Amy Feng

Clinical benefit in patients with metastatic bone disease: Results of a phase 3 study of denosumab versus zoledronic acid

BACKGROUND Patients with metastatic bone disease are living longer in the metastatic stage due to improvements in cancer therapy, making strategies to prevent the aggravation of bone disease and its complications, such as skeletal-related events (SREs) and pain, increasingly important. PATIENTS AND RESULTS In this phase 3 trial in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma, denosumab reduced the risk of radiation to bone by 22% relative to zoledronic acid (P = 0.026), prevented worsening of pain and pain interference (2-point increase in Brief Pain Inventory score; P < 0.05 versus zoledronic acid), and reduced the frequency of a shift from no/weak opioid analgesic use to strong opioids (P < 0.05 versus zoledronic acid at months 3-5). Denosumab delayed the time to moderate-to-severe pain compared with zoledronic acid in patients with mild or no pain at the baseline (P = 0.04), supporting early treatment. Health-related quality-of-life scores were similar in both groups. The number needed to treat to avoid one SRE for denosumab was 3 patient-years versus placebo and 10 patient-years versus zoledronic acid. CONCLUSION The use of denosumab was associated with better prevention of the complications of metastatic bone disease secondary to solid tumors or multiple myeloma versus zoledronic acid.

Effects of denosumab on pain and analgesic use in giant cell tumor of bone: Interim results from a phase II study

Abstract Background. Giant cell tumor of bone (GCTB) is an aggressive primary osteolytic tumor. GCTB often involves the epiphysis, usually causing substantial pain and functional disability. Denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor κΒ ligand (RANKL), is an effective treatment option for patients with advanced GCTB. This analysis of data from an ongoing, open-label study describes denosumabs effects on pain and analgesic use in patients with GCTB. Material and methods. Patients with unresectable disease (e.g. sacral or spinal GCTB, or multiple lesions including pulmonary metastases) were enrolled into Cohort 1 (N = 170), and patients with resectable disease whose planned surgery was associated with severe morbidity (e.g. joint resection, limb amputation, or hemipelvectomy) were enrolled into Cohort 2 (N = 101). Patients received denosumab (120 mg) subcutaneously every four weeks, with additional doses on study days 8 and 15. Patients assessed worst pain severity with the Brief Pain Inventory – Short Form (BPI-SF) at baseline, at each visit for the first six months, and every three months thereafter. Results. Clinically relevant pain improvement was reported by 29% of patients in Cohort 1 and 35% in Cohort 2 during week 1 and by ≥ 50% of patients in each cohort at each study visit from months 2–30. Median time to clinically relevant improvement was 30 (95% CI 16, 57) days in Cohort 1 and 15 (95% CI 15, 29) days in Cohort 2. Results in patients with moderate/severe pain at baseline were similar. Fewer than 30% of patients in Cohort 1 and 10% in Cohort 2 experienced clinically relevant pain worsening at any visit through 27 months. Most patients had no/low analgesic use during the study. Conclusion. Most patients treated with denosumab experienced clinically relevant decreases in pain within two months.

Evaluating results from the multiple myeloma patient subset treated with denosumab or zoledronic acid in a randomized phase 3 trial

In a phase 3 trial of denosumab vs zoledronic acid in patients (n=1776) with bone metastases and solid tumors or multiple myeloma, denosumab was superior to zoledronic acid for the primary end point of prevention of skeletal-related events. There was no difference in overall survival between the two groups; however, an ad hoc overall survival analysis in the multiple myeloma subset of patients (n=180) favored zoledronic acid (hazard ratio (HR) 2.26; 95% confidence interval (CI) 1.13–4.50; P=0.014). In the present analysis, we found imbalances between the groups with respect to baseline risk characteristics. HRs with two-sided 95% CIs were estimated using the Cox model. After adjustment in a covariate analysis, the CI crossed unity (HR 1.86; 95% CI 0.90–3.84; P=0.0954). Furthermore, we found a higher rate of early withdrawals for the reasons of lost to follow-up and withdrawal of consent in the zoledronic acid group; after accounting for these, the HR was 1.31 (95% CI 0.80–2.15; P=0.278). In conclusion, the survival results in multiple myeloma patients in this trial were confounded and will eventually be resolved by an ongoing phase 3 trial.

The role of denosumab in the prevention of hypercalcaemia of malignancy in cancer patients with metastatic bone disease

BACKGROUND We compared the activity of denosumab with zoledronic acid for delaying or preventing hypercalcaemia of malignancy (HCM) in patients with advanced cancer and bone metastases or with multiple myeloma. METHODS Patient-level data were combined from two identically designed, randomised, double-blind, active-controlled, phase III trials of advanced cancer patients with breast cancer and other solid tumours (excluding breast or prostate cancer) or multiple myeloma. End-points included time to first on-study HCM, time to first and subsequent on-study HCM, proportion of patients experiencing HCM and proportion of patients experiencing recurrent HCM. RESULTS Denosumab significantly delayed the time to first on-study HCM, representing a 37% reduction in the hazard ratio (HR) compared with zoledronic acid (HR, 0.63; 95% confidence interval (CI): 0.41-0.98; P = 0.042) and reduced the risk of developing recurrent HCM (time to first and subsequent on-study HCM) by 52% (rate ratio, 0.48; 95% CI: 0.29-0.81; P = 0.006). The median time on study was 12.9 months. Fewer patients receiving denosumab compared with zoledronic acid experienced an HCM event (1.7% versus 2.7%; P = 0.028). Of the 84 patients experiencing an HCM event, 40% of those receiving zoledronic acid experienced >1 event of HCM compared with 31% of those receiving denosumab. CONCLUSION Denosumab treatment was more efficacious than treatment with zoledronic acid in delaying or preventing HCM in advanced cancer patients with breast cancer, other solid tumours or multiple myeloma.

