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

Abstract

Purpose Currently, antiangiogenic strategies in metastatic breast cancer have demonstrated modest improvements in progression-free survival (PFS) but not improved quality or duration of survival, warranting evaluation of new agents in a placebo-controlled setting. Ramucirumab is a human immunoglobulin G1 antibody that binds vascular endothelial growth factor receptor-2 and blocks ligand-stimulated activation. The ROSE/TRIO-012 trial evaluated ramucirumab with docetaxel in unresectable, locally recurrent, or metastatic breast cancer. Patients and Methods In this double-blind, placebo-controlled, randomized, multinational phase III trial, 1,144 patients with human epidermal growth factor receptor 2 (HER2) –negative breast cancer who had not received cytotoxic chemotherapy in the advanced setting were randomly assigned at a two-to-one ratio to receive docetaxel 75 mg/m2 plus ramucirumab 10 mg/kg or docetaxel 75 mg/m2 plus placebo once every 3 weeks. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria. Patients were stratified by previous taxane therapy, visceral metastasis, hormone receptor status, and geographic region. An independent data monitoring committee oversaw the trial. The primary end point was investigator-assessed PFS. Results Median PFS in patients treated with ramucirumab plus docetaxel was 9.5 months, compared with 8.2 months in patients who received placebo plus docetaxel (hazard ratio [HR], 0.88; P = .077). Median overall survival was 27.3 months in patients who received ramucirumab plus docetaxel, compared with 27.2 months in patients who received placebo plus docetaxel (HR, 1.01; P = .915). Toxicities seen at significantly higher rates in patients receiving ramucirumab included fatigue, hypertension, febrile neutropenia, palmar-plantar erythrodysesthesia syndrome, and stomatitis. Conclusion Addition of ramucirumab to docetaxel in HER2-negative advanced breast cancer did not meaningfully improve important clinical outcomes.

Failures in Phase III: Causes and Consequences

“…In some of these studies results of the prior phase I clinical trials were considered sufficiently promising to conduct phase III RCTs (35)(36)(37)(38). Furthermore, investigators sometimes justified evaluation of a new anticancer therapy on the basis of preclinical data, or on results of RCTs, which evaluated the same treatment in different cancer types (39). In recent published reports of RCTs, investigators openly stated that results of phase II trials were not available when phase III RCTs were initiated (40,41).…”

Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor

“…However, in metastatic, human epidermal growth factor receptor 2-negative (HER2-negative) breast cancer, results have been somewhat disappointing. In the ROSE/TRIO trial, ramucirumab in combination with docetaxel failed to demonstrate a meaningful improvement in important clinical outcomes versus docetaxel alone (OS: 27.3 vs. 27.2 months; HR: 1.01; 95% CI: 0.83-1.23; p 5 .915) [34]. Phase III trials of ramucirumab are also ongoing in mCRC, and results of its use in advanced hepatocellular carcinoma (HCC) as a second-line treatment (REACH trial) have been presented recently [35].…”

“…The variability in response to antiangiogenic therapy in breast cancer is most likely explained by the extent of vascularization in this tumor type, the highly heterogeneous nature of the disease, the development of drug resistance, and the utilization of compensatory angiogenic mechanisms [17]. Recent results with ramucirumab plus docetaxel in the ROSE/TRIO trial in advanced HER2-negative breast cancer were disappointing [34].Nomeaningful improvementin importantclinical outcomes such as OS versus docetaxel alone were observed, and there was significantly more toxicity [34]. However, results from the TANIA and IMELDA trials in this indication demonstrated that continued second-line treatment with bevacizumab plus chemotherapy significantly improved PFS compared with bevacizumab alone [143,144].…”

Vascular Endothelial Growth Factor: An Overview Across Multiple Disease Conditions

“…In these poor prognosis diseases, even a small absolute survival benefit of two months is clinically valuable. Disappointing clinical results reported for the ROSE study confirm that breast cancer may limitedly benefit from angiogenic inhibitors (Mackey et al, 2014). While ongoing studies will clarify the role of ramucirumab in metastatic colorectal cancer, translational research will provide more details about how to properly select optimal candidates and corroborate the ethnical difference in benefit.…”