Abstract
BackgroundTriple-negative breast cancer (TNBC) remains an aggressive breast cancer subtype with limited treatment options. ENMD-2076 is a small-molecule inhibitor of Aurora and angiogenic kinases with proapoptotic and antiproliferative activity in preclinical models of TNBC.MethodsThis dual-institution, single-arm, two-stage, phase II clinical trial enrolled patients with locally advanced or metastatic TNBC previously treated with one to three prior lines of chemotherapy in the advanced setting. Patients were treated with ENMD-2076 250 mg orally once daily with continuous dosing in 4-week cycles until disease progression or unacceptable toxicity occurred. The primary endpoint was 6-month clinical benefit rate (CBR), and secondary endpoints included progression-free survival, pharmacokinetic profile, safety, and biologic correlates in archival and fresh serial tumor biopsies in a subset of patients.ResultsForty-one patients were enrolled. The 6-month CBR was 16.7% (95% CI, 6–32.8%) and included two partial responses. The 4-month CBR was 27.8% (95% CI, 14–45.2%), and the average duration of benefit was 6.5 cycles. Common adverse events included hypertension, fatigue, diarrhea, and nausea. Treatment with ENMD-2076 resulted in a decrease in cellular proliferation and microvessel density and an increase in p53 and p73 expression, consistent with preclinical observations.ConclusionsSingle-agent ENMD-2076 treatment resulted in partial response or clinical benefit lasting more than 6 months in 16.7% of patients with pretreated, advanced, or metastatic TNBC. These results support the development of predictive biomarkers using archival and fresh tumor tissue, as well as consideration of mechanism-based combination strategies.Trial registrationClinicalTrials.gov, NCT01639248. Registered on July 12, 2012.
Highlights
Triple-negative breast cancer (TNBC) remains an aggressive breast cancer subtype with limited treatment options
The antiangiogenic activity of ENMD-2076 is mediated through the inhibition of vascular endothelial growth factor receptors (VEGFRs) and fibroblast growth factor receptors (FGFRs), whereas antiproliferative activity occurs via inhibition of mitotic kinases, including Aurora kinase A (Aur A) [6]
This study demonstrates that ENMD-2076 has durable clinical activity in a subset of patients with previously treated metastatic TNBC
Summary
Triple-negative breast cancer (TNBC) remains an aggressive breast cancer subtype with limited treatment options. ENMD-2076 is a small-molecule inhibitor of Aurora and angiogenic kinases with proapoptotic and antiproliferative activity in preclinical models of TNBC. Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype defined by a lack of expression of the estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) [1]. Despite the characterization of biologic subtypes within TNBC, this disease remains critically in need of effective targeted systemic therapies [5]. ENMD-2076 is active against preclinical TNBC models, including p53-mutated cancer cell lines and patient-derived tumor xenograft (PDX) models [7, 8]. The purpose of this study was to evaluate the anticancer activity of ENMD-2076 in patients with previously treated locally advanced or metastatic TNBC, to further characterize the side effect profile, and to explore pharmacodynamic changes in serial tumor biopsies
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