Annals of Oncology Advance Access originally published online on January 19, 2009
Annals of Oncology 2009 20(4):642-647; doi:10.1093/annonc/mdn689
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breast cancer |
Phase II trial of the farnesyltransferase inhibitor tipifarnib plus fulvestrant in hormone receptor-positive metastatic breast cancer: New York Cancer Consortium Trial P6205
1 From the New York Cancer Consortium®, including the Montefiore-Einstein Cancer Center, Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx
2 Weill Cornell Medical Center, Weill Cornell Medical College, New York
3 Columbia Presbyterian Medical College, New York
4 Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, USA
* Correspondence to: Dr T. Li, Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, 1825 Eastchester Road, 2 South, Room 55, Bronx, NY 10461, USA. Tel: +1-718-904-2900; Fax: +1-718-904-2892; E-mail: tli{at}montefiore.org
Background: Fulvestrant produces a clinical benefit rate (CBR) of 
45% in tamoxifen-resistant, hormone receptor (HR)-positive metastatic breast cancer (MBC) and 32% in aromatase inhibitor (AI)-resistant disease. The farnesyltransferase inhibitor tipifarnib inhibits Ras signaling and has preclinical and clinical activity in endocrine therapy-resistant disease. The objective of this study was to determine the efficacy and safety of tipifarnib–fulvestrant combination in HR-positive MBC.
Patients and methods: Postmenopausal women with no prior chemotherapy for metastatic disease received i.m. fulvestrant 250 mg on day 1 plus oral tipifarnib 300 mg twice daily on days 1–21 every 28 days. The primary end point was CBR.
Results: The CBR was 51.6% [95% confidence interval (CI) 34.0% to 69.2%] in 31 eligible patients and 47.6% (95% CI 26.3% to 69.0%) in 21 patients with AI-resistant disease. A futility analysis indicated that it was unlikely to achieve the prespecified 70% CBR. Tipifarnib dose modification was required in 8 of 33 treated patients (24%).
Conclusions: The target CBR of 70% for the tipifarnib–fulvestrant combination in HR-positive MBC was set too high and was not achieved. The 48% CBR in AI-resistant disease compares favorably with the 32% CBR observed with fulvestrant alone in prior studies and merit further clinical and translational evaluation.
Key words: farnesyltransferase inhibitor, fulvestrant, metastatic breast cancer, postmenopausal, selective estrogen receptor downregulator, tipifarnib
Received for publication September 22, 2008. Accepted for publication September 30, 2008.
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