Positive results from new analyses of denosumab Phase 3 trials

Amgen (Nasdaq: AMGN) today announced positive results from several new analyses of two Phase 3 trials studying denosumab compared with Zometa® (zoledronic acid), the current standard of care, for the treatment of bone metastases in patients with advanced breast cancer ("136 study") and solid tumors or multiple myeloma ("244 study").  Results from these trials reinforce denosumab's consistent ability to delay the complications of bone metastases in patients with advanced cancer.  These results are being presented during the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.  

Integrated Analysis Shows Denosumab Superiority in Delaying or Preventing Skeletal Related Events in a Broad Population with Advanced Cancer (Oral Presentation 9015)

An integrated analysis of the 136 and 244 studies was performed to further evaluate the efficacy of denosumab and understand treatment effects in key sub-groups. The analysis demonstrated that denosumab was superior to Zometa in delaying or preventing skeletal related events (SREs).  Denosumab delayed the time to first on-study SRE over Zometa (hazard ratio 0.83, 95 percent CI: 0.74, 0.92

"Bone metastases are a major clinical concern and cause significant suffering to our advanced cancer patients.  Since these two large head-to-head studies were identically designed, we were able to combine the data to obtain a broader view of denosumab's effect compared to the current standard of care in a diverse group of patients with advanced cancer," said Allan Lipton, M.D., professor of Medicine & Oncology, M.S. Hershey Medical Center of the Pennsylvania State University. "Due to its strong efficacy profile, no need for renal monitoring, and convenient subcutaneous dosing, denosumab provides a significant improvement over the standard of care for preventing skeletal related events."

Overall, adverse events (AEs; 96 percent denosumab, 97 percent Zometa), and serious AEs (53 percent denosumab, 56 percent Zometa) were similar in both groups and consistent with what has previously been reported for these two agents. Osteonecrosis of the jaw (ONJ) occurred in 30 (1.6 percent) denosumab patients and 25 (1.3 percent) Zometa patients. In addition, Zometa-treated patients had increased rates of AEs potentially associated with renal toxicity (6.5 percent denosumab, 9.6 percent Zometa) and with acute phase reactions (8.8 percent denosumab, 21.4 percent Zometa).  As with previous studies in advanced cancer patients, hypocalcemia was more frequent in the denosumab arm. Both overall survival (hazard ratio 0.95, 95 percent CI: 0.86, 1.05)

Sub-Analysis Shows Denosumab Superior to Zometa in Solid Tumor Subset of the 244 Study (Abstract 9133)

A post-hoc subset analysis of the 244 study evaluated patients with solid tumors only.  This analysis showed that denosumab was superior to Zometa in delaying the time to the first on-study SRE (hazard ratio 0.81, 95 percent CI: 0.68, 0.96; P<0.02); and for delaying the time to first and subsequent SREs (multiple events) (hazard ratio 0.85, 95 percent CI: 0.72, 1.00; P<0.05). Both treatment groups had similar rates of overall survival (hazard ratio 0.92, 95 percent CI: 0.81, 1.05).

Additional Analyses Show Denosumab Significantly Delays Onset and Worsening of Bone Pain Over Zometa (Abstracts 1024 and 9053)

Two additional pre-specified exploratory analyses presented at the meeting show denosumab treatment significantly delayed the onset or worsening of bone pain in both the 136 and 244 studies.  These are the most comprehensive analyses of pain measures from the denosumab trial program in SREs to be presented to date.

Bone pain is one of the first signs that metastatic disease has spread to the skeleton and affects approximately 70 percent of patients with metastatic disease.Bone pain dominates the daily lives of patients with metastatic disease and is often characterized as severe or intolerable.

In the 136 study, denosumab significantly extended the time breast cancer patients had no or mild pain, when compared to Zometa. In addition, fewer denosumab patients experienced worsening of pain. Patients with scores of no or mild pain at baseline. 

In the 244 trial of patients with advanced solid tumors (excluding breast and prostate) or multiple myeloma, denosumab-treated patients also experienced a delay in clinically significant worsening of pain compared with patients on Zometa (median 169 days: denosumab, 143 days: Zometa; hazard ratio 0.85, 95 percent CI: 0.73, 0.98).

Exploratory Analysis Shows Denosumab Superior to Zometa in Delaying Time to First SRE or Hypercalcemia of Malignancy (Abstract 9042)

A pre-specified exploratory analysis of the 244 trial found that patients receiving denosumab also experienced a significantly longer time to first SRE or hypercalcemia of malignancy, a severe and sudden increase of calcium in the bones that has a very poor prognosis (19.0 months denosumab versus 14.4 months Zometa, hazard ratio 0.83, 95 percent CI: 0.71, 0.97; Best of ASCO" for 2010).

Adverse Events in Study 136

Overall, the incidence of 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. 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. Infectious AEs were balanced between the two treatment arms. Overall survival (hazard ratio 0.95, 95 percent CI: 0.81, 1.11). 

Adverse Events in Study 244

AEs rates (96 percent denosumab, 96 percent Zometa) and serious AEs (63 percent denosumab, 66 percent Zometa) were similar between groups and were consistent with what has previously been reported for these two agents. Rates of ONJ were balanced and infrequent in both treatment groups (10 patients receiving denosumab as compared with 11 patients receiving Zometa). Infectious AEs were balanced between the two treatment arms (hazard ratio 0.95, 95 percent CI: 0.83, 1.08).