Alternative Dosing Intervals of Denosumab and Effects on Clinical Outcomes and Safety in Patients with Solid Tumor Malignancies with Bone Metastases Open Access

Jin, Qingchun (Spring 2020)

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Background: Bone metastases are common in patients with solid tumor malignancies such as breast cancer. Bone metastases disrupt normal bone function, which leads to increased skeletal-related events (SREs). Denosumab is a human monoclonal antibody that can inhibit osteoclast function to decrease SREs. The FDA-approved dose for Denosumab is 120 mg every 4 weeks, however, other schedules have been clinically utilized. Existing literature suggest there is no difference in the incidence of SREs between Denosumab administration 180 mg every 4 weeks and 12 weeks in solid tumor patients with bone metastases. However, there is limited evidence regarding efficacy and safety of alternative dosing regimens.

Methods: This is a single-center retrospective study on solid tumor patients with bone metastases. Patients were grouped by an average Denosumab dosing interval of <5 vs. 5-11 vs. >12 weeks. The primary endpoint was a composite of first occurrence of SRE or all-cause death. The secondary objective was to compare safety outcomes. The cumulative event rate for the primary endpoint was estimated by Kaplan-Meier method. Hazard ratios were calculated to measure the degree of association between baseline covariates and composite outcome by fitting Cox proportional hazards model. Cochran-Armitage trend tests were used to analyze safety events.   

Results: The 3-year cumulative composite event rate was approximately 27%, and the rates didn’t differ by dosing intervals (p=0.37). From multivariable Cox proportional hazards regression, independent predictors included prior radiation for primary cancer (HR=0.47, p=0.001), prior surgery for primary cancer (HR=0.74, p=0.12), ECOG (HR=0.48, grade 2 and3 versus grade 0 and 1, p=0.01), presence of visceral metastases (HR=2.10, p=0.0004), Vitamin D supplementation (HR=0.78, p=0.18), creatinine clearance (HR=0.995 per ten mL/min increase, p=0.10) and previous skeletal-related events (HR=1.59, p=0.02). There were significantly more subjects with hospitalizations and hypocalcemia in <5 weeks group (55.0%, p<0.0001; 31.1%, p=0.02).

Conclusion: Extending Denosumab dosing intervals outside labeling recommendations does not appear to significantly affect the time to SRE (or all-cause mortality) among solid tumor patients with bone metastases. Dosing intervals consistent with labeled recommendations were associated with increased incidence of hospitalizations and hypocalcemia compared to less frequent dosing schedules.

KEYWORDS: Bone metastases, SREs, Denosumab, Dosing intervals

Table of Contents

1.Introduction. 1

2. Methods. 2

2.1 Study Population and Design. 2

2.2 Endpoints. 3

2.3 Statistical Analysis. 3

3. Results. 5

3.1 Demographic and Clinical Characteristics. 5

3.2 Description of Exposures and Outcomes. 7

3.3 Risk Factors for First SRE(or all-cause mortality) 9

3.4 Safety Outcomes. 11

4. Discussion. 12

5. Conclusion. 14

6. References. 16


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