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PurposeSorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. A randomized, double-blind, placebo-controlled phase IIB trial assessed sorafenib with capecitabine for locally advanced or metastatic human epidermal growth factor receptor 2 (HER2) –negative breast cancer.Patients and MethodsPatients were randomly assigned to first- or second-line capecitabine 1,000 mg/m2orally twice a day for days 1 to 14 of every 21-day cycle with sorafenib 400 mg orally twice a day or placebo. The primary end point was progression-free survival (PFS).ResultsIn total, 229 patients were enrolled. The addition of sorafenib to capecitabine resulted in a significant improvement in PFS versus placebo (median, 6.4 v 4.1 months; hazard ratio [HR], 0.58; 95% CI, 0.41 to 0.81; P = .001) with sorafenib favored across subgroups, including first-line (HR, 0.50; 95% CI, 0.30 to 0.82) and second-line (HR, 0.65; 95% CI, 0.41 to 1.04) treatment. There was no significant improvement for overall survival (median, 22.2 v 20.9 months; HR, 0.86; 95% CI, 0.61 to 1.23; P = .42) and overall response (38% v 31%; P = .25). Toxicities (sorafenib v placebo) of any grade included rash (22% v 8%), diarrhea (58% v 30%), mucosal inflammation (33% v 21%), neutropenia (13% v 4%), hypertension (18% v 12%), and hand-foot skin reaction/hand- foot syndrome (HFSR/HFS; 90% v 66%); grade 3 to 4 toxicities were comparable between treatment arms except HFSR/HFS (44% v 14%). Reasons for discontinuation in the sorafenib and placebo arms included disease progression (63% v 82%, respectively), adverse events (20% v 9%, respectively), and death (0% v 1%, respectively).ConclusionAddition of sorafenib to capecitabine improved PFS in patients with HER2-negative advanced breast cancer. The dose of sorafenib used in this trial resulted in unacceptable toxicity for many patients. A phase III confirmatory trial has been initiated with a reduced sorafenib dose.

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INTRODUCTION: Sorafenib (SOR) is a potent multikinase inhibitor with anti-angiogenic and anti-proliferation activity. It is indicated for the treatment of advanced renal cell carcinoma and unresectable hepatocellular carcinoma. As a single agent, SOR has shown modest activity in patients with advanced BC. Here, we report results from one (SOLTI-0701) of four Phase 2b trials of sorafenib in combination with chemotherapy for advanced breast cancer.METHODS: SOLTI-0701 is a multinational, double-blind, randomized, placebo-controlled phase 2b study in patients with locally advanced or metastatic BC. Eligibility criteria included HER-2 negative tumors and <2 prior chemo regimens for advanced/metastatic BC. Patients with active brain metastasis were excluded. Patients were randomized (1:1) to receive CAP (1000 mg/m2, orally, twice daily [BID], for 14 of every 21 days) with placebo (pl) or SOR (400 mg, orally, BID, continuously). Randomization is stratified by metastatic site (visceral vs nonvisceral). The primary endpoint is progression-free survival (PFS), and secondary endpoints include overall survival, time to progression, response rate, response duration, safety, and QoL. Disease assessments occur every 6 weeks for the first 24 weeks of the study and then every 9 weeks thereafter until disease progression. Based on projected event and accrual rates, a sample size of 220 patients has been calculated. We estimate 120 PFS events within 17 months of study initiation. The study is registered at EudraCT (ID 2007-000290-32).RESULTS: Enrollment began in August 2007 and was completed in December 2008 with 229 patients randomized. Study findings demonstrated that the median PFS was extended in patients treated with SOR and CAP compared to patients receiving CAP and PL. These results were statistically significant (p=0.0006). The safety and tolerability of the combination did not show any new or unexpected toxicities. A subset analysis will be presented.CONCLUSION: The SOLTI-0701 study will provide important efficacy and safety data for the use of sorafenib in combination with oral chemotherapy for advanced breast cancer. These data will help us better understand the potential role for sorafenib in BC and if phase III trials are warranted. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 45.

LV and LG seem to be active combinations in patients with HER2(+) MBC after taxane failure. The overall toxicity was manageable in all regimens.