SAN ANTONIOR115777, an orally active farnesyl
transferase inhibitor (FTI), has shown clinical activity in the first phase II
trial of an FTI in breast cancer, according to Stephen RD Johnston, PhD, senior
lecturer and consultant medical oncologist, Royal Marsden Hospital and
Institute of Cancer Research, London.
The researchers initially evaluated the effect of R115777 in a
breast cancer xenograft murine model using MCF-7 cells.
To test the agent’s ability to inhibit farnesylation (see box), they developed an assay to detect the precursor for a normally
farnesylated protein, reasoning that successful inhibition of farnesyl
transferase should result in increasing levels of the precursor.
"In the control tumors, there was no evidence of the
precursorprelamin Abecause all of the protein was farnesylated," Dr.
Johnston reported. "But as we gradually inhibited the enzyme, we started
to detect more of the prelamin A precursor, indicating a blockage of the
pathway in a dose-dependent manner."
In the excised tumors, he said, increased detection of prelamin
A was consistent with a dose-dependent increase in apoptosis. Doses of 50 mg/kg
and 100 mg/kg both resulted in an approximately two- to threefold increase in
induction of apoptosis.
Phase II Results
The clinical trial, reported at the 23rd Annual San Antonio
Breast Cancer Symposium, enrolled 41 patients with locally advanced or
metastatic breast cancer who were not suitable for further endocrine therapy,
either because they were estrogen-receptor (ER) negative or they had failed
first- and second-line endocrine therapy.
Patients were allowed to have received one prior chemotherapy
for their metastatic disease, and they had to have good performance status and
normal organ function.
The mean age of the group was 58 years (range, 32 to 79 years).
Patients received oral R115777 twice a day, most often in a 300-mg dose. The
primary endpoint of the study was evidence of clinical activity. Four patients
(10%) achieved a partial clinical response, and six patients (15%) had clear
stabilization of their disease for at least 6 months, Dr. Johnston reported.
"This is a validated and respected clinical endpoint for
endocrine therapy and indeed for agents believed to be cytostatic in
action," Dr. Johnston said. "So using the clinical benefit rate that
we’re used to talking about with endocrine therapy, we can say that 25% of
the patients derived some form of clinical benefit."
Among the remaining patients, 11 experienced no change, 19 had
progressive disease, and one was not evaluable.
Some of the sites of response to R115777 were lung, liver, and
skin. Duration of response ranged from 4 to 12 months for the objective
responses and from 6 to 12 months for patients with disease stabilization.
The researchers could find no significant correlations between
response and hormone-receptor status, HER-2 status, or epidermal growth factor
receptor (EGFR) status.
"Hematologic toxicity is the dose-limiting toxicity with
this agent," Dr. Johnston said. "We initially treated six patients
with a 400-mg dose, based on phase I data at the time, but it was clear that
with continuous dosing, the patients were developing grade 3-4
Therefore, he said, the remaining 35 patients were started at
300 mg twice daily. Of these patients, 43% developed an episode of grade 3-4
neutropenia, but it was not clinically significant in the majority of patients.
In addition, six patients had evidence of peripheral neuropathy
after 3 to 4 months of therapy. The dosing schedule has since been changed to 3
weeks on/1 week off, and no peripheral neuropathy has been seen in an
additional 20 patients treated on this schedule.
R115777 is otherwise well tolerated, Dr. Johnston said. Minor
toxicities include fatigue (three patients), rash (one patient), and diarrhea
Implications for Breast Cancer
"Farnesyl transferase inhibitors represent a novel therapy
that has potential implications for breast cancer," Dr. Johnston
Responses have been seen independent of HER-2 or ER status,
"but there is a cluster of responses in the HER-2/ER-positive
phenotype," he noted. "If nothing else, this is proof of the
principle that you can get a response to this therapy independent of ras
mutation status in situations in which growth factors may be driving the tumor