Amgen has announced results from the XGEVA® (denosumab) Phase III ‘482 study, the largest international multiple myeloma trial for the prevention of skeletal-related events ever conducted (n=1718), were published in The Lancet Oncology.
In this study, XGEVA successfully met the primary endpoint, demonstrating non-inferiority to zoledronic acid in delaying the time to first on-study skeletal-related event in patients with multiple myeloma (HR=0.98, 95% CI: 0.85-1.14).
“Osteolytic bone disease and renal dysfunction are the most frequent complications of multiple myeloma, affecting up to 90 and 60% of patients respectively,” said Noopur Raje, MD, director, Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, Boston. “Until recently, treatment options for the prevention of skeletal-related events in multiple myeloma were limited to bisphosphonates, which are cleared through the kidneys and can be associated with increased renal impairment. Denosumab, which is not cleared through the kidneys, provides a new treatment option for the prevention of skeletal-related events in patients with multiple myeloma.”
“Preventing bone complications is critical for patients with multiple myeloma,” said David M Reese, MD, senior vice president of Translational Sciences and Oncology at Amgen. “The bone-specific effects combined with the renal safety profile demonstrate that XGEVA is an important new alternative to the current standard of care for the prevention of skeletal-related events in patients with multiple myeloma.”
The median time to first on-study skeletal-related event was 22.8 months for XGEVA and 24 months for zoledronic acid. Approximately 60% of all first skeletal-related events occurred within the first three months, and 81% occurred within the first six months. Overall survival, a secondary endpoint of the study, was similar between the XGEVA and zoledronic acid arms, with a hazard ratio of 0.90 (95% CI: 0.70-1.16). Progression-free survival, an exploratory endpoint not powered for statistical significance, was 46.1 months (95% CI: 34.3 months-not estimable [NE], n=219) for XGEVA and 35.4 months (95% CI: 30.2 months-NE, n=260) for zoledronic acid on top of standard of care anti-myeloma therapy.
The safety profile was consistent with known adverse events of both XGEVA and zoledronic acid. There were fewer renal treatment-emergent adverse events in the XGEVA arm compared to the zoledronic acid arm (10% versus 17%, respectively). Hypocalcaemia events were higher in the XGEVA arm compared to the zoledronic acid arm (17% versus 12%, respectively). Osteonecrosis of the jaw was observed in 4% of the XGEVA-treated patients versus 3% of the zoledronic acid-treated patients. The most common treatment-emergent adverse events (greater than 25%) were diarrhoea and nausea.
XGEVA is the first fully human monoclonal antibody that binds to and neutralizes RANK ligand (RANKL) – a protein essential for the formation, function and survival of osteoclasts, cells which break down bone – thereby inhibiting osteoclast-mediated bone destruction. XGEVA is not cleared by the kidneys. On 5 January, the US Food and Drug Administration (FDA) approved the supplemental Biologics License Application (sBLA) for XGEVA 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 was based on data from the ‘482 study. Additional regulatory applications for XGEVA for the prevention of skeletal-related events in patients with multiple myeloma are underway and have been submitted to health authorities worldwide.