Sunitinib Disappoints in First-line Phase 3 Trial in Advanced Breast Cancer

October 1, 2012
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By William B. Ershler, MD

Synopsis: Preclinical studies provide a rationale for examining a role for sunitinib in the treatment of breast cancer. However, in this large, multicenter trial, the combination of sunitinib with docetaxel did not prolong progression-free or overall survival when compared to docetaxel alone, and it appeared to be less well tolerated. The role for sunitinib remains to be established for the treatment of breast cancer.

Source: Berg J, et al. First-line treatment of advanced breast cancer with sunitinib in combination with docetaxel versus doctaxel alone: Results of a prospective, randomized phase III study. J Clin Oncol 2012;30:921-929.

In laboratory and early clinical trials, sunitinib, an oral inhibitor of receptor tyrosine kinases including vascular endothelial growth factor (VEGF) receptors,1 platelet-derived growth factor (PDGF) receptors,1,2 stem cell factor receptor,2 and colony-stimulating factor-1 (CSF-1) receptor3,4 has demonstrable activity against breast cancer,4 either when used alone,5 or in combination with cytotoxic chemotherapy.6 Thus, a rationale was established for examining sunitinib in a larger Phase 3 setting. The Pfizer-sponsored trial conducted throughout Europe was presented in early form at ASCO 2010 and in more detail in this manuscript.

The underlying hypothesis was that the combination of sunitinib with docetaxel would be superior to docetaxel alone in prolonging progression-free survival (PFS) as first-line therapy for women with advanced breast cancer. This was a multi-institutional study enrolling 593 patients from 127 sites in 27 countries. Patients were randomly assigned to open-label combination therapy (sunitinib 37.5 mg/d, days 2 to 15, every 3 weeks; and docetaxel 75 mg/m2, day 1, every 3 weeks) or monotherapy (docetaxel 100 mg/m2, every 3 weeks). PFS was the primary endpoint.

Patients were randomly assigned to combination therapy (n = 296) or monotherapy (n = 297). Median PFS times were 8.6 and 8.3 months with combination therapy and monotherapy, respectively (hazard ratio, 0.92; one-sided P = 0.265). The objective response rate was significantly higher with the combination (55%) than with monotherapy (42%; one-sided P = 0.001). Duration of response was similar in both arms (7.5 months with the combination vs 7.2 months with monotherapy). Median overall survival (OS) times were 24.8 and 25.5 months with combination therapy and monotherapy, respectively (one-sided P = 0.904). There were 107 deaths with the combination and 91 deaths with monotherapy. The frequency of common adverse events (AEs) was higher with the combination, as were treatment discontinuations caused by AEs.


This was a large and very well coordinated clinical trial. Because of the varying doses of docetaxel used in the two different arms, the study was conducted open-label, and methodologically this could introduce some bias. Acknowledging this, all responses and endpoints were confirmed by a central committee and compared with the clinical responses recorded at each center. In general, there was agreement, and where there was some discordance, it was of little consequence to the overall study results and conclusions. Curiously, responses early-on were more apparent in the combination group, but this better response rate did not translate to improvements in either PFS or OS.

Furthermore, despite the lower dose of docetaxel used in the combination, adverse events were, if anything, greater with the combination group, as was the death rate (107 in the combination group and 91 in the docetaxel alone group), including those patients who died during the treatment phase (12 in the combination and four in the docetaxel alone group). The range of toxicities was comparable in both groups except for the appearance of hand-foot syndrome, which was greater in the combination (17% vs 1%).

Two other Phase 3 studies have been reported in which sunitinib has been combined with cytotoxic chemotherapy. The Robert study7 also compared first-line treatment for advanced breast cancer using either sunitinib or bevacizumab in combination with paclitaxel, and the authors concluded that the bevacizumab combination was superior in that response duration was longer and the combination better tolerated. In an additional Phase 3 study in pre-treated advanced breast cancer patients and published in abstract form,8 capecitabine plus sunitinib was not superior and had greater toxicity than capecitabine alone.

Thus, despite the encouraging preclinical results, the use of sunitinib for patients with advanced breast cancer is not recommended. Its role in this disease either in combination with other drugs or at different doses remains to be established.


1. Mendel DB, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: Determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003;9:327-337.

2. Abrams TJ, et al. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther 2003;2:471-478.

3. Murray LJ, et al. SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model. Clin Exp Metastasis 2003;20:757-766.

4. Abrams TJ, et al. Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a single agent and in combination with "standard of care" therapeutic agents for the treatment of breast cancer. Mol Cancer Ther 2003;2:1011-1021.

5. Burstein HJ, et al. Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 2008;26:1810-1816.

6. Bergh J, et al. Clinical and pharmacokinetic study of sunitinib and docetaxel in women with advanced breast cancer. Breast 2012;21:507-513.

7. Robert NJ, et al. Sunitinib plus paclitaxel versus bevacizumab plus paclitaxel for first-line treatment of patients with advanced breast cancer: A phase III, randomized, open-label trial. Clin Breast Cancer 2011;11:82-92.

8. Crown J, et al. Phase 3 trial of sunitinib in combination with capecitabine vs capecitabine alone in previously treated HER2-neagative advanced breast cancer. J Clin Oncol 2010;28(116s):LBA1011.