A Double-Blind, Randomized, Placebo-Controlled, Phase 2b Study Evaluating the Efficacy and Safety of Sorafenib (SOR) in Combination with Paclitaxel (PAC) as a First-Line Therapy in Patients (pts) with Locally Recurrent or Metastatic Breast Cancer (BC).
Authors: Gradishar W. , Kaklamani V. , Prasad Sahoo T. , Lokanatha D. , Raina V. , Bondarde S. , Jain M. 
Published: December 2010

Abstract
Introduction: SOR is a targeted therapeutic agent indicated for advanced renal cell carcinoma and hepatocellular carcinoma. SOR targets multiple kinases involved in tumor growth and angiogenesis. The TIES (Trials to Investigate the Effects of Sorafenib in BC) program includes 4 phase 2b randomized, double-blind, placebo-controlled screening trials in HER2-negative BC. Recently, the first of these trials, SOR+capecitabine (CAP) vs placebo (PL)+CAP demonstrated a significant progression-free survival (PFS) benefit in pts with advanced BC. Here we present initial results from the second of the 4 trials. This study evaluated the efficacy and safety of SOR in combination with PAC as a first-line regimen for pts with advanced BC.Methods: Pts with HER2-negative, locally recurrent or metastatic BC were eligible for first-line treatment for advanced BC. Previous cytotoxic (non-metastatic), endocrine, or radiation therapy was allowed. Pts were randomized 1:1 (stratified by visceral vs non-visceral metastatic disease) to SOR (400 mg, orally, twice daily, continuously) or PL in combination with PAC (90 mg/m2 weekly, IV, 3 weeks on/1 week off). The primary endpoint was PFS. Secondary endpoints included overall survival (OS), time to progression (TTP), overall response rate (ORR), and safety. A sample size of 220 pts was planned to detect a targeted HR of 0.65 (90% power and 1-sided a=0.14). The study is registered at ClinicalTrials.gov (NCT00499525).Results: From January 2008 to January 2009, 237 pts were randomized to SOR+PAC (n=119) vs PL+PAC (n=118), with 170 pts in India (74% vs 69%), 52 pts in the United States (21% vs 23%), and 15 pts in Brazil (5% vs 8%). Treatment groups were balanced for age (mean, 51.9 y), ECOG performance 0 (45%) and 1 (53%), stage IV disease (85%), visceral metastatic disease (75%), and previous non-metastatic chemo (58%). Results of the study were as follows for SOR+PAC vs PL+PAC: median PFS 6.9 vs 5.6 mos (HR 0.788; 95% CI, 0.558-1.112; 1-sided log rank P=0.0857), median TTP 8.1 vs 5.6 mo (HR 0.674; 95% CI, 0.465-0.975; 1-sided log rank P=0.0171), and ORR of 67% vs 54% (1-sided Cochran-Mantel-Haenszel P=0.0234). OS data are pending. Discontinuation of study treatment due to adverse events occurred in 23 pts (19%) in the SOR+PAC vs 5 pts (4%) in the PL+PAC. Grade 3/4 toxicities (SOR+PAC vs PL+PAC) included hand-foot skin reaction (30% vs 3%), asthenia (7% vs 3%), peripheral neuropathy (6% vs 7%), neutropenia (13% vs 7%), and anemia (11% vs 6%). Treatment-related deaths occurred in 2 pts (malaria and liver dysfunction), both in the SOR+PAC arm.Conclusions: Results of the primary endpoint, PFS, demonstrated a trend favoring SOR+PAC over PL+PAC in the treatment of advanced BC (HR 0.788; P=0.0857). In addition, significant improvements in TTP and ORR were observed. OS data are pending. There were no new toxicities observed with the combination and AEs were manageable. These data indicate that SOR provides added benefit when combined with PAC compared with single-agent PAC in the first-line treatment of advanced BC.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 44.