Clinical Overview of Sorafenib in Breast Cancer

Alvaro Moreno-Aspitia


Future Oncol. 2010;6(5):655-663. 

In This Article

Sorafenib Plus Endocrine Therapy

Preclinical data have demonstrated that the combination of the aromatase inhibitor letrozole and sorafenib on breast cancer cells produced a synergistic inhibition of cell proliferation associated with a downregulation of the cell cycle regulatory proteins c-myc, cyclin D1 and phospho-Rb and possibly preventing the acquisition of resistance towards letrozole.[59] A Phase I/II trial of letrozole and sorafenib was presented at the 2009 American Society of Clinical Oncology Breast Cancer symposium.[60] In this study, letrozole was given at 2.5 mg daily with escalating doses of sorafenib as first-line treatment for hormone-receptor positive MBC. The primary objectives were to determine the safety and CBR of letrozole and sorafenib. A total of nine patients were enrolled in the Phase I portion and dose-limiting toxicity was defined in cycle 1. Among the six patients who were evaluable for response (with the caveat that all of them were part of the Phase I portion of the study), three patients achieved a partial response and three had stable disease (one at 5 months, two at ≥ 6 months). The combination was deemed to have a manageable toxicity profile, and the recommended dose for the ongoing Phase II trial is letrozole 2.5 mg daily with sorafenib 400 mg twice daily. A fairly similar Phase I/II study of sorafenib with anastrozole to overcome resistance to the aromatase inhibitors in patients with hormone receptor-positive MBC who had developed resistance to one of the aromatase inhibitors was presented at the 2009 SABCS.[61] Eligibility criteria included post-menopausal women with estrogen or progesterone receptor-positive MBC with disease recurrence or progression on an aromatase inhibitor, who had received no more than two prior chemotherapies for MBC. Primary objectives were to determine the recommended dose and CBR (complete response, partial response and stable disease ≥ 24 weeks) of sorafenib with anastrozole. Secondary objectives were to determine toxicity, enumerate circulating endothelial cells as an angiogenesis biomarker and analyze the effect of treatment on CYP3A4-metabolized steroids. Based on the Phase I portion of the trial, the recommended Phase II dose of sorafenib was 400 mg twice daily. Interim analysis of the first 12 patients showed more than 30% CBR, allowing for continued accrual to the planned 35 patients. Results indicated that among these 35 patients, the overall CBR was 20% (five patients had stable disease for > 24 weeks, two had durable partial response for > 6 months, 19 had progressive disease before 6 months, 8 were not response evaluable and one on active therapy was deemed too early to evaluate for response). The combination was well tolerated and most AEs were generally grade 1/2. The most common AEs (all grades; grades 3/4) were fatigue (66%; 14%), diarrhea (54%; 6%), nausea/vomiting (60%; 9%) and skin rash of any kind (66%; 43%) including hand–foot syndrome (57%; 34%). Grade 3/4 hypertension occurred in 11% of patients. Preliminary correlative analysis suggested that a decrease in circulating endothelial cells from baseline to 1 week after treatment appeared to predict a positive response. Given the modest-to-negligible activity of single-agent sorafenib in MBC,[49–50] the authors of the study felt that the benefit may be attributable to the restoration of sensitivity to aromatase inhibitors through inhibition of the Ras/Raf/MAPK pathway.


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