BY ED SUSMAN
The investigative monoclonal antibody ramucirumab when added to docetaxel for first-line treatment did not provide significant additional benefit in delaying progression of advanced HER2-negative breast cancer, according to a report at the San Antonio Breast Cancer Symposium.
As reported by John Mackey, MD, Professor of Oncology at the University of Alberta, patients in the ROSE (Ramucirumab Overall Survival Evaluation) trial receiving ramucirumab plus docetaxel had an overall survival of 9.5 months compared with 9.2 months for patients receiving docetaxel alone, a difference that was not statistically significant.
“Overall survival did not suggest that there was an advantage to the new treatment or a survival disadvantage. This is the interim overall survival analysis, which was triggered by the primary endpoint. We have a final overall survival analysis planned, probably in a year,” he said.
As expected, though, he noted, the addition of ramucirumab did increase side effects: “Adverse effects were higher with the ramucirumab arm. There were the on-target side effects you would expect in an anti-angiogenic therapy: fatigue, hypertension, bleeding – mainly nose bleeds -- febrile neutropenia, and stomatitis.”
The ROSE trial, which was supported by Eli Lilly, was designed to evaluate ramucirumab in the setting of HER2-negative, unresectable locally recurrent, or metastatic breast cancer. In the placebo-controlled, randomized, multinational Phase III trial, patients with HER2-negative breast cancer were randomized to receive docetaxel at 75 mg/m2 plus placebo in an intravenous infusion every three weeks, or to the same chemotherapy plus ramucirumab at 10 mg/kg by intravenous infusion every three weeks.
Most of the patients were younger than 65; more than 80 percent were white; and most had a performance status of zero (the rest were in performance status 1). More than 70 percent had positive hormone receptor status.
Patients were eligible for entry into the trial if they had not received prior cytotoxic of biologic therapy for advanced disease. Treatment was continued with each agent until investigator-determined progressive disease using Response Evaluation Criteria in Solid Tumors criteria, or until unacceptable toxicity. Patients were stratified for prior taxane therapy, the presence of visceral metastasis, hormone-receptor status, and geographic region.
Between August 2008 and December 2011, researchers in 25 countries assigned 759 patients to receive ramucirumab plus docetaxel. There were 528 events that met the criteria for disease progression – about 70 percent of the women were assigned to the combination therapy – after a median follow-up of 16.2 months. Of the 385 women receiving docetaxel and placebo, disease progression occurred in 291 (75.6%) during that time period.
Of the women assigned to ramucirumab and docetaxel, 311 (41%) died compared with 160 (41.6%) of the women assigned to docetaxel and placebo.
“This was a negative trial,” Mackey said. “There was no clinically defined subgroup that showed a benefit.” In most of the prespecified progression free survival stratifications, the use of ramucirumab appeared better numerically, but in none of the cases was statistical significance documented.
Outliers, he said, appeared to be non-white women who appeared to do better in the placebo arm, but only 127 of the 1,144 women in the trial were non-white, and the numerical difference there also was not significant.
“Not every new drug pans out,” said Peter W. Ravdin, MD, Director of the Comprehensive Breast Health Clinic at the Cancer Therapy and Research Center at the University of Texas Health Science Center at San Antonio, who moderated a news briefing that featured the study. “Clinical trials are designed to ask questions about treatment pathways and sometimes the answer is no, this is not a road we want to go down. But that is a very important answer.
“We are now recognizing that breast cancer is really a diverse disease. There are hints of certain markers that may predict particular benefit for angiogenic strategies. Drugs that may in general have little advantage in breast cancer on average, in selected populations may be very effective. It is still a work in progress.”
Mackey explained that the trial was conducted because ramucirumab is known to bind to the extracellular domain of the vascular endothelial growth factor receptor-2 (VEGFR-2), which is an important mediator of angiogenesis
“This was an anti-angiogenic trial,” he said. “The preclinical rationale is that angiogenesis is an important process by which breast tumors are able to metastasize and it is related to poor prognosis. In addition we had preclinical data that this agent was synergistic with docetaxel and that this was a very interesting combination.
“However, when we designed this study in 2007-2008, at the time and it still remains the case today, anti-angiogenic therapy in breast cancer had not yet demonstrated improvements in overall survival. Anti-angiogenic agents have been successful in prolonging survival in colon cancer and a number of other solid tumor types, but unfortunately, for reasons that we don’t understand, this has not yet been shown for breast cancer.
“We had hoped that ramucirumab would give patients a new option for metastatic breast cancer,” he continued. “The outcome is disappointing, especially for the patients who participated on the trial and the many others suffering with this disease. Unlike bevacizumab, ramucirumab actually targets the VEGF receptor-2, which is responsible for endothelial cell proliferation.
“We will, though, be conducting biomarker analyses, and are hopeful that we can go back to the tissue that we have collected in this trial and find biomarkers to see if we can identify a subgroup of patients for whom the antibody therapy might be beneficial, but it will be a while before we have results.”
He added that ramucirumab is being tested in other cancers, including in gastric cancer, where there have been positive result; and there are now Phase III trials ongoing in colon and lung cancers.