The addition of sorafenib (Nexavar) to capecitabine (Xeloda) improved progression-free survival among women with locally advanced or metastatic HER2-negative breast cancer in a randomized, double-blind, placebo-controlled phase IIB trial. “There was no significant improvement for overall survival,” the investigators reported in the Journal of Clinical Oncology. Median survival was 22.2 months for patients receiving sorafenib vs 20.9 months for those receiving placebo.
SOLTI-0701 Study
A total of 229 patients were randomly assigned to first-line or second-line capecitabine at 1,000 mg/m2 orally twice a day for days 1 to 14 of every 21-day cycle, with sorafenib at 400 mg orally twice a day or placebo. Sorafenib is an oral multikinase inhibitor that has both antiproliferative and antiangiogenic activity. “Prior chemotherapy, including taxane and/or anthracycline treatment, was allowed but was limited to one regimen for advanced disease. Prior hormone therapy and radiation were allowed,” the researchers noted.
Patients receiving sorafenib had a significant improvement in progression-free survival, with a median of 6.4 months vs 4.1 months for those receiving placebo. “This translated into a 42% reduction in the relative risk of disease progression or death,” the authors stated.
The study, SOLTI-0701, was conducted by the SOLTI Spanish Breast Cancer Research Group and supported in part by Onyx Pharmaceuticals and Bayer HealthCare Pharmaceuticals, which also provided sorafenib free of charge and editorial support.
“The dose of sorafenib used in this trial resulted in unacceptable toxicity for many patients,” the investigators concluded. “A phase III confirmatory trial has been initiated with a reduced sorafenib dose.” The most common toxicity was hand-foot skin reaction/hand-foot syndrome, which occurred more frequently in patients receiving sorafenib (90% vs 66% in the control group) and earlier (median time to first incidence 14 vs 64 days). Hand-foot skin reaction/syndrome and diarrhea, which occurred in 58% of patients receiving sorafenib vs 30% of those receiving placebo, were the most common adverse effects leading to discontinuation in both groups of patients.
RESILIENCE Study
The phase III trial, known as RESILIENCE, began recruiting patients in November 2010 and is similar in design to SOLTI-0701, but “uses a different dosing schema and requires a more aggressive and proactive strategy for managing [hand-foot skin reaction/syndrome], with the objective of reducing its incidence, duration, and severity, the authors noted.
In the new trial, “sorafenib is initiated at a total daily dose of 600 mg (200 mg in the morning and 400 mg in the evening) and capecitabine at 1,000 mg/m2 twice a day for 14 of every 21 days, with the option of escalating the daily dose to 800 mg (400 mg twice a day) and 1,250 mg/m2 twice a day, respectively, as tolerated, or reducing the dose to manage toxicity. Because [hand-foot skin reaction/syndrome] emerged early on during the SOLTI-0701 trial, RESILIENCE provides detailed guidance for prophylactic and symptomatic treatment and calls for patients to be monitored closely during the first few months of treatment. The RESILIENCE study will also provide a more robust assessment of [overall survival],” for which SOLTI-0701 was not sufficiently powered, according to the investigators.
“The SOLTI-0701 results suggest a potential role for the combination of sorafenib plus capecitabine in HER2-negative advanced breast cancer but will need to be confirmed in the phase III setting. These results should not be considered practice changing,” the authors stated. “The RESILIENCE study will definitively ascertain the efficacy and safety of this combination.” ■
Baselga J, et al: J Clin Oncol. March 12, 2012 (early release online).
