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Sorafenib plus Capecitabine Superior to Capecitabine Alone in Advanced Breast Cancer
December 11, 2009–During the 2009 San Antonio Breast Cancer Symposium in San Antonio, results were presented by José Baselga, MD (Vall d'Hebron University Hospital), from SOLTI-0701, a trial evaluating the efficacy and safety of sorafenib in combination with capecitabine for the treatment of patients with locally advanced or metastatic breast cancer.
Angiogenesis plays a critical role in the pathogenesis and progression of breast cancer. Sorafenib, an oral multikinase inhibitor targeting VEGFR-1, -2, -3, PDGFR-β, RAF kinase, c-KIT, and Flt-3, is approved for the treatment of patients with hepatocellular carcinoma and advanced renal cell carcinoma, and has also demonstrated activity in combination with cytotoxic agents commonly utilized in breast cancer. Capecitabine is an active antimetabolite commonly used in the treatment of advanced breast cancer.
SOLTI-0701 was a multinational, double-blind, randomized, placebo-controlled phase IIb study evaluating the efficacy and safety of sorafenib versus placebo when administered in combination with capecitabine in patients with locally advanced or metastatic breast cancer. The primary endpoint of SOLTI-0701 was progression-free survival, and secondary endpoints included overall survival, time to disease progression, response rate, duration of response, and safety.
A total of 229 patients with locally advanced or metastatic HER2-negative breast cancer who had received ≤1 prior chemotherapy regimens were randomized to receive capecitabine (1000 mg/m2, orally, twice daily, for 14 of every 21 days) with sorafenib (400 mg orally, twice daily, for 14 of every 21 days) or placebo until disease progression or toxicity. Randomization was stratified by the presence of visceral versus non-visceral disease. Treatment arms were balanced for age, ECOG status, stage, number of metastatic sites, hormone receptor status, and prior chemotherapy.
The following results were obtained from the trial:
- The median progression-free survival in the intent-to-treat population was significantly improved in patients receiving sorafenib plus capecitabine compared with placebo plus capecitabine
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6.4 months versus 4.1 months; P = .0006
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42% reduction in risk of disease progression
- The median progression-free survival benefit was significantly improved with sorafenib when the population in the trial was sub-analyzed by line of therapy
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First-line treatment: 7.6 months versus 4.1 months; P = .0022
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Second-line treatment: 5.7 months versus 4.1 months; P = .0339
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Sorafenib plus capecitabine was favored across all prespecified (hormone receptor status; age; visceral disease; measurable disease; line of therapy; prior use of taxane; prior use of anthracycline) and exploratory (age; disease free interval; number of metastatic sites; country) subgroup analyses
- Overall response rates in both treatment arms were not significantly different
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The all-oral regimen of capecitabine plus sorafenib was tolerable and exhibited a clinically manageable toxicity profile
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The most common adverse events related to treatment discontinuation were hand-foot skin reaction and diarrhea
In summary, the oral combination of sorafenib plus capecitabine demonstrated significant improvement in progression-free survival in patients with locally advanced or metastatic breast cancer. SOLTI-0701 is the first randomized study to demonstrate the efficacy of an all oral regimen for patients with HER2-negative, advanced breast cancer. This study suggests that sorafenib may be a valuable addition to breast cancer therapy when given in combination with chemotherapy. Further evaluation of the combination of sorafenib and capecitabine for the treatment of advanced breast cancer will commence in 2010 with a phase III registration trial.
Cancer Res. 2009;69(Suppl 2): Abstract 45.
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