The US Food and Drug Administration (FDA) has approved denosumab (XGEVA) to treat hypercalcemia of malignancy (HCM) that is refractory to bisphosphonate therapy.
HCM results from cancer-driven increases in bone resorption. If left untreated, the condition can lead to renal failure, progressive mental impairment, coma, and death.
Denosumab works by binding to RANK ligand, a protein essential for the formation, function, and survival of osteoclasts.
The drug prevents RANK ligand from activating its receptor, RANK, on the surface of osteoclasts, thereby decreasing bone destruction and calcium release.
Denosumab previously received FDA approval to treat giant cell tumor of the bone and for the prevention of skeletal-related events in patients with bone metastases from solid tumors.
The FDA’s approval of denosumab for HCM is based on positive results from an open-label, single-arm study, which enrolled 33 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; adverse events grade < 1) within 10 days of the first dose of denosumab.
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 primary endpoint was met. At day 10, the response rate was 63.6%. Likewise, the overall complete response rate was 63.6%. The estimated median time to response was 9 days, and the median duration of response was 104 days.
The most common adverse events were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.
Potential safety risks
Patients with HCM should receive 120 mg of denosumab as a subcutaneous injection every 4 weeks with additional doses of 120 mg on days 8 and 15 of the first month of therapy.
Pre-existing hypocalcemia must be corrected prior to initiating denosumab therapy. The drug can cause severe, symptomatic hypocalcemia, and fatal cases have been reported.
Physicians should monitor patients’ calcium levels and administer calcium, magnesium, and vitamin D as necessary. Levels should be monitored more frequently when denosumab is given with other drugs that can lower calcium levels. Patients should be advised to contact a healthcare professional if they experience symptoms of hypocalcemia.
Osteonecrosis of the jaw can occur in patients receiving denosumab. Patients who are suspected of having or who develop osteonecrosis of the jaw while on treatment should receive care by a dentist or an oral surgeon.
Atypical femoral fracture has been reported with denosumab, so patients should be advised to report new or unusual thigh, hip, or groin pain. Patients presenting with an atypical femur fracture should be assessed for signs of fracture in the contralateral limb. Physicians should consider interrupting denosumab pending a risk/benefit assessment.
Denosumab can cause fetal harm when administered to a pregnant woman. Physicians should advise females of reproductive potential to use highly effective contraception during therapy and for at least 5 months after the last dose of denosumab.
Amgen, the company developing denosumab, markets the drug as both XGEVA and Prolia (for different indications). Patients receiving XGEVA should not take Prolia.
For more information on denosumab (XGEVA), visit www.xgeva.com.
