J Clin Oncol 25: by American Society of Clinical Oncology INTRODUCTION

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1 VOLUME 25 NUMBER 28 OCTOBER JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Randomized Active-Controlled Phase II Study of Denosumab Efficacy and Safety in Patients With Breast Cancer-Related Bone Metastases Allan Lipton, Guenther G. Steger, Jazmin Figueroa, Cristina Alvarado, Philippe Solal-Celigny, Jean-Jacques Body, Richard de Boer, Rossana Berardi, Pere Gascon, Katia S. Tonkin, Robert Coleman, Alexander H.G. Paterson, Mark C. Peterson, Michelle Fan, Amy Kinsey, and Susie Jun From the Penn State Milton S. Hershey Medical Center, Hershey, PA; Universitätsklinik für Innere Medizin, Wien, Austria; Hospital General de Mexico; Hospital Juarez de Mexico, Mexico City, Mexico; Clinique Victor Hugo, LeMans, France; Institut Jules Bordet, Brussels, Belgium; Western Hospital, Footscray, Australia; Università Politecnica delle Marche, Ancona, Italy; Hospital Clínic de Barcelona, Barcelona, Spain; Cross Cancer Center, Edmonton; Tom Baker Cancer Centre, Calgary, Alberta, Canada; Weston Park Hospital, Sheffield, United Kingdom; and Amgen Inc, Thousand Oaks, CA. Submitted March 28, 2007; accepted July 9, 2007; published online ahead of print at on September 4, Supported by Amgen Inc, Thousand Oaks, CA. Presented in part at 42nd Annual Meeting of the American Society of Clinical Oncology Atlanta, GA, June 3-6, 2006; First International Symposium on Secondary Causes of Osteoporosis, Florence, Italy, July 7-8, 2006; 31st ESMO Congress, Istanbul, Turkey, September 29-October 2, 2006; Second Annual Oncology Congress, New York, NY, October 19-21, 2006; Chemotherapy Foundation Symposium XXIV, New York, NY, November 8-11, 2006; and the Sixth International Meeting on Cancer Induced Bone Disease, San Antonio, TX, December 10-14, Authors disclosures of potential conflicts of interest and author contributions are found at the end of this article. Address reprint requests to Allan Lipton, MD, Milton S. Hershey Medical Center Oncology, 500 University Dr, Hershey, PA ; alipton@psu.edu by American Society of Clinical Oncology X/07/ /$20.00 DOI: /JCO A B S T R A C T Purpose Denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor- B ligand, suppresses bone resorption. In this study, we evaluated the efficacy and safety of five dosing regimens of denosumab in patients with breast cancer-related bone metastases not previously treated with intravenous bisphosphonates (s). Patients and Methods Eligible women (n 255) with breast cancer-related bone metastases were stratified by type of antineoplastic therapy received and randomly assigned to one of six cohorts (five denosumab cohorts [blinded to dose and frequency]; one open-label cohort). Denosumab was administered subcutaneously every 4 weeks (30, 120, or 180 mg) or every 12 weeks (60 or 180 mg). The primary end point was percentage of change in the bone turnover marker urine N-telopeptide corrected for urine creatinine (untx/cr) from baseline to study week 13. The percentage of patients achieving more than 65% untx/cr reduction, time to more than 65% untx/cr reduction, patients experiencing one or more on-study skeletal-related events (SRE), and safety were also evaluated. Results At study week 13, the median percent reduction in untx/cr was 71% for the pooled denosumab groups and 79% for the group. Overall, 74% of denosumab-treated patients (157 of 211) achieved a more than 65% reduction in untx/cr compared with 63% of bisphosphonate-treated patients (27 of 43). On-study SREs were experienced by 9% of denosumab-treated patients (20 of 211) versus 16% of bisphosphonate-treated patients (seven of 43). No serious or fatal adverse events related to denosumab occurred. Conclusion Subcutaneous denosumab may be similar to s in suppressing bone turnover and reducing SRE risk. The safety profile was consistent with an advanced breast cancer population receiving systemic therapy. J Clin Oncol 25: by American Society of Clinical Oncology INTRODUCTION Bone is a common site for metastasis in breast cancer; approximately 75% of women with advanced breast cancer will develop bone metastases. 1-3 Bone metastases associated with breast cancer are predominately osteolytic 4 ; complications include hypercalcemia, increased fracture risk, need for surgery or radiotherapy, and spinal cord compression. 1,5 Bone metastases in breast cancer are also characterized by elevated bone turnover markers such as the urinary-n-telopeptide/creatinine ratio (untx/cr); patients with elevated levels of untx/cr are at increased risk for skeletal complications, disease progression, and death. 6-8 Receptor activator of nuclear factor- B ligand (RANKL) is a key mediator in the vicious cycle of bone destruction in metastatic cancer. Within the bone microenvironment, factors secreted by tumor cells stimulate stromal cells and osteoblasts to express and secrete RANKL, which binds to RANK on the surface of precursor and mature osteoclasts. RANKL is a critical mediator of osteoclast differentiation, function, and survival Osteoclastmediated bone resorption releases growth factors that further stimulate tumor growth, resulting in a 4431

