Clinical Overview of Sorafenib in Breast Cancer

Authors and Disclosures

Alvaro Moreno-Aspitia

Mayo College of Medicine, Multidisciplinary Breast Clinic, Mayo Clinic Florida, FL, USA Tel.: +1 904 953 7291 Fax: +1 904 953 2315 morenoaspitia.alvaro@mayo.edu

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Executive Summary

General Overview

• Sorafenib is an oral tyrosine kinase inhibitor able to inhibit VEGF receptors 1, 2 and 3, PDGF receptors α and β, RET, Flt3, c-KIT and the RAF kinase and MAPK pathways.

• Over 10,000 patients have been treated with sorafenib as single agent or in combination regimens.

• Sorafenib is US FDA approved for the treatment of advanced renal cell carcinoma and unresectable hepatocellular carcinoma.

• The recommended single-agent dose is 400 mg orally twice a day, at least 1 h before or 2 h after eating.

• Drug-related adverse events include hand–foot syndrome, diarrhea, fatigue, hypertension, pain and rash.

• Concurrent use with docetaxel, doxorubicin or irinotecan increases the exposure to these chemotherapy drugs.

• Concurrent use with carbamazepine, phenobarbital and phenytoin decreases sorafenib concentrations. Similar effects are observed with dexamethasone and St John's wort.

• Monitor international normalized ratio regularly for patients taking concomitant warfarin.

• No dose adjustment is necessary for patients with mild-to-moderate renal or hepatic impairment.

Sorafenib in Breast Cancer

• Sorafenib as a single agent, although well tolerated, does not exhibit significant activity in the treatment of metastatic breast cancer (MBC).

• Sorafenib, in combination with capecitabine, had a statistically significant improvement in the median progression-free survival and time-to-progression in comparison with capecitabine/placebo for patients with MBC.

• Sorafenib-plus-capecitabine is associated with a high incidence of grade 3 hand–foot syndrome/skin reaction (45%).

• Sorafenib-plus-paclitaxel demonstrated a statistically significant improvement in the median time-to-progression, duration of response and objective response rate in comparison with paclitaxel/placebo for patients with MBC. Improvement of progression-free survival also favored the two-drug combination.

• Sorafenib-plus-paclitaxel is also associated with a high incidence of grade 3 hand–foot syndrome/skin reaction (30%).

• Sorafenib might help overcome resistance to the aromatase inhibitors in patients with hormone receptor-positive MBC who have developed resistance to one of these agents.

The Trials to Investigate the Effects of Sorafenib in Breast Cancer program

• The Trials to Investigate the Effects of Sorafenib in Breast Cancer (TIES) program includes four Phase IIb randomized, double-blind, placebo-controlled trials to evaluate the efficacy and tolerability of sorafenib in patients with HER-2 negative locally advanced or MBC:

  • Trial 1: the SOLTI-0701, a multinational study comparing sorafenib-plus-capecitabine versus capecitabine-plus-placebo in previously treated patients with MBC.

  • Trial 2: the NU 07B1, a multinational trial comparing sorafenib-plus-paclitaxel versus paclitaxel-plus-placebo as a first-line regimen in MBC.

  • Trial 3: An American trial comparing sorafenib plus gemcitabine or capecitabine versus gemcitabine or capecitabine plus placebo in MBC patients who have progressed during or after bevacizumab therapy.

  • Trial 4: A multinational European trial comparing sorafenib-plus-docetaxel or -letrozole versus docetaxel- or letrozole-plus-placebo as first-line therapy in patients with MBC.

Future Perspective

• Potential trials may include sorafenib, capecitabine and lapatinib for HER-2-positive MBC and the use of sorafenib as an anti-angiogenic agent in the adjuvant setting of early-stage breast cancer.