Ramucirumab added to first-line docetaxel failed to improve progression-free survival in patients with metastatic breast cancer in the large, randomized, placebo-controlled ROSE/TRIO-12 trial.1 An interim analysis of overall survival showed no advantage for the addition of ramucirumab. This study, presented at the 2013 San Antonio Breast Cancer Symposium, joins a number of other failed antiangiogenesis trials in breast cancer, most of them evaluating bevacizumab (Avastin).
“Thus far, no antiangiogenesis strategy has improved survival in breast cancer. Ramucirumab did not significantly prolong progression-free survival in this trial, and there is no signal that it will prolong overall survival. This was a failed trial,” said lead author John R. Mackey, MD, Professor of Medical Oncology at the University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada.
Ramucirumab is a recombinant human monoclonal antibody targeted to vascular epidermal growth factor receptor (VEGFR)-2. This drug has been granted priority review by the U.S. Food and Drug Administration as second-line therapy for advanced gastric cancer based on results of the REGARD trial, a single-agent study.2 Ramucirumab is also being studied as second-line therapy of advanced gastric cancer in combination with paclitaxel in the RAINBOW trial (see here).3 Results of phase III trials of ramucirumab in colorectal, hepatocellular, and lung cancer are expected in 2014.
ROSE/TRIO-12 was conducted in 25 countries and included 1,144 patients with metastatic breast cancer taking standard-dose docetaxel as first-line therapy. Patients were randomly assigned 2:1 to also receive ramucirumab vs placebo and were treated until disease progression.
For the primary endpoint of investigator-assessed progression-free survival, the addition of ramucirumab failed to make a significant difference. Median progression-free survival was 8.2 months with placebo and 9.5 months with ramucirumab. No advantage in overall survival was observed for ramucirumab at the interim analysis. Final analysis of overall survival is planned in 1 year.
No advantage in progression-free or overall survival was detected in any subgroup analyzed, including those assessed by age, race, performance status, prior taxane treatment, site of metastasis, hormone receptor status, and geographic region, Dr. Mackey said.
As expected, more side effects—including fatigue, hypertension, bleeding, febrile neutropenia, and stomatitis—were observed in patients assigned to ramucirumab.
“Is it time to throw in the towel for the strategy of antiangiogenesis in breast cancer?” asked press conference moderator Peter Ravdin, MD, PhD, a Breast Cancer Researcher and Biostatistician in San Antonio, Texas.
“At the time the trial was designed, we had reason to hope ramucirumab would benefit our patients. I believe that there is a role for antiangiogenesis, if we could find a biomarker,” Dr. Mackey responded. Thus far, efforts at finding a biomarker for antiangiogenesis strategies have been unsuccessful.
“There are hints that certain markers might predict the benefit of antiangiogenesis, but these markers have not yet been included in analysis of studies. Drugs with no overall benefit may be of benefit in a particular subset of patients. It is still a work in progress to identify subsets that will benefit,” said Dr. Ravdin, who noted that the diversity of breast cancer is well recognized. ■
Disclosure: Drs. Mackey and Ravdin reported no potential conflicts of interest.
1. 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. 2013 San Antonio Breast Cancer Symposium. Abstract S5-04. Presented December 13, 2013.
2. Fuchs CS, Tomasek J, Yong CJ, et al: Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD). Lancet 383:31-39, 2014.
3. Wilke H, Van Cutsem E, Oh SC, et al: RAINBOW: A global, phase III, randomized, double-blind trial of ramucirumab and paclitaxel versus placebo and paclitaxel in the treatment of metastatic gastric or gastroesophageal junction adenocarcinoma following disease progression of first-line platinum and fluoropyrimidine-containing combination therapy. 2014 Gastrointestinal Cancers Symposium. Abstract LBA7. Presented January 16, 2014.