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FDA Says ‘Yes’ to Denosumab (Xgeva) for Patients With Hypercalcemia of Malignancy

Treatment achieves 64% complete response rate in clinical trial

The FDA has approved a new indication for denosumab (Xgeva, Amgen) for the treatment of hypercalcemia of malignancy (HCM) refractory to bisphosphonate therapy.

The agency’s decision was based on positive results from an open-label, single-arm study, which enrolled patients with advanced cancer and persistent hypercalcemia after recent bisphosphonate treatment. The study’s primary endpoint was the proportion of patients with a clinical response, defined as albumin-corrected serum calcium (CSC) levels of 11.5 mg/dL (2.9 mmol/L) or less within 10 days after the first dose of denosumab. Secondary endpoints included the proportion of patients who experienced a complete response (defined as CSC of 10.8 mg/dL [2.7 mmol/L] or less) by day 10, the time to response, and the response duration (defined as the number of days from the first occurrence of CSC of 11.5 mg/dL or less).

The study achieved its primary endpoint with a response rate at day 10 of 63.6% among the 33 patients evaluated. The overall complete response rate was also 63.6%. The estimated median time to response (CSC of 11.5 mg/dL or less) was 9 days, and the median duration of response was 104 days.

The most common adverse reactions in patients receiving denosumab for HCM included nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.

In patients with HCM, denosumab is administered as a subcutaneous injection (120 mg) every 4 weeks, with additional doses of 120 mg on days 8 and 15 of the first month of therapy.

Denosumab binds to RANK ligand (RANKL), a protein essential for the formation, function, and survival of osteoclasts (the cells responsible for bone resorption), thereby modulating the release of calcium from bone. The drug prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts, thereby decreasing bone destruction and calcium release.

HCM is a serious complication in patients with advanced cancer, including those with hematologic malignancies. The condition results from cancer-driven increases in bone resorption and, if untreated, can lead to renal failure, progressive mental impairment, coma, and death. In 2012, the estimated prevalence of HCM in cancer patients in the U.S. was 2.7%. The disorder has a poor prognosis and occurs most often in patients with squamous-cell cancer (e.g., lung cancer and head-and-neck cancer), breast cancer, kidney cancer, myeloma, and lymphoma.

Denosumab (Xgeva) was approved by the FDA for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors in 2010. The drug is not indicated for the prevention of SREs in patients with multiple myeloma. In clinical trials, denosumab demonstrated a clinically meaningful improvement compared with the previous standard of care in preventing SREs.

In 2013, denosumab was also approved by the FDA as the only treatment for adults and skeletally mature adolescents with giant-cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity.

Source: Amgen; December 8, 2014.


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