Amgen announced the submission of a supplemental Biologics License Application to FDA and the European Medicines Agency for XGEVA (denosumab).
The submissions to regulatory authorities seek to expand the currently approved XGEVA indication for the prevention of skeletal-related events in solid tumors to include patients with multiple myeloma. The applications include new data from the pivotal phase III head-to-head ‘482 study, the largest international multiple myeloma trial ever conducted.
XGEVA is a fully human monoclonal antibody that binds to and neutralizes RANK ligand (RANKL)—a protein essential for the formation, function and survival of osteoclasts, which break down bone—thereby inhibiting osteoclast-mediated bone destruction.
XGEVA is indicated for the prevention of SREs in patients with bone metastases from solid tumors based on results from three previous pivotal phase III head-to-head studies. In these phase III studies, XGEVA demonstrated superiority in the solid tumors studied compared to zoledronic acid.
In the U.S., XGEVA has a limitation of use noting that it is not indicated for the prevention of SREs in patients with multiple myeloma. The sBLA is based on efficacy and safety data from the pivotal phase III ‘482 study, which demonstrated that XGEVA is non-inferior to zoledronic acid in delaying the time to first on-study SRE in patients with multiple myeloma (HR=0.98, 95 percent CI: 0.85, 1.14; p=0.01).
The secondary endpoints of superiority in delaying time to first SRE and delaying time to first-and-subsequent SRE were not met in this study. Overall survival, another secondary endpoint, was also in favor of XGEVA over zoledronic acid (HR=0.90, 95 percent CI: 0.70, 1.16; p=0.41); however, it was not statistically significant. The hazard ratio of XGEVA versus zoledronic acid for progression-free survival was 0.82 (95 percent CI: 0.68, 0.99; descriptive p=0.036). The median PFS difference between arms was 10.7 months in favor of XGEVA.
Adverse events observed in patients treated with XGEVA were consistent with the known safety profile of XGEVA. The most common adverse events (greater than 25 percent) were diarrhea (33.5 percent XGEVA and 32.4 percent zoledronic acid) and nausea (31.5 percent XGEVA and 30.4 percent zoledronic acid).
