Efficacy and Tolerability of Two Dosing Regimens of R115777 (Zarnestra), a Farnesyl Protein Transferase Inhibitor, in Patients with Advanced Breast Cancer

Reviewer: Mary Kara Bucci, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: May 19, 2002

Presenter: Stephen R. Johnston
Presenter's Affiliation: Royal Bournemouth Hospital, Bournemouth, UK
Type of Session: Scientific

Background

Farnesylation is a process that activates proteins involved in growth factor dependent signal transduction pathways. Farnesyl transferase inhibitors are a novel class of agents that specifically block this process. The ras gene encodes for a membrane associated protein that is an integral part of these signal transduction pathways, and is activated by farnesylation. Farnesyl transferase inhibitors were specifically designed to be active in tumors with a mutated ras pathway. Zarnestra, an orally active farnesyl transferase inhibitor, has been previously demonstrated to have anti-tumor activity both in vitro and in vivo, independent of a mutation in the ras pathway. This phase II study is designed to assess the safety and efficacy of this agent in advanced breast cancer.

Materials and Methods

Zarnestra was given as single agent oral therapy to 76 patients treated on two different dosing schedules.
The first 41 patients received a continuous dose (CD) of either 300 or 400 mg twice a day.
The dose was reduced from 400 mg to 300mg after 6 patients in the CD group developed grade 3/4 neutropenia at the 400 mg dose.
The second group of 35 patients received an intermittent dose (ID) of 300 mg twice a day for 21 days, followed by 7 days of no therapy.

Results

4 (10%) patients in CD group and 5 (14%)in the ID group had a partial resonse.
6 (15%) in the CD group and 3 (9%) in the ID group had stable disease.
Mean time to progession was 13.6 months in the CD group, and 12.0 months in the ID group.
Duration of PR was 6.1 months in the CD group and 9.6 months in the ID group.
Duration of clinical benefit, defined as the rate of PR + SD, was 11.9 months in the CD group and 8.7 months in the ID group.
15 patients in the CD group developed neuro-toxicity, including 14 patients in the 300mg dose group, comared to no patients in the ID chort (0 vs. 37%, p<0.001).
Medain time to onset of neurotoxicity was 12.4 weeks.
By cumulative dose received, pts in the ID group had markedly less neurotxocity of any grade than patients in the CD group.

Author's Conclusions

Zarnestra shows evidence of activity with durable response in metastatic breast cancer.
The neuro-toxicity associated with Zarnestra was affected by the dosing schedule, with less toxicity seen in the intermittent dose group.
Zarnestra showed similar clinical efficacy in both the continuous dose and the intermittent dose groups.
Further studies of this agent in combination with other chemotherapeutics in breast cancer are planned.

Clinical/Scientific Implications

The FTI drugs are another of the unique classes of agents that target an abnormally expressed gene product. Specifically this drug works in the presence of overexpression of RAS which is also associated with resistance to radiation therapy. The effect of dosing schedule on toxicity profile seen here is consistent with data from GI cancers. Further studies of this agent, both alone and with other agents, are warranted. Also, studies are ongoing using this agent combined with radiation therapy for locally advanced lung cancer.

Oncolink's ASCO Coverage made possible by an unrestricted Educational Grant from Bristol-Myers Squibb Oncology.