The FDA has approved denosumab (Xgeva) for the prevention of skeletal-related events in patients with bone metastases and multiple myeloma.
The US Food and Drug Administration (FDA) has approved denosumab (Xgeva) for the prevention of skeletal-related events (SREs) in patients with bone metastases and multiple myeloma. The drug was previously approved for SREs in patients with prostate cancer, breast cancer, and other solid tumors in 2010.
Denosumab 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. Multiple myeloma is typically characterized by osteolytic bone lesions as well as renal failure. More than 90% of patients will develop osteolytic lesions during the course of the disease.
“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 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.”
The approval was based on results of the phase III 482 study, which included 1,718 patients who were randomly assigned to zoledronic acid (the standard of care for the prevention of SREs in multiple myeloma since 2002) or 120-mg subcutaneous denosumab (859 patients in each arm). All patients had adequate organ function; ECOG performance status ranged from 0–2. The primary endpoint was non-inferiority of denosumab for time to first on-study SRE.
The study met its primary endpoint, with denosumab demonstrating non-inferiority to zoledronic acid (hazard ratio, 0.98; 95% CI, 0.85–1.14; P = .01). The median time to first on-study SRE was similar between the two treatments, at 22.83 months with denosumab compared with 23.98 months with zoledronic acid. The median progression-free survival was more than 10 months higher in the denosumab arm. In addition, overall survival was comparable between the two treatment arms.
The most common adverse events for patients treated with denosumab were diarrhea, nausea, anemia, back pain, thrombocytopenia, peripheral edema, hypocalcemia, upper respiratory tract infection, rash, and headache. Osteonecrosis of the jaw was the most common adverse event resulting in discontinuation of denosumab; it occurred in 4.1% of patients assigned to denosumab and 2.8% of patients in the zoledronic acid group.