Drug Discovery & Development - November 09, 2010
Amgen announced the publication of results from a pivotal Phase 3 study of 2,046 patients which compared denosumab with Zometa (zoledronic acid) in delaying or preventing skeletal-related events (SREs) in breast cancer patients with bone metastases. An SRE consists of any of the following: a pathologic fracture, the need for radiation or surgery to ameliorate bone pathology secondary to tumor growth, or spinal cord compression. The study, published in the Journal of Clinical Oncology, found that denosumab was superior to Zometa in delaying or preventing SREs in breast cancer patients with bone metastases.
“Patients with bone metastases from cancer are at increased risk of experiencing debilitating pathologic fractures and other skeletal-related events. The results of this study show that denosumab is better than the current standard of care (Zometa) in delaying or preventing these skeletal complications for our patients with advanced breast cancer,” said Alison Stopeck, M.D., associate professor of Medicine, Arizona Cancer Center, University of Arizona Health Sciences Center. “In addition to improving skeletal outcomes, denosumab has no requirement for renal monitoring and is administered as a simple subcutaneous injection.”
In the study, denosumab was superior to Zometa in delaying time to first on-study SRE (hazard ratio [HR] 0.82; 95 percent CI: 0.71-0.95; P=0.01 superiority) and time to first and subsequent (multiple) SREs (rate ratio 0.77; 95 percent CI: 0.66-0.89; P=0.001). Reduction in bone turnover markers was greater with denosumab.
The incidence of adverse events (AEs) (96 percent denosumab, 97 percent Zometa) and serious AEs (44 percent denosumab, 46 percent Zometa) was consistent with what has previously been reported for these two agents. AEs potentially associated with renal toxicity occurred in 4.9 percent of patients treated with denosumab compared to 8.5 percent in patients treated with Zometa.
Osteonecrosis of the jaw (ONJ) was seen infrequently in both treatment groups (20 patients receiving denosumab (2.0 percent) as compared with 14 patients (1.4 percent) receiving Zometa). There was no statistically significant difference in the rate of ONJ between the two treatment arms. Hypocalcemia occurred more frequently with denosumab. No AEs of hypocalcemia were reported as fatal, and grade 3 or 4 AEs of hypocalcemia were similar between groups (1.6 percent denosumab, 1.2 percent zoledronic acid). Overall survival (hazard ratio 0.95, 95 percent CI: 0.81, 1.11; p=0.50) and time to cancer progression (hazard ratio 0.99, 95 percent CI: 0.89, 1.11; p=0.90) was balanced between treatment arms.
This study was an international, randomized, double-blind, double-dummy, active-controlled study, in which breast cancer patients were randomized to receive either subcutaneous denosumab 120 mg and intravenous placebo (N=1,026), or Zometa administered intravenously as at least a 15 minute infusion at a dose of 4 mg (or equivalent creatinine clearance-adjusted dose in patients with baseline creatinine clearance ≤ 60 mL/min) every four weeks as per the labeled instructions. All patients were strongly recommended to take daily calcium and vitamin D supplements. The primary endpoint was time to first on-study SRE.
Date: November 8, 2010
Source: Amgen
“Patients with bone metastases from cancer are at increased risk of experiencing debilitating pathologic fractures and other skeletal-related events. The results of this study show that denosumab is better than the current standard of care (Zometa) in delaying or preventing these skeletal complications for our patients with advanced breast cancer,” said Alison Stopeck, M.D., associate professor of Medicine, Arizona Cancer Center, University of Arizona Health Sciences Center. “In addition to improving skeletal outcomes, denosumab has no requirement for renal monitoring and is administered as a simple subcutaneous injection.”
In the study, denosumab was superior to Zometa in delaying time to first on-study SRE (hazard ratio [HR] 0.82; 95 percent CI: 0.71-0.95; P=0.01 superiority) and time to first and subsequent (multiple) SREs (rate ratio 0.77; 95 percent CI: 0.66-0.89; P=0.001). Reduction in bone turnover markers was greater with denosumab.
The incidence of adverse events (AEs) (96 percent denosumab, 97 percent Zometa) and serious AEs (44 percent denosumab, 46 percent Zometa) was consistent with what has previously been reported for these two agents. AEs potentially associated with renal toxicity occurred in 4.9 percent of patients treated with denosumab compared to 8.5 percent in patients treated with Zometa.
Osteonecrosis of the jaw (ONJ) was seen infrequently in both treatment groups (20 patients receiving denosumab (2.0 percent) as compared with 14 patients (1.4 percent) receiving Zometa). There was no statistically significant difference in the rate of ONJ between the two treatment arms. Hypocalcemia occurred more frequently with denosumab. No AEs of hypocalcemia were reported as fatal, and grade 3 or 4 AEs of hypocalcemia were similar between groups (1.6 percent denosumab, 1.2 percent zoledronic acid). Overall survival (hazard ratio 0.95, 95 percent CI: 0.81, 1.11; p=0.50) and time to cancer progression (hazard ratio 0.99, 95 percent CI: 0.89, 1.11; p=0.90) was balanced between treatment arms.
This study was an international, randomized, double-blind, double-dummy, active-controlled study, in which breast cancer patients were randomized to receive either subcutaneous denosumab 120 mg and intravenous placebo (N=1,026), or Zometa administered intravenously as at least a 15 minute infusion at a dose of 4 mg (or equivalent creatinine clearance-adjusted dose in patients with baseline creatinine clearance ≤ 60 mL/min) every four weeks as per the labeled instructions. All patients were strongly recommended to take daily calcium and vitamin D supplements. The primary endpoint was time to first on-study SRE.
Date: November 8, 2010
Source: Amgen
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