BETHESDA, Md--Herceptin (trastuzumab, Genentech) has become the first
monoclonal antibody to win support from the Oncologic Drugs Advisory
Committee (ODAC) for use in treating breast cancer. The group voted
unanimously to recommend that the FDA approve Herceptin for treatment
of women with metastatic breast cancers that overexpress the HER2/neu
gene, both as a single agent after first-line chemotherapy has failed
and in combination with paclitaxel (Taxol) as first-line treatment.
Panel member Richard L. Schilsky, MD, director of the University of
Chicago Cancer Research Center, called the studies supporting
Herceptin "perhaps the greatest demonstration of clinical
therapy Ive seen in a solid tumor."
In making the recommendation, ODAC members devoted considerable time
to discussing two issues--the incidence of serious cardiotoxicity
revealed in clinical trials and whether the use of Herceptin should
be limited to women whose tumors carry three times or more the normal
number of HER2 receptors.
Concerns about cardiotoxicity led the panel to vote 9-to-2 against
recommending use of Herceptin in combination with an anthracycline,
while the idea of excluding women with less than triple HER2
expression from Herceptin therapy garnered a mixed reaction from the panel.
HER2 receptors play a role in cell division and multiplication. About
25% to 30% of women have breast tumors that overexpress the gene.
Overexpression is associated with more aggressive tumor growth,
shorter disease-free survival, and a negative prognosis. Herceptin is
a monoclonal antibody (95% human-5% mouse) that binds to HER2
receptors and blocks their growth signals.
Genentech presented two trials in support of its biologics license
application for Herceptin. H0649g was a multicenter, open-label,
single-arm study that involved 222 patients who had had extensive
prior treatment for their metastatic disease. H0648g was a
multicenter, randomized controlled trial in 469 women, none of whom
had been previously treated with a cytotoxic agent for their
metastatic cancer. It compared Herceptin combined with either
paclitaxel or an anthracycline (doxorubicin or epirubicin) plus
cyclophosphamide against chemotherapy alone (paclitaxel alone or anthracycline/cyclophosphamide).
In both studies, patients received a 4 mg/kg infusion of Herceptin to
start and then a weekly dose of 2 mg/kg throughout the course of the
study until they showed evidence of disease progression. In the
Herceptin-alone study, physicians had the option of giving the weekly
dose at 4 mg/kg when they believed it was appropriate for a patient.
According to analyses presented by the company, 34 (15%) of the 222
women in H0649g responded: 8 complete responders and 26 partial
responders. The median time to treatment failure for responders was
11 months; the median duration of response was 9.1 months; median
survival for all patients was 13 months.
In study H0648g, 143 women received Herceptin plus
anthracycline/cyclophosphamide, and 138 received anthracycline/cyclophosphamide
alone; another 92 women got Herceptin plus paclitaxel, while 96
received paclitaxel only.
Total responses were seen in 114 patients (49%) in the
Herceptin-chemotherapy arms vs 74 (32%) in the chemotherapy-only
groups, a difference of 53%. Median time to disease progression was
7.6 months, and median duration of response was 9.3 months in the
Herceptin-chemotherapy women, compared with 4.6 months and 5.9
months, respectively, in the chemotherapy-only arms.
Survival at 1 year was as follows: Herceptin-anthracycline, 58%;
anthra-cycline-only, 52%; Herceptin-paclitaxel, 78%; paclitaxel-only, 62.5%.
Much of the common toxicity associated with Herceptin--diarrhea,
abdominal pain, and stomatitis--was self-limited and could be
controlled with medications and/or adjustments to the infusion rate,
the company and FDA agreed. However, both described an incidence of
cardiotoxicity that troubled the panel.
Genentech first learned about the problem in 1997 when it heard of
four serious cases of cardiotoxicity, Steven Shak, MD, a company
senior scientist told the committee. This finding was unexpected
because no heart problems had been noted in previous animal studies
and phase I and II trials. The company has screened the records of
1,024 women who have taken Herceptin and identified 97 with some form
of cardiac dysfunction, ranging from mild and easily treatable to
severe, said Virginia Paton, PharmD, a Genentech clinical scientist.
The FDA analysis said that car-diotoxicity occurred in 7% of the
patients in H0649g. In the second study, cardiotoxicity rates were
28% in Hercep-tin-anthracycline patients; 7% in the
anthracycline-only arm; 11% with Her-ceptin-paclitaxel; 1% for
Who Is At Risk?
The company attributed no deaths in the study to cardiotoxicity.
However, FDA reviewer Susan Jerian, MD, raised issue with four
deaths, two in the Her-ceptin-anthracycline arm and two in the
anthracycline-only arm. "We certainly feel that cardiotoxicity
contributed to these deaths," she said.
Dr. Shak said that extensive analysis had failed to identify any
particularly high-risk group, with the possible exception of women
over age 60. "So we dont have any way of figuring out who
is at greatest risk," remarked panel member Kathy S. Albain, MD,
of Loyola University Medical Center, Maywood, Illinois.
ODAC members urged further research on the issue and recommended that
the FDA describe the cardiotoxicity issue thoroughly in labeling Herceptin.
How Much Gene Expression?
In examining the Herceptin results, some committee members questioned
its use in women with less than triple (3+) HER2 gene expression.
Data presented by Genentech showed significant benefit in 3+ women,
but little difference in benefit below that level, although the trend
favored women receiving Herceptin.
"I, myself, feel there is no benefit for women with 2+; I would
say restrict Herceptin to 3+ women," said panel member Richard
M. Simon, DSc, chief of NCIs Biometric Research Branch. But
Timothy OLeary, of the Armed Forces Institute of Pathology, who
served as a guest expert for the committee, argued that one could
expect 20% of 2+ women to benefit from Herceptin. And Julie M. Vose
of the University of Nebraska, another ODAC consultant, opposed
restricting Herceptin to 3+ women.