Intermittent R115777 Equally Effective but Better Tolerated in Breast Cancer Patients

LONDON—Intermittent dosing with R115777 (tipifarnib, also known as Zarnestra) is equally effective as continuous dosing in advanced breast cancer patients, but has significantly less hematologic toxicity, according to a study presented at the American Society of Clinical Oncology 38th annual meeting (ASCO abstract 138).

"This is the first time this novel treatment involving signal transduction inhibition has been tried in a phase II study," said lead author Stephen R.D. Johnston, MD, consultant in medical oncology, Royal Marsden Hospital in London. "Breast is one of the cancers where Zarnestra may prove useful."

R115777 is a potent, orally active nonpeptidomimetic inhibitor of the enzyme farnesyl protein transferase. This class of compounds was initially developed as a therapeutic strategy for tumors with oncogenic Ras mutations because of their action at a key step in the post-translational processing of the Ras protein. By specifically blocking isoprenylation of proteins involved in growth factor dependent cellular signal transduction pathways, these compounds inhibit cell signaling in Ras-transformed cells.

Farnesyl transferase inhibitors have additional effects on other signaling pathways in cancer cells that may also prove useful against breast cancer and other tumors without oncogenic Ras mutations. R115777 in particular has been effective against a variety of breast tumor cell lines regardless of Ras status, and has reduced proliferation in human breast cancer xenografts in vivo.

Two Cohorts of Patients

In this study of 76 patients with locally advanced, recurrent, or progressive metastatic breast cancer, investigators sequentially recruited two cohorts of patients. The first cohort of 41 patients received a continuous dosing regimen of R115777 at 400 mg, later reduced to 300 mg, twice daily. The second cohort of 35 patients received an intermittent cyclical dosing regimen of R115777 at 300 mg twice daily for 21 days every 4 weeks, with 7 days of rest between treatments.

The two cohorts were well matched for demographic and clinical variables, with overall median age 53.5 years (range 32-82) and Eastern Cooperative Oncology Group (ECOG) status of 0 to 2. Prior treatment for advanced disease was similar in both cohorts, including adjuvant endocrine therapy in two-thirds of both groups, and prior chemotherapy in 46% of those on continuous dosing vs 63% of those on intermittent dosing. No patients were deemed eligible for further endocrine therapy, because they had failed tamoxifen or were estrogen-receptor negative.

Median time to progression was 12 to 13 weeks in both cohorts. In the continuous dosing cohort, four patients (10%) had a partial response, and six patients (15%) had stable disease for at least 24 weeks, which in advanced breast cancer may predict as good an outcome as in those with tumor shrinkage, according to Dr. Johnston. In the intermittent dosing cohort, four patients (11%) have had a partial response to date, four patients (11%) have had stable disease for longer than 24 weeks, and in six patients treatment is still ongoing.

"These responses were durable," Dr. Johnston said. Median duration of response was 6 months in patients on continuous dosing and 10 months in those on intermittent dosing. Responses occurred at several sites, including liver, lung, lymph nodes, and skin nodules. Responses occurred in patients who were either estrogen receptor-negative or estrogen receptor-positive, and in patients who were either HER-positive or HER-negative. Only one patient had a Ras mutation.

Continuous Dose Reduced

Because the first six patients in the continuous dosing cohort treated with R115777 at 400 mg twice daily all developed grade 3/4 neutropenia, the subsequent 35 patients on continuous dosing were treated with 300 mg twice daily. The incidence of drug-related hematologic toxicity was significantly lower in the cohort on intermittent dosing than in the group receiving continuous dosing with 300 mg twice daily.

Grade 3/4 neutropenia occurred in 11% of patients on intermittent dosing and in 43% on continuous dosing (P = .003), and grade 3/4 thrombocytopenia occurred in 3% vs 26% (P = .006). While no patients on intermittent dosing developed grade 2/3 neurotoxicity, 15 patients on continuous dosing developed peripheral neuropathy (37%, P < .0001).

"Of the two different schedules tested, the intermittent dosing with 3 weeks on and 1 week off was much better tolerated and much safer from a hematologic and neurologic viewpoint. It is encouraging that it shows activity even in these patients with advanced breast cancer," Dr. Johnston told ONI.

On the basis of these preliminary findings, Dr. Johnston said that R115777 merits further studies among patients with breast cancer, especially with the intermittent dosing regimen. Studies in combination with endocrine therapy are scheduled to start shortly, as preclinical data have suggested that these two therapies may act synergistically.