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

William J. Gradishar, Virginia Kaklamani, Tarini P. Sahoo, Dasappa Lokanatha, Vinod Raina, Shailesh Bondarde, Minish Jain, Sunhee Kwon Ro, Nathalie A. Lokker, Lee Schwartzberg

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)312-322
Number of pages11
JournalEuropean Journal of Cancer
Volume49
Issue number2
DOIs
StatePublished - Jan 1 2013

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Paclitaxel
Placebos
Breast Neoplasms
Disease-Free Survival
Confidence Intervals
Therapeutics
human ERBB2 protein
sorafenib
Neutropenia
Pharmaceutical Preparations
Sample Size
Malaria
Brazil
Liver Diseases
Foot
Anemia
India
Arm
Hand
Delivery of Health Care

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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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. / Gradishar, William J.; Kaklamani, Virginia; Sahoo, Tarini P.; Lokanatha, Dasappa; Raina, Vinod; Bondarde, Shailesh; Jain, Minish; Ro, Sunhee Kwon; Lokker, Nathalie A.; Schwartzberg, Lee.

In: European Journal of Cancer, Vol. 49, No. 2, 01.01.2013, p. 312-322.

Research output: Contribution to journalArticle

Gradishar, William J. ; Kaklamani, Virginia ; Sahoo, Tarini P. ; Lokanatha, Dasappa ; Raina, Vinod ; Bondarde, Shailesh ; Jain, Minish ; Ro, Sunhee Kwon ; Lokker, Nathalie A. ; Schwartzberg, Lee. / 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. In: European Journal of Cancer. 2013 ; Vol. 49, No. 2. pp. 312-322.
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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

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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.

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