Xgeva Approved for Hypercalcemia of Malignancy

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Sean E. Harper, MD

Xgeva (denosumab) has received approval from the US Food and Drug Administration (FDA) for the treatment of hypercalcemia of malignancy (HCM) refractory to bisphosphonate therapy, and the agent was granted Orphan Drug Designation.

HCM is a serious complication in patients with advanced cancer, which may indicate poor prognosis. In 2012, the estimated prevalence of HCM in cancer patients in the US was 2.7%. HCM occurs most often in patients with squamous cell cancer (eg, lung cancer, head and neck cancer), breast cancer, kidney cancer, myeloma, and lymphoma. The condition results from cancer-driven increases in bone resorption. If untreated, it can lead to renal failure, progressive mental impairment, coma, and death.

Xgeva binds to RANK Ligand (RANKL); a protein that contributes to the formation, function, and survival of osteoclasts, the cells responsible for bone resorption, thereby modulating calcium release from bone. Xgeva prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts, thereby decreasing bone destruction and calcium release.

"Our continued study of Xgeva reinforces Amgen's ongoing commitment to address the unmet needs of cancer patient," said Sean E. Harper, MD, executive vice president of research and development at Amgen. "This latest FDA approval for Xgeva provides an important new therapeutic option for patients with a rare condition that cannot be resolved with bisphosphonate therapy."

The approval of Xgeva is based on results from an open-label, single-arm study, involving patients with advanced cancer and persistent hypercalcemia after recent bisphosphonate treatment. The primary endpoint was the proportion of patients with a response, defined as albumin-corrected serum calcium (CSC) <11.5 mg/dL (2.9 mmol/L; Common Terminology for Adverse Events [CTCAE] grade <1) within 10 days after the first dose of Xgeva. Secondary endpoints included the proportion of patients who experienced a complete response (defined as CSC <10.8 mg/dL [2.7 mmol/L]) by day 10, time to response and response duration (defined as the number of days from the first occurrence of CSC <11.5 mg/dL).

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

The most common adverse reactions observed in patients with hypercalcemia of malignancy taking Xgeva were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.

Xgeva 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.