Amgen said FDA has approved the supplemental Biologics License Application for Xgeva (denosumab) to expand the currently approved indication for the prevention of skeletal-related events in patients with bone metastases from solid tumors to include patients with multiple myeloma.
The approval is based on data from the pivotal phase III ‘482 study, which enrolled 1,718 patients.
“Up to 40 percent of patients remain untreated for the prevention of bone complications, and the percentage is highest among patients with renal impairment at the time of diagnosis,” said Noopur Raje, director of the Center for Multiple Myeloma at Massachusetts General Hospital Cancer Center. “Denosumab, which is not cleared through the kidneys, offers multiple myeloma patients bone protection with a convenient subcutaneous administration, providing patients with a novel treatment option.”
Xgeva is a fully human monoclonal antibody that binds to and neutralizes RANK ligand—a protein essential for the formation, function and survival of osteoclasts, which break down bone—thereby inhibiting osteoclast-mediated bone destruction.
The ‘482 study was an international, phase III, randomized, double-blind, multicenter trial of Xgeva compared with zoledronic acid for the prevention of skeletal-related events in adult patients with newly diagnosed multiple myeloma and bone disease.
In the study, a total of 1,718 patients (859 on each arm) were randomized to receive either subcutaneous Xgeva 120 mg and intravenous placebo every four weeks, or intravenous zoledronic acid 4 mg (adjusted for renal function) and subcutaneous placebo every four weeks.
The primary endpoint of the study was non-inferiority of Xgeva versus zoledronic acid with respect to time to first on-study skeletal-related event (pathologic fracture, radiation to bone, surgery to bone or spinal cord compression). Secondary endpoints included superiority of Xgeva versus zoledronic acid with respect to time to first on-study skeletal-related event and first-and-subsequent on-study skeletal-related event and evaluation of overall survival. Progression-free survival was an exploratory endpoint. The safety and tolerability of Xgeva were also compared with zoledronic acid.
The study met the primary endpoint, demonstrating non-inferiority of Xgeva to zoledronic acid in delaying the time to first on-study skeletal-related event in patients with multiple myeloma (HR=0.98, 95 percent CI: 0.85, 1.14; p=0.01). The secondary endpoints, delaying time to first skeletal-related event and delaying time to first-and-subsequent skeletal-related events, did not demonstrate superiority.
Overall survival was comparable between Xgeva and zoledronic acid, with a hazard ratio of 0.90 (95 percent CI: 0.70, 1.16; p=0.41). The median difference in progression-free survival favored Xgeva by 10.7 months (HR=0.82, 95 percent CI: 0.68-0.99; descriptive p=0.036). Median progression-free survival was 46.1 months (95 percent CI: 34.3 months, not estimable [NE], n=219) for Xgeva and 35.4 months (95 percent CI: 30.2 months, NE, n=260) for zoledronic acid.
Adverse events observed in patients treated with Xgeva were generally consistent with the known safety profile of Xgeva. The most common adverse reactions (greater than or equal to 10 percent) were diarrhea (34 percent), nausea (32 percent), anemia (22 percent), back pain (21 percent), thrombocytopenia (19 percent), peripheral edema (17 percent), hypocalcemia (16 percent), upper respiratory tract infection (15 percent), rash (14 percent) and headache (11 percent).
The most common adverse reaction resulting in discontinuation of Xgeva (greater than or equal to 1.0 percent) was osteonecrosis of the jaw. In the primary treatment phase of the ‘482 study, ONJ was confirmed in 4.1 percent of patients in the Xgeva group (median exposure of 16 months; range: 1 – 50) and 2.8 percent of patients in the zoledronic acid group (median 15 months, range: 1 – 45 months).
