Farnesyl Transferase Inhibitor Active in Advanced Breast Cancer

March 1, 2001

SAN ANTONIO-R115777, 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.

SAN ANTONIO—R115777, 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.

HOW FTIs Work: Inhibiting Farnesylation

Farnesyl transferase inhibitors (FTIs) originally were designed to target tumors with a mutated ras oncogene, Dr. Stephen RD Johnston said at the San Antonio Breast Cancer Symposium. But it has become clear, he said, that they may also target tumors with upregulated growth factor receptor pathways that signal through abnormal wild-type ras.

"It is equally clear that inhibition of farnesylation may inhibit other intracellular signaling pathways that are independent of ras," he added.

Farnesylation—the addition of a 15-carbon lipid moiety to the ras protein—makes the protein more hydrophilic and allows it to hook up on the inner surface of the plasma membrane. There, ras can bind GTP and become activated following signaling from upstream-activated growth factors. That can trigger a variety of downstream effector pathways, one of which is the ras MAP kinase pathway.

Ras mutations cause conformational changes in the protein that prevent it from interacting with its hydrolyzing protein. Because the hydrolyzing protein is responsible for deactivating ras (by removing GTP), the ras protein remains permanently activated, which leads to continuous cell proliferation. But ras also could be continuously activated if it were being driven by upstream growth factors that were themselves activated or oncogenic, Dr. Johnston noted.

"In theory at least, it made sense to try to develop a drug that would target this enzyme—which prevents the processing of ras—and that could work either in tumors with mutated ras or in tumors that are being driven through upstream abnormal ras pathways," Dr. Johnston said.

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.

Prelamin A

"In the control tumors, there was no evidence of the precursor—prelamin A—because 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.

Toxicity

"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 neutropenia."

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 (one patient).

Implications for Breast Cancer

"Farnesyl transferase inhibitors represent a novel therapy that has potential implications for breast cancer," Dr. Johnston concluded.

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 [see box]."