TY - JOUR
T1 - 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
AU - Gradishar, William J.
AU - Kaklamani, Virginia
AU - Sahoo, Tarini P.
AU - Lokanatha, Dasappa
AU - Raina, Vinod
AU - Bondarde, Shailesh
AU - Jain, Minish
AU - Ro, Sunhee Kwon
AU - Lokker, Nathalie A.
AU - Schwartzberg, Lee
PY - 2013/1/1
Y1 - 2013/1/1
N2 - 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 (90 mg/m2, weekly, intravenously, 3 weeks on/1 week off) plus sorafenib (400 mg, 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. Funding: Northwestern University, Onyx Pharmaceuticals, Bayer Healthcare Pharmaceuticals.
AB - 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 (90 mg/m2, weekly, intravenously, 3 weeks on/1 week off) plus sorafenib (400 mg, 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. Funding: Northwestern University, Onyx Pharmaceuticals, Bayer Healthcare Pharmaceuticals.
KW - Breast cancer
KW - HER2-negative
KW - Kinase inhibitor
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U2 - 10.1016/j.ejca.2012.08.005
DO - 10.1016/j.ejca.2012.08.005
M3 - Article
C2 - 22954665
AN - SCOPUS:84872110165
VL - 49
SP - 312
EP - 322
JO - European Journal of Cancer
JF - European Journal of Cancer
SN - 0959-8049
IS - 2
ER -