2 Lipton et al pattern of bone destruction and tumor cell proliferation. 12 RANKL has recently been shown to promote migration of RANK-expressing tumor cells to bone. 13 Current therapies for bone metastasis include antineoplastic treatments, radiation or surgery to bone, and intravenous (IV) bisphosphonates (BPs). s reduce the risk of skeletal-related events (SREs), decrease bone pain, 15,17 and correct hypercalcemia. 18,19 While BPs such as zoledronic acid (Zometa; Novartis Pharma Stein AG, Stein, Switzerland), pamidronate (Aredia; Novartis Pharmaceuticals Corporation, East Hanover, NJ), clodronate (Bonefos; Schering AG, Berlin, Germany), and ibandronate (Boniva; Roche Laboratories Inc, Nutley, NJ) effectively prevent and treat complications from bone metastases, not all patients respond to treatment. In addition, renal toxicity limits the dosage and use of s in some patients. Additional therapies are needed to treat patients with bone metastases. Denosumab (Amgen Inc, Thousand Oaks, CA) is a fully human monoclonal antibody with high affinity and specificity for RANKL. 20 By binding and neutralizing RANKL, 20 denosumab inhibits osteoclast function and bone resorption. Denosumab could potentially be used to treat bone loss caused by bone metastases, multiple myeloma, or osteoporosis. After a single subcutaneous (SC) dose, denosumab caused rapid and sustained suppression of bone turnover in postmenopausal women with low bone mass and in patients with multiple myeloma or breast cancer. 20,21 This trial investigated the efficacy and safety of five dosing regimens of denosumab in patients with breast cancer-related bone metastases not previously treated with s, and compared the results with those of patients treated with s. A population pharmacokinetic/pharmacodynamic (PK/PD) model was also developed to explore doses for subsequent phase III studies and assist in dose selection. This interim analysis describes results of the study after 13 weeks of treatment. PATIENTS AND METHODS Study Design This was a phase II, randomized, active-controlled, international, multicenter, multidose, parallel group study, with blinding of assigned dose and frequency for patients receiving denosumab. Patients were stratified by type of antineoplastic treatment at enrollment: hormone therapy or chemotherapy. Patients receiving both were assigned to the chemotherapy stratum. Patients were randomly assigned with equal chances to receive SC injections of denosumab every 4 weeks (30, 120, or 180 mg) or every 12 weeks (60 or 180 mg; Appendix Fig A1, online only) or open-label every 4 weeks (zoledronic acid, pamidronate, or ibandronate at the physician s discretion). The primary end point of the study was the median percentage change from baseline to week 13 in untx/cr. Additional efficacy end points were the proportion of patients achieving a more than 65% reduction in untx/cr from baseline and the median time to achieve this reduction. A reduction of more than 65% was chosen because this is the average percentage decrease reported in the literature for patients with bone metastases treated with s The percentage of patients experiencing an on-study SRE (fracture, surgery or radiation to bone, or spinal cord compression) was also evaluated. Safety parameters summarized were the incidence of treatment-emergent adverse events, changes from baseline in laboratory values for albumin-adjusted calcium, serum creatinine, liver enzymes, and electrolytes; and development of antidenosumab antibodies. The denosumab serum concentration-time profile was evaluated and PK parameters were explored. Study Patients Women with breast cancer and radiologic evidence of bone metastases were enrolled at 56 centers in North America, Australia, and Europe. Patients were at least 18 years old, naïve to treatment, and ambulatory, with adequate organ function and no evidence of impending fracture in weightbearing bones. Patients were instructed to take 500 mg calcium and 400 U vitamin D daily. Patients were excluded if they were pregnant; had disorders associated with abnormal bone metabolism including uncontrolled hyper- or hypothyroidism or Paget s disease; untreated or symptomatic brain metastases; prior malignancy except breast cancer, basal cell carcinoma, or cervical carcinoma in situ; were currently receiving therapy with chronic systemic corticosteroid administration; or received calcitonin, parathyroid hormonerelated peptides, mithramycin, strontium ranelate, or gallium nitrate within 8 weeks of random assignment. All patients provided written informed consent. The study was approved by the institutional review board or ethics committee for each site. Study Procedures In the denosumab groups, patients received SC injections (denosumab or placebo to maintain blinding) on study day 1 (week 1), and at study weeks 5, 9, 13, 17, and 21. In the BP group, patients received BPs as an IV infusion, administered according to country-specific product information, on study day 1 and at weeks 5, 9, 13, 17, and 21. Patients were to be observed for a total of 56 weeks after the first dose: 24 weeks of treatment with 32 subsequent weeks of follow-up. Medical and medication history were recorded; physical examinations, assessment of Eastern Cooperative Oncology Group status, monitoring of