FDA Approves Xgeva for Prevention of Skeletal Events In Multiple Myeloma

Drug previously limited to those with solid tumors

The FDA has expanded the approved indications for denosumab (Xgeva, Amgen) to include the prevention of skeletal-related events in patients with bone metastases with multiple myeloma. The medication was already approved to prevent skeletal events in patients with bone metastases from solid tumors.

The approval is based on data from the pivotal phase 3 '482 study, the largest international multiple myeloma clinical trial ever conducted, which enrolled 1,718 patients.

"Up to 40% 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, MD, director of the Center for Multiple Myeloma at the Massachusetts General Hospital Cancer Center in Boston. "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."

Previously, treatment options for the prevention of bone complications were limited to bisphosphonates, which are cleared by the kidneys.

Denosumab 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. Denosumab is the number-one prescribed bone-targeting agent in the U.S. for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

The '482 study was an international, phase 3, randomized, double-blind, multicenter trial of denosumab 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 denosumab 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 noninferiority of denosumab versus zoledronic acid with respect to time to first on-study skeletal-related event (pathological fracture, radiation to bone, surgery to bone, or spinal cord compression). Secondary endpoints included superiority of denosumab 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 denosumab were also compared with zoledronic acid.

The study met the primary endpoint, demonstrating noninferiority of denosumab to zoledronic acid in delaying the time to first on-study skeletal-related event in patients with multiple myeloma (hazard ratio [HR], 0.98; 95% confidence interval [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 denosumab and zoledronic acid, with an HR of 0.90 (95% CI, 0.70–1.16; P = 0.41). The median difference in progression-free survival favored denosumab by 10.7 months (HR, 0.82; 95% CI, 0.68–0.99; descriptive P = 0.036). Median progression-free survival was 46.1 months (95% CI, 34.3 months; not estimable [NE]; n = 219) for denosumab and 35.4 months (95% CI, 30.2 months; NE; n = 260) for zoledronic acid.

Adverse events observed in patients treated with denosumab were generally consistent with the known safety profile of denosumab. The most common adverse reactions (greater than or equal to 10%) were diarrhea (34%), nausea (32%), anemia (22%), back pain (21%), thrombocytopenia (19%), peripheral edema (17%), hypocalcemia (16%), upper respiratory tract infection (15%), rash (14%), and headache (11%).  The most common adverse reaction resulting in discontinuation of denosumab (greater than or equal to 1.0%) was osteonecrosis of the jaw (ONJ). In the primary treatment phase of the '482 study, ONJ was confirmed in 4.1% of patients in the denosumab group (median exposure of 16 months; range: 1­50) and 2.8% of patients in the zoledronic acid group (median 15 months, range: 1–45 months).

Source: Amgen; January 5, 2018.