B31, paclitaxel was
given at 175 mg/m2 every 3 weeks for four cycles; in NCCTG-N9831,
paclitaxel was given at 80 mg/m2 every week for 12 cycles. Women
with hormone-positive tumors received adjuvant hormonal therapy.
In both trials, trastuzumab was administered at a 4 mg/kg
loading dose plus 2 mg/kg weekly for 51 cycles. NCCTG-N9831 had three study
arms, two of which included trastuzumab given either sequentially (arm B) or
concurrently (arm C) with paclitaxel at the 80 mg/m2 dose. Data from
arm B of N9831 were not included in the joint analysis, Dr. Romond explained,
because the NSABP-B31 trial only looked at trastuzumab concurrent with
paclitaxel. The study arm for the joint analysis, therefore, was AC followed by
paclitaxel plus trastuzumab, and the control arm was AC followed by paclitaxel.
Findings of the first interim intent-to-treat analysis of
395 DFS events were dramatic: Use of trastuzumab reduced the overall risk of
local recurrence at 3 years by 52% (hazard ratio [HR] = 0.48, 2P = 3 ´ 10-12),
with 261 recurrences in women on chemotherapy alone vs 134 in those on
trastuzumab. The absolute reduction in risk of recurrence by Kaplan-Meier
analysis was 12% with trastuzumab at 3 years, and 18% at 4 years. No difference
was seen in relative benefit from trastuzumab by age, hormone-receptor status,
tumor size, number of positive nodes, or the trastuzumab protocol in which the
patient was enrolled.
Time to first distant recurrence, assessed as a surrogate
for overall survival, showed that trastuzumab plus chemotherapy reduced the
overall probability of distant metastases by 53% at 3 years, (HR = 0.47, 2P = 8
´ 10-10). The estimated absolute reduction in risk with trastuzumab
was 9% at 3 years and 16% at 4 years. Results at a median overall follow-up
time of 2 years showed trastuzumab conferred a 33% reduction in mortality (HR =
0.67, 2P = .015). The estimated absolute reduction in risk of death with
trastuzumab was 2.5% at 3 years and 4.8% at 4 years.
In a separate discussion of findings from NCCTG-9831, which
assessed benefits of trastuzumab given sequentially vs concurrent with
chemotherapy, Dr. Perez commented that "a 36% improvement in [disease-free]
survival was seen with the concurrent vs the sequential approach" (P =
.0114), with 84 recurrences seen among patients who received trastuzumab
sequentially vs 53 among women who received it concurrently with chemotherapy,
though "more follow-up is needed to determine whether this trend continues." A
13% decreased recurrence was seen with sequential vs control treatment (P
= .2936, NS).
While chemotherapy of the type given in the NCCTG and NSABP
trials carries a risk of congestive heart failure (CHF) of less than 1%,
investigators found in the joint analysis that the risk of CHF in women
receiving chemotherapy plus trastuzumab was increased by 3% to 4%. In the
separate cardiac safety analysis of NCCTG-N9831, a 2.2% greater incidence of
cardiac events vs control was seen with sequential therapy, and a 3.3%
increased incidence was seen with concurrent therapy, but at this point in the
analysis the confidence intervals overlap, Dr. Perez pointed out.
Drs. Romond and Perez both underscored the importance of
general cardiac monitoring in all patients if trastuzumab is to be used in this
regimen in the adjuvant setting.
"I’m very honored to have been a part of this trial," Dr.
Perez told ONI. "These [HER2-positive women] are patients who might have
poor prognosis despite antiestrogen treatment and the chemotherapeutic agents
available. As physicians, we work in the hope that we will be able to
positively impact people’s lives. It has been 7 years since we devised this
study, but the results will affect treatment for breast cancer for years to
come. We have changed the standard of care: Patients following resection should
have chemotherapy plus Herceptin to minimize the risk that cancer could return.
We may be able to improve on the answer, but now we have the answer."
In an interview, Dr. Perez said that many physicians and
patients have contacted her about starting trastuzumab even if their
chemotherapy was completed several years ago. "At this time, she said, "we do
not know if there is a benefit of adding Herceptin beyond 7 weeks of completion
of chemotherapy [as was done in the HERA study, described below], but our
preliminary data suggest that it is best to add Herceptin along with paclitaxel
instead of waiting to complete chemotherapy."
The randomized phase III HERA study evaluated duration of
trastuzumab treatment in women with early-stage HER2-positive invasive breast
cancer, and was conducted by investigators from the Breast International Group
(BIG) and other non-BIG groups in collaboration with Roche.
HERA evaluated use of adjuvant trastuzumab given every 3
weeks for 12 or 24 months vs observation following a variety of standard
adjuvant chemotherapy regimens given before or after surgery, and radiotherapy
Both lymph-node-positive and lymph- node-negative patients
were included in the trial, with about one-third of patients being node
negative. Most patients received an anthracycline but did not receive a taxane.
The findings were presented at ASCO by lead investigator and
chair of BIG Martine J. Piccart-Gebhart, MD, PhD, associate professor of
oncology, Universite Libre de Bruxelles, and head of the Department of
Medicine, Jules Bordet Institute, Brussels, Belgium.
The interim analysis in 3,387 women compared Herceptin vs
observation but did not include a comparison of 12 months vs 24 months; these
data are not mature but will become available later in the study.
An interim intent-to-treat analysis at 475 DFS events in
3,387 women at 1-year follow-up met its primary efficacy endpoint by showing
that patients who received trastuzumab had significant improvement in DFS, with
a 46% reduction in likelihood of recurrence (HR = 0.54, P < .0001);
recurrences of all types (two-thirds, however, were distant metastases) were
seen in 127 patients randomized to 12-month trastuzumab vs 220 randomized to
observation. This reduction translates to an absolute improvement in 2-year DFS
In discussing the DFS benefit according to subgroups, Dr.
Piccart commented, "There does not appear to be significant heterogeneity of
the impressive treatment benefit observed according to nodal status, type of
prior adjuvant chemotherapy, receptor status, age, and region of the world."
The secondary endpoint of overall survival has not yet been reached, possibly
owing to short follow up, with 37 deaths in the observation group and 29 in the
12-month trastuzumab group.
Incidence of CHF was 0.5% in the 12-month trastuzumab group
vs 0 for patients randomized to observation. The study’s Independent Data
Monitoring Committee found no safety concerns, and patients will continue to be
followed for side effects.
Breast Cancer Endgame
In discussing results of both the joint analysis and HERA,
Dr. Sledge noted that "we can now see the outlines of the breast cancer
endgame," with treatment targeting based on biological subsets of patients,
such as those with ER and HER2 positivity; "upstream-downstream" targeting of
the HER2 pathway; combinations with novel therapeutics such as anti-VEGF
agents; and genomic/proteomic tailored strategies using older agents, eg, CMF [cyclophosphamide-methotrexate-fluorouracil]
It is telling that in both the joint analysis and HERA,
trastuzumab not only significantly reduced the risk of locoregional recurrence
but also cut the risk of distant metastases, he said, pointing out that both
trials illustrate "how rapidly patients suffer a recurrence of their disease in
the absence of Herceptin."
Regarding cardiac risk , he said, "there is no question that
the benefits of Herceptin far outweigh the risks here, but the price is real,
and it has to be discussed with every patient receiving an anthracycline in
close proximity to trastuzumab."