A double-blind, randomised, placebo-controlled, phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer.

Background: We conducted a phase 2b, randomised, double-blind, placebo-controlled screening trial to evaluate the addition of the multikinase inhibitor sorafenib (antiproliferative/antiangiogenic) to first-line paclitaxel for human epidermal growth factor receptor 2 (HER2)-negative locally recurrent/metastatic breast cancer.

Methods: Patients were randomised to paclitaxel (90mg/m(2), weekly, intravenously, 3 weeks on/1 week off) plus sorafenib (400mg, orally, twice daily) or placebo. The primary endpoint was progression-free survival (PFS). A sample size of 220 patients was planned with relative risk ≤ 0.82 (1-sided α=0.14) after 120 events supporting a treatment effect.

Findings: Patients were randomised in India (n=170), the United States (n=52) and Brazil (n=15). Median PFS was 6.9 months for sorafenib versus 5.6 months for placebo (hazard ratio (HR)=0.788; 95% confidence interval (CI), 0.558-1.112; P=0.1715 [1-sided P=0.0857]). The addition of sorafenib increased time to progression (median, 8.1 versus 5.6 months; HR=0.674; 95% CI 0.465-0.975; P=0.0343) and improved overall response (67% versus 54%; P=0.0468). Overall survival did not statistically differ (median, 16.8 versus 17.4 months; HR=1.022; 95% CI 0.715-1.461; P=0.904). Grade 3/4 toxicities (sorafenib versus placebo) included hand-foot skin reaction (31% versus 3%), neutropenia (13% versus 7%) and anaemia (11% versus 6%). Two treatment-related deaths occurred (malaria and liver dysfunction) in the sorafenib arm.

Interpretation: The addition of sorafenib to paclitaxel improved disease control but did not significantly improve PFS to support a phase 3 trial of similar design. Toxicity of the combination was manageable with dose reductions.