Ramucirumab Does Not Prolong PFS in HER2-Negative Metastatic Breast Cancer

Wayne Kuznar
Published: Friday, Dec 13, 2013

Dr. John R. Mackey

Photo Courtesy © SABCS/Todd Buchanan 2013

John R. Mackey, MD
Antiangiogenic therapy with ramucirumab, an investigational agent that binds to the vascular endothelial growth factor receptor (VEGFR)-2, added to first-line docetaxel failed to delay the progression of HER2-negative metastatic breast cancer. Data from a randomized placebo-controlled phase III trial were presented by John R. Mackey, MD, at the 2013 San Antonio Breast Cancer Symposium.

The study is the latest in a series of failures with angiogenesis inhibitors in the setting of breast cancer.

In human breast cancer, intensive neovascularization and tumor angiogenesis correlate with metastases and poor prognosis. Preclinical data had indicated synergy between ramucirumab and docetaxel in several solid tumors, providing the rationale for this study, said Mackey, professor of oncology and director of Translational Research in Oncology, University of Alberta, Edmonton, Canada. Subsequently, phase III studies in colon and gastric tumors demonstrated survival improvement with ramucirumab.

Ramucirumab is a novel recombinant human IgG1 monoclonal antibody that binds to the extracellular domain of VEGFR-2. As such, it shuts down signaling that would maintain endothelial cell proliferation. The selectivity for VEGFR-2 sets it apart from bevacizumab and generated excitement over its potential for superior efficacy in metastatic breast cancer.

In the study, patients were randomized in a 2:1 ratio to the combination of ramucirumab, 10 mg/kg IV every 3 weeks, and docetaxel, 75 mg/m2, or placebo and docetaxel as a first-line treatment in 1144 patients with unresectable, locally recurrent, or metastatic HER2-negative breast cancer. Treatment was continued with each agent until progressive disease using RECIST criteria or until unacceptable toxicity.

About half the patients had fewer than three metastatic sites and half had three or more. Approximately 75% of patients were hormone receptor-positive, and one quarter had prior taxane therapy.

The trial did not meet its primary endpoint of an improvement in progression-free survival (PFS).

After a median follow-up of 16.2 months, investigator-assessed PFS was 9.5 months in the ramucirumab arm and 8.2 months in the control arm (HR = 0.88; P = .077).

In an analysis stratifying for prior taxane therapy, visceral metastasis, hormone-receptor status, and geographical region, no advantage to ramucirumab was found in any subgroup.

An interim analysis of overall survival (OS) again showed no difference between arms, with a median OS of 27.3 months in the ramucirumab arm and 27.2 months in the placebo arm (HR = 1.01; P = .915).

The objective response rates were 44.7% in the ramucirumab arm versus 37.9% in the control arm (P = .027) and the disease control rates were 86.4% versus 81.3% (P = .022), respectively. The percentage of patients with disease progression was 65.3% of those assigned to ramucirumab compared with 73.0% in those assigned to placebo, with the median time to progression being 9.7 months versus 8.2 months (HR: 0.78; P = .034), respectively.

Treatment-emergent adverse events occurring at a higher rate in the ramucirumab arm compared with the control arm included fatigue (68.4% vs. 66.0%), bleeding/hemorrhage (48.0% vs. 22.3%), epistaxis (39.9% vs. 16.8%), weight loss (21.9% vs. 10.5%), neutropenia (17.6% vs. 16%), febrile neutropenia (8.1% vs. 4.2%), hypertension (27.0% vs. 11.5%), and stomatitis (50.7% vs. 30.6%). Grade 3 or higher hypertension occurred in 6.8% vs. 1.8% of patients in the ramucirumab and control arms, respectively.

“We’re hopeful that we can go back to the tissue we have in the trial and find biomarkers, because there is a signal here,” said Mackey. “We are seeing improvement in several endpoints. I still think there potentially is a role for antiangiogenesis were we to find a predictive biomarker.”


Mackey JR, Ramos-Vasquez M, Lipatov O, et al. Primary results of ROSE/TRIO-12, a randomized placebo controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer. Presented at: the 36th Annual San Antonio Breast Cancer Symposium held December 10-14, 2013, San Antonio, TX. Abstract S5-04.

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