1. The addition of ramucirumab, a VEGF-2 receptor blocker, to docetaxel did not significantly increase progression free or overall survival in HER-2 negative advanced breast cancer.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Anti-angiogenic agents have emerged as a new line of chemotherapy and have demonstrated clinical benefit in colorectal, cervical, and epithelial ovarian cancers. Vascular Endothelial Growth Factor (VEGF) receptor-2 has been previously associated with breast cancer metastasis and poor clinical outcomes. Ramucirumab, a monoclonal antibody that blocks VEGF-2 receptors, has been proposed as a potential agent in the treatment of advanced breast cancer. The purpose of this phase III clinical trial was to evaluate progression-free or overall survival of patients on ramucirumab plus docetaxel treatment compared to docetaxel plus placebo. The trial enrolled 1,144 patients with a median follow-up of 18.6 months. At the conclusion of the trial, the authors found no significant differences in progression-free or overall survival with the addition of ramucirumab compared to placebo. Additionally, there was significant toxicity related to the ramucirumab-arm including stomatitis, hypertension, and febrile neutropenia. The strength of this trial is its randomized study design and the large sample size designed to demonstrate progression free survival effects. Based on these results, the authors suggest that anti-angiogenic agents may play only a limited role in the treatment of advanced breast cancer until further understanding of the pathophysiology of vasculogenesis in breast cancer is obtained.
In-Depth [randomized controlled trial]: This phase III clinical trial was a randomized, double-blinded, placebo-controlled study that included 1144 patients with HER2 negative, unresectable, locally recurrent or metastatic breast cancer. Patients were recruited from multiple centers, and then assigned to docetaxel plus ramucirumab (n=752) or docetaxel plus placebo (n=382). Primary outcomes measured included median progression free survival (PFS) and overall survival (OS). After a median follow-up of 18.6 months, the median PFS in patients treated with ramucirumab was 9.5 months compared with 8.2 months in patients on placebo (HR 0.88; P = 0.077). Median OS was 27.3 months in patients on ramucirumab compared to placebo (HR 1.01; P = 0.915). Time to progression (TTP) was 9.7 months versus 8.2 months (P = 0.033) for the ramucirumab and placebo arms, respectively. There was a significantly increased frequency of adverse events in the ramucirumab group including stomatitis, epistaxis, hypertension, and febrile neutropenia.
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