Denosumab For The Treatment Of Hypercalcemia Of Malignancy Refractory To IV Bisphosphonates In Patients With Hematologic Malignancies
Authors: Gucalp Rasim , Insogna Karl , Hu Mimi , Glezerman Ilya , Leboulleux Sophie , Misiorowski Waldemar , Yu Bennett , Zorsky Paul , Tosi Diego , Bessudo Alberto , Jaccard Arnaud , Tonini Giuseppe , Ying Wendy , Braun Ada H. , Jain Rajul K. 
Published: October 2019

Abstract

Background
Hypercalcemia of malignancy (HCM) is a serious complication in patients with advanced cancer, including those with hematologic malignancies. HCM is commonly treated with intravenous (IV) bisphosphonates, but HCM may persist or relapse despite bisphosphonate therapy. Denosumab (XGEVA®) is a fully human monoclonal antibody that binds to RANK ligand (RANKL) to inhibit osteoclast-mediated bone resorption.

Methods
In this single-arm, open-label study, patients with solid tumors or hematologic malignancies who had HCM (corrected serum calcium [CSC] >12.5 mg/dL) despite IV bisphosphonate treatment ≥7 and ≤30 days before screening received subcutaneous denosumab 120 mg on days 1, 8, 15, and 29, then every 4 weeks thereafter. The primary endpoint was the proportion of patients who had a treatment response (defined as CSC ≤11.5 mg/dL) within 10 days of denosumab initiation. Key secondary endpoints included the proportion of patients with a treatment response at each study visit and the proportion of patients with a complete response (defined as CSC ≤10.8 mg/dL) by day 10 or at each study visit. This ad hoc analysis summarizes results for patients with hematologic malignancies.

Results
The study enrolled 33 patients, of whom 9 had hematologic malignancies (5 myeloma, 2 non-Hodgkin lymphoma, 2 chronic lymphocytic leukemia [CLL] with Richter's transformation). Key baseline characteristics are shown in the Table.
By day 10, 21 of the 33 patients in the study (64%) had a treatment response. Also by day 10, all 9 patients (100%) with hematologic malignancies had a treatment response, and 5 of 9 (56%) had a complete response. Eight of the 9 hematologic malignancy patients (89%) had a complete response over the course of the study.
The most frequently reported serious adverse events (SAEs) in the overall study population were worsening of hypercalcemia (n=5, 15%) and dyspnea (n=3, 9%). In patients with hematologic malignancies, disease progression was reported in 2 patients (22%), and worsening of hypercalcemia was reported in 1 patient (11%); all other SAEs occurred in only 1 patient each. Two patients, including 1 with CLL, had isolated episodes of CSC levels ≤8.0 mg/dL; none had CSC <7.0 mg/dL. No osteonecrosis of the jaw was reported.

Conclusions
In this ad hoc analysis from a study of patients with persistent or relapsed HCM despite recent IV bisphosphonate treatment, 100% of patients with hematologic malignancies responded to denosumab within 10 days. No unexpected safety findings were identified.

Disclosures:
Off Label Use: This abstract describes the use of denosumab for the treatment of hypercalcemia of malignancy, which is investigational and not an approved indication for denosumab. Hu:Amgen Inc.: Research Funding. Glezerman:Amgen Inc.: Research Funding. Misiorowski:Amgen Inc.: Research Funding. Zorsky:Galena Biopharma: Equity Ownership; RxI: Equity Ownership. Tosi:Novartis: Research Funding. Ying:Amgen Inc.: Employment. Braun:Amgen Inc.: Employment, Equity Ownership. Jain:Amgen Inc.: Employment.