1419PDASSESSMENT OF SURGICAL DOWNSTAGING IN AN OPEN-LABEL PHASE 2 TRIAL OF DENOSUMAB IN PATIENTS WITH GIANT CELL TUMOR OF BONE

Annals of Oncology 25 (Supplement 4): iv494–iv510, 2014 doi:10.1093/annonc/mdu354.8 sarcoma 1419PD ASSESSMENT OF SURGICAL DOWNSTAGING IN AN OPEN-LABEL PHASE 2 TRIAL OF DENOSUMAB IN PATIENTS WITH GIANT CELL TUMOR OF BONE Aim: Surgical resection, the standard treatment for giant cell tumor of bone (GCTB), may be associated with severe morbidity and may not be curative for all lesions. In an open-label phase 2 study, treatment with denosumab was associated with delayed surgery and/or a less morbid procedure in most patients with resectable GCTB. We report an unplanned, interim analysis of surgical downstaging in patients with Table: 1419PD abstracts Actual On-Study Procedure Planned Procedure Curettage (n=80) Marginal Excision (n=3) En Bloc Excision (n=1) Hemipelvectomy (n=10) Amputation (n=40) Joint/prosthesis replacement (n=25) Joint resection/fusion (n=35) En bloc resection (n=85) En bloc excision (n=8) Marginal excision (n=1) Curettage (n=18) En Bloc Resection (n=20) Joint Resection/ Fusion (n=5) Joint/Prosthesis Replacement (n=6) Amputation (n=1)

1330TiPA PHASE 2, RANDOMIZED, DOUBLE-BLIND, MULTICENTER TRIAL OF DENOSUMAB IN COMBINATION WITH CHEMOTHERAPY AS FIRST-LINE TREATMENT OF METASTATIC NON-SMALL CELL LUNG CANCER

ABSTRACT Background: Non-Small Cell Lung Cancer (NSCLC) is a heterogeneous disease for which patients (pts) may benefit from targeted therapies. RANK ligand (RANKL) and its receptor RANK are expressed in a subset of NSCLC tumors (Branstetter, 2013). Results from preclinical models show that RANKL acts directly on RANK-expressing tumor cells to promote tumor progression and metastases (Gonzalez-Suarez, 2010; Tan, 2011). Denosumab is a fully human monoclonal antibody that binds RANKL, approved for the prevention of skeletal-related events in pts with solid tumors and bone metastases. In a study of pts with solid tumors receiving standard treatment, post hoc analysis of those with stage IV NSCLC (n = 702) showed that pts who received denosumab had improved median overall survival (OS) vs those who received zoledronic acid (ZA) (HR [95% CI] 0.78 [0.65–0.94], p = 0.01; Scagliotti, 2012). The current trial will correlate tumor RANK and RANKL expression and OS in pts with metastatic NSCLC receiving denosumab in combination with standard chemotherapy vs those receiving chemotherapy alone. The trial is sponsored by Amgen Inc. and registered with ClinicalTrials.gov (NCT01951586). Trial design: ∼216 pts with untreated stage IV NSCLC will receive 4–6 cycles of standard of care chemotherapy and be randomized (2:1) to denosumab 120 mg or placebo SC Q3W or Q4W plus a loading dose on day 8. ZA or placebo IV may be offered in a blinded manner if requested. The sample size is powered to test the interaction between treatment effect and RANK or RANKL expression under various reasonable scenarios. Pts will receive calcium and vit D daily. Randomization will be stratified based on bone metastasis (yes or no), histology (squamous vs nonsquamous), and region (North America, Western Europe/Australia, rest of world). The primary endpoint is tumor RANK expression correlated with OS. Primary analysis will occur when ∼149 deaths have occurred. Eligible pts will have ECOG status 0–1 and radiographically evaluable disease. Pts with known EGFR-activating mutations, EML-4-ALK translocation, or brain metastasis will be excluded. Pt screening and enrollment is planned or underway in ∼10 countries. Reused with permission from the American Society of Clinical Oncology. This Abstract was accepted and previously presented at the 2014 ASCO Annual Meeting #TPS8130. Disclosure: F.R. Hirsch: Fred R. Hirsch has been a consultant/advisor for Amgen and has received research funding fro Amgen; R.H. De Boer: Richard De Boer has received research funding and other renumeration from Amgen; R. Natale: Ronald Natale has an immediate family member who is an employee of Amgen and has received research funding from Amgen; J. Crawford: J.C. has been a consultant/advisor for Amgen and has received research funding from Amgen; G.J. Weiss: Glen Weiss has received honoraria from Genentech, Celgene, Pfizer, Quintiles, and Medscape; A. Feng: Amy Feng is an employee of Amgen and holds stock in the company; A. Braun: Ada Braun was formerly employed by Amgen and holds stock in the company; R. Jain: Rajul Jain is an employee of Amgen and holds stock in the company. All other authors have declared no conflicts of interest.