No Significant Progression-Free Survival Benefit of Adding Ramucirumab to First-Line Docetaxel in Advanced HER2-Negative Breast Cancer
In the phase III ROSE/TRIO-12 trial, reported in the Journal of Clinical Oncology, Mackey et al found no significant improvement in investigator-assessed progression-free survival by adding the antiangiogenic VEGFR-2 inhibitor ramucirumab (Cyramza) to first-line docetaxel in women with HER2-negative advanced breast cancer. An interim analysis suggested no difference in overall survival.
Study Details
In this double-blind trial, 1,144 patients with unresectable, locally recurrent, or metastatic breast cancer were randomly assigned 2:1 between August 2008 and December 2011 to receive docetaxel at 75 mg/m2 plus ramucirumab at 10 mg/kg (n = 752) or docetaxel at 75 mg/m2 plus placebo (n = 382) once every 3 weeks until disease progression, unacceptable toxicity, or withdrawal. Patients were stratified by previous taxane therapy, visceral metastasis, hormone receptor status, and geographic region. The primary endpoint was investigator-assessed progression-free survival.
The ramucirumab and placebo groups were generally balanced for age (median, 54 years in both), Eastern Cooperative Oncology Group performance status (0 in 58% and 62%, 1 in 42% and 37%), number of metastatic sites (≥ 3 in 52% and 48%), visceral involvement (71% and 72%), prior adjuvant taxane (26% and 27%), geographic region (North or South America for 24% in both; Europe, Australia, New Zealand for 64% in both; Asia, Middle East, Africa for 12% and 13%), hormone receptor status (72% and 75% estrogen receptor–positive, 28% and 25% estrogen receptor–negative or unknown; 53% and 61% progesterone receptor–positive, 47% and 39% progesterone receptor–negative or unknown), and proportion with triple-negative disease (25% and 22%).
Progression-Free Survival
After median follow-up of 18.6 months, median progression-free survival was 9.5 months in the ramucirumab group vs 8.2 months in the placebo group (hazard ratio [HR] = 0.88, P = .077). Findings were similar across clinical subgroups. In a sensitivity analysis, median progression-free survival was 11.1 vs 8.5 months (HR = 0.79, P =.008) on independent radiologic assessment.
At interim analysis, median overall survival was 27.3 months vs 27.2 months (HR = 1.01, P = .915).
Secondary Endpoints
The ramucirumab group had significantly better time to progression (median, 9.7 vs 8.2 months, HR = 0.85, P = .033), overall response rate (44.7% vs 37.9%, P = .027), and disease control rate (86.4% vs 81.3%, P = .022). Among patients with response, median duration of response was 8.4 vs 8.1 months (P = .150).
Quality of life appeared to be similar in the two groups according to Functional Assessment of Cancer Therapy-Breast scores and subscores.
Toxicity
Grade ≥ 3 adverse events were more common in the ramucirumab group (62% vs 52%, P < .05), with significantly greater (all P < .05) rates of grade ≥ 3 fatigue (16.4% vs 9.7%), febrile neutropenia (7.8% vs 3.9%), hypertension (6.8% vs 1.8%), stomatitis (6.1% vs 1.0%), and palmar-plantar erythrodysesthesia syndrome (3.9% vs 1.0%). Grade ≥ 3 venous thrombotic events were less common in the ramucirumab group (1.3% vs 3.1%).
The investigators concluded: “Addition of ramucirumab to docetaxel in HER2-negative advanced breast cancer did not meaningfully improve important clinical outcomes.”
They noted: “Although [progression-free survival] and [overall survival] were similar across predefined clinical subgroups, protocol-specified correlative assessments are under way to identify molecularly defined populations with ramucirumab-sensitive disease. Ultimately, a better understanding of breast cancer responses to available antiangiogenic therapies and assays to identify relevant biomarkers and sensitive patients are needed for antiangiogenic therapy for breast cancer to fulfill its original promise.”
John R. Mackey, MD, of University of Alberta, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by Eli Lilly/ImClone Systems. For full disclosures of the study authors, visit jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
