Novel Antiangiogenic Fails Test in Metastatic Breast Cancer

Neil Osterweil

December 16, 2013

SAN ANTONIO — Once again, the strategy of antiangiogenesis — limiting a tumor's blood supply — promised more than it delivered in metastatic breast cancer.

When the experimental antiangiogenic ramucirumab (Eli Lilly) was added to docetaxel (Taxotere and generics), neither overall survival nor progression-free survival improved, reported John R. Mackey, MD, from the University of Alberta in Edmonton, Canada.

"The future of antiangiogenic therapy in breast cancer is an open one, I think," he said here at the 36th Annual San Antonio Breast Cancer Symposium.

"We have not yet defined a clinical subgroup that derives particular benefit from the agents we've tested to date," said Dr. Mackey. However, with better clinical science, the class of drug could be valuable, he explained.

"I believe that, with better understanding of the biology and development of predictive biomarkers for antiangiogenic therapy, there's still the possibility of helping patients," he noted. "We are seeing signals [of activity] in many trials, and I think we just need to refine our tools before we're able to routinely make a difference to our patients."

Vascular endothelial growth-factor receptor 2 (VEGFR-2) and the VEGF A, C, and D ligands are known mediators of angiogenesis. In human breast cancer, intensive neovascularization of the tumor has been shown to correlate with metastasis and is associated with poor prognosis.

Ramucirumab is an investigational recombinant human monoclonal antibody that binds the extracellular domain of VEGFR-2 and blocks VEGF ligand binding, shutting down VEGF signaling and inhibiting the growth of new blood vessels that feed the tumor.

In 2007 and 2008, Dr. Mackey and colleagues designed a randomized phase 3 trial in which women with HER2-negative, unresectable, locally recurrent or metastatic disease received intravenous (IV) docetaxel 75 mg/m² every 3 weeks. In addition, the women were randomized to frontline IV ramucirumab 10 mg/kg or placebo.

Treatment was continued until disease progression, according to Response Evaluation in Solid Tumors (RECIST) criteria, or until the patient experienced unacceptable toxicity.

The patients were stratified by previous taxane use, visceral metastases, hormone-receptor status, and geographic region.

There were no significant differences between the groups in the primary end point of investigator-assessed progression-free survival or in overall survival.

Median progression-free survival was 9.5 months in the ramucirumab group and 8.2 months in the placebo group. The hazard ratio (HR) was 0.88, and was not significant.

Median overall survival was nearly identical between the ramucirumab and placebo groups (27.3 vs 27.2 months), and the HR was a nonsignificant 1.01.

When the investigators looked for potential benefits of adding the antiangiogenic to the taxane, they found no significant evidence of benefit by age, race, performance status, previous taxane use, metastatic site, hormonal status, or geographic region.

However, rates of adverse events, including fatigue, hypertension (commonly seen with antiangiogenics), bleeding, febrile neutropenia, and stomatitis, were higher with the combination of docetaxel and ramucirumab.

Asked by Medscape Medical News whether it is time to abandon the notion of a benefit for antiangiogenics in breast cancer, Peter Ravdin, MD, PhD, from the University of Texas Health Science Center in San Antonio, said that it might be too early to pull the plug.

"We're now recognizing that breast cancer is a really diverse disease. There are hints of certain markers may actually predict the particular benefit for antiangiogenic strategies, but they haven't been included in the analysis. Drugs that may, in general, have little value in breast cancer on average, in selected populations may be very effective," Dr. Ravdin noted.

"It's still a work in progress," he said.

The study was funded by Eli Lilly and Co. Dr. Mackey and Dr. Ravdin have disclosed no relevant financial relationships.

36th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S5-04. Presented December 13, 2013.

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