BACKGROUND

Farnesyltransferase inhibitors (FTIs) target multiple pathways implicated in the pathogenesis of solid and hematologic malignancies.

METHODS

Novel preclinical and clinical data on FTIs.

RESULTS

Results of clinical trials of FTIs are critically summarized: Phase I - II studies demonstrated that tipifarnib (the most extensively investigated FTI) had antileukemic activity. The rates of complete response (CR), partial response (PR) and/or CR with incomplete platelet recovery (CRp) in patients with MDS and refractory/poor-risk AML were 5 - 25% and 11 - 14%, respectively (hematological improvement, 17 - 35% and 8 - 9.5%, respectively). A Phase III study comparing tipifarnib with best supportive care, including hydroxyurea in patients with untreated AML ≥ 70 years old showed no survival benefit in the tipifarnib arm. A two-gene classifier (RASGRP1:APTX gene expression ratio) predicted response and survival, indicating that a two-gene expression assay may help select patients with AML who would benefit from tipifarnib.

CONCLUSIONS

Patient selection should become a priority for targeted agent drug development. Clinical trials selecting patients who would benefit from FTIs should be designed to define the role of FTIs in the treatment of hematological malignancies and solid tumors.