Amgen announced results from new analyses comparing Xgeva (denosumab), the first new treatment for advanced cancer patients with bone metastases in nearly a decade to prevent skeletal-related events, to Zometa (zoledronic acid). These results underscore the efficacy profile of Xgeva in preventing Skeletal-Related Events (SREs) in patients with bone metastases from advanced breast cancer, as well as explore Xgeva's impact on pain and quality of life outcomes, compared to Zometa. These new results were presented at the 33rd Annual San Antonio Breast Cancer Symposium.

Xgeva was approved on November 18, 2010 by the US Food and Drug Administration (FDA) after a priority review, a designation reserved for drugs that offer major advances in treatment or provide a treatment where no adequate therapy exists. Xgeva is indicated for the prevention of SREs in patients with bone metastases from solid tumours. Xgeva is not indicated for the prevention of SREs in patients with multiple myeloma.

New extended treatment phase data from Pivotal phase 3 Study “136” demonstrates continued superiority of Xgeva compared to Zometa. An additional four months of double-blinded treatment data from the pivotal Phase 3 “136” study was presented in a press briefing at SABCS. The data showed that Xgeva was superior to Zometa in delaying the time to first on-study SRE by 18 per cent and time to first-and-subsequent on-study event by 22 per cent. Further, the median time to first on-study SRE was five months longer for the patients at risk in the Xgeva group (32.4 months) versus the Zometa group (27.4 months) in patients with advanced breast cancer and bone metastases HR 0.82 (95 percent CI 0.71, 0.95), p= 0.0096 (superiority). Additionally, continued Xgeva treatment significantly reduced the proportion of patients who experienced pathologic fractures or radiation to bone compared with Zometa.

Overall survival and disease progression were similar for both treatment groups and a similar percentage of patients reported adverse events and serious adverse events. Osteonecrosis of the jaw was reported in 2.5 per cent of Xgeva patients and 1.8 per cent of Zometa patients, while hypocalcemia was reported in 6.1 per cent of Xgeva treated patients and 3.7 Zometa treated patients.

“These results reinforce the superior efficacy profile of Xgeva versus Zometa and provide us additional reassurance of this important new product's safety profile,” said Allison Stopeck MD associate professor of Medicine, Arizona Cancer Centre, University of Arizona Health Sciences Centre, Tucson, Ariz. “I feel confident that Xgeva can provide patients with advanced breast cancer that have developed a bone metastases an excellent option to prevent debilitating and costly bone complications.”

Patients receiving Xgeva experienced less pain, and report pain interfered less with daily functioning, compared to patients receiving Zometa. Bone pain is one of the first signs that metastatic disease has spread to the bone, and affects approximately 70 per cent of patients with metastatic disease, and nearly 80 per cent of patients with advanced breast cancer. A new analysis of study “136” data showed that those patients treated with Xgeva experienced less pain-related interference with their daily functioning than those receiving Zometa.

The analysis, presented yesterday, was based on a patient completed Brief Pain Inventory (BPI). Results demonstrated that patients on Xgeva tended to experience a reduction in pain interference with their daily functioning compared to those on Zometa (n=1124; median: 70 days Xgeva vs. 86 days Zometa; p=0.09) and time to pain worsening tended to be longer with Xgeva compared to Zometa (n=1676; median: 394 days Xgeva vs. 310 days Zometa; p=0.13).

In patients with no or mild pain at the beginning of the study, Xgeva also demonstrated a trend for shorter time to improvement for pain interference with daily functioning (n=388; 93 days Xgeva vs. 120 days Zometa; p=0.06) and levels of pain took a longer time to worsen, interfering with daily functioning (n=755; 369 days Xgeva vs. 232 days Zometa; p=0.12).

Breast Cancer Patients' Health-Related Quality of Life Improved When Receiving Xgeva Compared to those Receiving Zometa. A third analysis presented yesterday found that a greater proportion of breast cancer patients treated with Xgeva had a meaningful improvement in health-related quality of life compared to those treated with Zometa, regardless of their pain level at baseline.

Specifically, among patients who reported no or mild pain at the beginning of the study, more patients receiving Xgeva had a meaningful (greater than 5 point increase) in their functional assessment score (as measured by FACT-G) compared to patients receiving Zometa. Over the 18 month period, an average of 4.1 percent more (range: -0.6 percent to 9.3 percent) Xgeva -treated patients experienced meaningful improvement in health-related quality of life than Zometa patients. Additionally, fewer patients on Xgeva experienced a meaningful decrease in health-related quality of life over the same timeframe (average of 2.4 per cent fewer [range:-4.4 per cent to 6.3 per cent fewer]).

Similar patterns were found in patients with moderate to severe pain at the beginning of the study. An average of three percent more (range:-1.7 per cent to 7.9 per cent) Xgeva -treated patients experienced a meaningful increase in their health-related quality of life compared with Zometa patients over 18 months. Also, a lower proportion of Xgeva patients (3.5 per cent fewer [range: -1.1 per cent to 11.5 per cent fewer]) than Zometa treated patients had a meaningful decrease in health-related quality of life over the 18 months.

Interim results demonstrate Skeletal-Related Events in breast cancer patients are associated with considerable health resource utilization. SREs have an adverse financial impact on healthcare systems, consuming significant resources. The first interim results from the breast cancer section (n=67) of an ongoing study assessing the health resource utilization per type of SRE (119 discreet SREs) found that pathologic fracture required the longest hospital stay (19 days, n=18), with spinal cord compression requiring the second most days (13.3 days, n=5). Additionally, radiation to bone required the most procedures (14.7, n=87), such as imaging, followed by spinal cord compression (10.4, n=5).

This section of an ongoing observational, multinational study assessed SRE-related utilization of health resources by SRE type (surgery or radiation to bone, pathologic fracture, or spinal cord compression) in breast patients with bone metastases. Data was collected on inpatient hospitalizations, length of stay, outpatient visits, emergency room (ER) visits, nursing home/long-term care facility stays, home health visits, procedures, and medications.

Study “136” is an international, Phase 3, randomized, double-blind study comparing Xgeva with Zometa in the treatment of bone metastases in patients with advanced breast cancer to prevent SREs. Patients enrolled in the study were randomized in a one-to-one ratio to receive either 120 mg of Xgeva subcutaneously every four weeks (Q4W) or Zometa administered intravenously at a dose of 4 mg in a 15 minute infusion every four weeks adjusted for renal function as per the Zometa label instructions.

The primary endpoint of the study was to evaluate if Xgeva was non-inferior to Zometa with respect to the first, on-study SRE in patients with advanced breast cancer and bone metastases. Secondary endpoints were to evaluate if denosumab was superior to Zometa with respect to the first, on-study SRE, as well as the first-and-subsequent on-study SREs, and to assess the safety and tolerability of denosumab compared with Zometa.

Results from the primary analysis of the “136” study showed that Xgeva was superior to Zometa in delaying time to first on-study skeletal-related event in patients with breast cancer and bone metastases and that Xgeva was superior to Zometa in delaying the time to first-and-subsequent on-study SREs.

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