CHICAGO—The addition of sorafenib, a multikinase inhibitor, to chemotherapy improved progression-free survival (PFS) in patients with advanced breast cancer who had been previously treated with bevacizumab, according to results of a study in the TIES (Trials to Investigate Efficacy of Sorafenib) program presented by Clifford Hudis, MD, and colleagues from Memorial Sloan-Kettering Cancer Center, New York, at the American Society of Clinical Oncology’s 2011 Annual Meeting. The TIES program, four Phase 2b double-blind, randomized, placebo-controlled screening trials, is evaluating sorafenib + chemotherapy (SOR+CRx) for HER2-negative locally advanced or metastatic breast cancer.

Inhibition of receptor tyrosine kinase activity by sorafenib may overcome bevacizumab resistance in patients treated with bevacizumab whose disease progressed. In two previous TIES studies (SOLTI-0701, NU07B1), SOR+CRx was reported to have activity compared with placebo + chemotherapy (PL+CRx) in patients with no previous bevacizumab therapy. Dr. Hudis and colleagues conducted a third Phase 2b TIES study (AC01B07) to assess if sorafenib improved PFS in 160 patients with disease progression during or following bevacizumab.

Patients were randomized to receive CRx + SOR (400mg orally twice daily) or placebo. Chemotherapy initially consisted of gemcitabine (1,000mg/m2 IV on Days 1 and 8 of a 21-day cycle), but capecitabine (1,000mg/m2 orally twice daily) was later added as an alternative at the physician’s discretion—more than 80% of patients in both arms received gemicitabine versus capecitabine.

Analysis was conducted after 120 PFS events (1-sided α=0.14); with 120 events, an observed hazard ratio (HR) of 0.70 corresponds to 1-sided false-positive error of 0.025. Study results demonstrated that sorafenib was associated with statistically significant improvements in PFS and time to progression (TTP). Median PFS and median TTP was 3.4 months (HR 0.65 [95% CI 0.45–0.95]; P=0.01) and 3.6 months (HR 0.64 [95% CI 0.44–0.93]; P=0.009), respectively, for the SOR+CRx group compared with 2.7 months for the PL+CRx group for both.

The most common Grade 3 adverse event, hand-foot skin reaction/syndrome, occurred in 39% of patients in the SOR+CRx group and 5% of those in the PL+CRx group. Other adverse events included fatigue, stomatitis, thrombocytopenia, and anemia.

Dr. Hudis et al concluded that sorafenib + chemotherapy provides a PFS benefit to patients with disease progression following bevacizumab therapy. Results of the TIES studies support a potential role for sorafenib + chemotherapy in advanced breast cancer. A Phase 3 study, RESILIENCE, is comparing capecitabine in combination with sorafenib or placebo for treatment of locally advanced or metastatic HER2-negative breast cancer. The primary endpoint is PFS and target enrollment is 519 patients.