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Background: In 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Based on the preclinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, ECOG-ACRIN E1105 trial was developed to determine if the addition of bevacizumab to a chemotherapy and trastuzumab combination for first-line therapy would improve progression-free survival (PFS) in patients with HER2-positive MBC. Findings: 96 patients were randomized to receive standard first-line chemotherapy and trastuzumab with or without bevacizumab between November 2007 and October 2009, and 93 began protocol therapy. Induction therapy was given for 24 weeks, followed by maintenance trastuzumab with or without bevacizumab. 60% (56/93) began carboplatin and 74% (69/93) completed 6 cycles of induction therapy. Primary endpoint was PFS. Median PFS was 11.1 and 13.8 months for placebo and bevacizumab arms, respectively (hazard ratio [HR] 95%, Confidence Interval [Cl] for bevacizumab vs. placebo: 0.73 [0.43-1.23], p = 0.24), and at a median follow-up of 70.7 months, median survival was 49.1 and 63 months (HR [95% Cl] for OS: 1.09 [0.61-1.97], p = 0.75). The most common toxicities across both arms were neutropenia and hypertension, with left ventricular systolic dysfunction, fatigue, and sensory neuropathy reported more frequently with bevacizumab. Conclusions: In this trial, the addition of bevacizumab did not improve outcomes in patients with metastatic HER2-positive breast cancer. Although the trial was underpowered due to smaller than anticipated sample size, these findings corroborated other clinical trials during this time.
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INTRODUCTION: Sorafenib is a multikinase inhibitor affecting pathways involved in tumor progression and angiogenesis. We conducted a phase II trial of sorafenib in platinum-treated patients with extensive stage small cell lung cancer to determine the tumor response rate, toxicity, and overall survival. METHODS: Patients with histologically confirmed, measurable disease, Zubrod performance status 0 to 1, and no more than 1 prior platinum-based treatment were eligible. Patients were stratified by platinum-sensitivity status: sensitive (progression >90 days after platinum) or refractory (progression during or ≤90 days after platinum). Patients were treated with sorafenib 400 mg orally twice a day continuously on a 28-day cycle. RESULTS: Of 89 patients registered, 82 were evaluable for toxicity assessment, and 83 were evaluable for response. There were four partial responses seen among the 38 patients in the platinum-sensitive stratum, for an estimated response rate of 11% (95% confidence interval: 3-25%), and one partial response among the 45 patients in the platinum-refractory stratum, for an estimated response rate of 2% (95% confidence interval: 0-12%). The median overall survival estimates were 6.7 months (95% confidence interval: 6.1-9.1 months) for the platinum-sensitive stratum and 5.3 months (95% confidence interval: 3.3-7.5 months) in the platinum-refractory stratum. Nineteen patients discontinued treatment because of adverse events or side effects from therapy. CONCLUSIONS: Based on the lack of disease control seen in our trial, further investigation of single-agent sorafenib in the small cell lung cancer population is not recommended. Combination trials of sorafenib and chemotherapy are ongoing.
