Denosumab for Treatment of Hypercalcemia of Malignancy in Patients with Solid Tumors or Hematological Malignancies Refractory to IV Bisphosphonates: A Single-Arm Multicenter Study

Hypercalcemia of malignancy (HCM) is a serious complication in patients with advanced cancer, including those with hematological malignancies. HCM is thought to largely result from tumor-driven increases in bone resorption. IV bisphosphonates (BP) are used for treatment of HCM, but patients may relapse after treatment or become refractory to IV BP treatment. In animal models of HCM, inhibition of RANK ligand (RANKL), the key mediator of bone resorption, reversed established HCM more effectively than BP. Denosumab (Xgeva^®) is a fully human monoclonal antibody against RANKL. We present data from a planned interim analysis of a single-arm study evaluating the effect of denosumab treatment in patients with HCM who have not responded to recent BP treatment.

Patients eligible for enrollment in this trial are those with confirmed solid tumors or hematologic malignancies, recent IV BP treatment (7 to 30 days prior), and corrected serum calcium (CSC) levels of > 3.1 mmol/L (12.5 mg/dL). Patients with benign hyperparathyroidism, hyperthyroidism, adrenal insufficiency, or on dialysis are ineligible. Patients receive a single subcutaneous injection of denosumab (120 mg) on study days 1, 8, 15, 28, and every 4 weeks thereafter. Evaluable patients are those who received ≥ 1 dose of denosumab. The primary endpoint is the proportion of responding patients, defined as a CSC level ≤ 2.9 mmol/L (11.5 mg/dL) by day 10 of treatment. Secondary endpoints include complete response (CSC ≤ 2.7 mmol/L [10.8 mg/dL] by day 10 of treatment), response duration, and safety. The interim analysis was planned after at least 10 denosumab-treated patients received ≥ 2 doses of denosumab and provided a serum sample at study day 10 for measurement of CSC level. This trial is registered at clinicaltrials.gov (NCT00896454) and is sponsored by Amgen Inc. Enrollment is ongoing for this trial.

To date, 15 patients have enrolled and received ≥ 1 dose of denosumab. Five patients have advanced stages of hematological malignancies (multiple myeloma, chronic lymphocytic leukemia, and non-Hodgkin's lymphoma). The median baseline CSC level was 3.4 mmol/L (13.6 mg/dL). At day 10, 12 of the 15 patients (80%; 95% exact confidence interval [CI]: 51.9%, 95.7%) achieved a response, with a median decrease in CSC from baseline of 0.68 mmol/L (2.71 mg/dL). Among these 12 patients, the median duration of response was 28 days (95% CI: 7, not estimable) based on Kaplan-Meier estimates. A complete response was achieved by 10 of the15 patients (66.7%; 95% exact CI: 38.4%, 88.2%). Adverse events (AEs), serious AEs, and deaths were reported for 14, 12, and 8 patients, respectively, and were as expected in this population of patients with advanced cancer.

Results from this interim analysis demonstrate that denosumab effectively lowers serum calcium in patients with HCM who did not or no longer respond to recent treatment with IV BP. These results suggest that denosumab may be an effective treatment for HCM in this challenging population.

Hu:Amgen Inc.: Speaker. Off Label Use: Denosumab for treatment of hypercalcemia of malignancy. Gucalp:Eisai: Consultancy. Glezerman:Amgen Inc.: Research Funding. Ying:Amgen Inc.: Employment. Yeh:Amgen Inc.: Employment.