vital signs, weight and height measurements, ECGs, and collection of urine and blood were performed periodically throughout the study. Serum chemistries and denosumab serum concentrations were measured on study day 1 and at weeks 2, 5, 9, 10 to 12, 13, 17, 18 to 20, 21, and 25. Antidenosumab antibodies were measured by enzyme-linked immunosorbent assay at weeks 1, 5, 13, 25, 33, 45, and 57. The effect of denosumab on bone resorption was assessed by measurement of untx/cr levels in the second morning void of urine. The baseline value for untx/cr was established before initial dosing; follow-up measurements were collected at weeks 1, 2, 5, 9, 13, 17, 21, 25, 33, 45, and 57. Adverse events, other laboratory variables, and concomitant medications were recorded and assessed at all study visits. Statistical Analyses This study planned to enroll 40 patients in each of six treatment arms for a sample size of 240 patients. With this sample size, a 95% CI of the primary end point would be within a relatively tight range ( 5.1%, assuming a 10% drop-out rate and a 15.7% standard deviation for the pooled patient group). Statistical tests were descriptive evaluations of differences between groups; because of the small sample size, statistical testing would be of limited utility and was not planned for this study. The control arm was included to further describe the effects of denosumab. Percentage changes in untx/cr from baseline were calculated for all patients who were randomly assigned, received at least 1 dose of study drug, and had a baseline (pretreatment) and at least one postbaseline measurement of untx/cr. The equation used to calculate the percentage change in untx/cr from baseline was: 100 (untx/cr untx/cr baseline )/untx/cr baseline The time from randomization to more than 65% reduction in untx/cr and time from randomization to first on-study SRE were analyzed using the Kaplan-Meier method. The safety analysis included all patients who were randomly assigned and received at least one dose of denosumab or. This interim analysis describes results after 13 weeks of treatment or, for patients who discontinued the study, at the last study visit. PK/PD Modeling and Simulation A population PK/PD model was fitted to the available denosumab serum concentrations and untx/cr data from denosumab-treated patients, with parameters estimated for use in subsequent simulations. 26 The fit of the population model provided estimates of the typical population parameters and interpatient variability that described denosumab disposition and the effects of 4432 JOURNAL OF CLINICAL ONCOLOGY

3 Denosumab Efficacy and Safety in Breast Cancer denosumab on untx/cr levels across all treated patients. Subsequently, the PK/PD model and estimated parameters were used to perform Monte Carlo simulations of PK/PD at various denosumab doses, to investigate the exposure-response relationship, and support phase III dose selection. RESULTS Demographics and Baseline Characteristics In total, 255 women with breast cancer-related bone metastases were enrolled (Appendix Fig A2, online only). All patients received denosumab or, except for one patient randomly assigned to the denosumab 120 mg every 4 weeks cohort but deemed ineligible after enrollment because of hemoglobin 9 g/dl. Overall, 18 patients discontinued the study by the time of the week 13 analysis, including 13 patients (6%) randomly assigned to denosumab arms and five patients (12%) randomly assigned to the arm. The most common reasons for study discontinuation were death (2%), consent withdrawn (2%), and disease progression (1%). Generally, baseline characteristics were balanced among all cohorts (Table 1). The patients in the denosumab cohorts were generally older than the patients in the cohort. The majority of patients had bone metastases at more than two sites. The median time since diagnosis of breast cancer was shorter for the denosumab 120 mg every 4 weeks cohort than for other cohorts (2.22 v 3.15 to 3.60 years), but time since diagnosis of bone metastases was comparable for all cohorts. The denosumab 120 mg every 4 weeks cohort had higher median levels of untx/cr at baseline; baseline untx/cr levels were similar among the other cohorts (Table 1). Of the patients randomly assigned to receive, 39 (91%) received zoledronic acid (Appendix Fig A1, online only). All of the patients were receiving systemic antineoplastic therapy at baseline; approximately equal proportions of patients received chemo- and hormone therapy (Table 1). Overall, this population represents patients recently diagnosed with breast cancerrelated bone metastases. Bone Metabolism Suppression of untx/cr occurred at all doses of denosumab; this suppression was seen at the first study visit after the initial dose and continued through week 13 (Fig 1). In the pooled group of denosumab-treated patients, the median percentage change in untx/cr for patients receiving concurrent hormone therapy ( 75%) and those receiving chemotherapy ( 68%). A more than 65% reduction in untx/cr occurred in 74% of denosumab-treated patients and 63% of -treated patients. The median time from random assignment to more than 65% reduction in untx/cr was 13 days (95% CI, 10 to 29 days) for all denosumab cohorts versus 29 days (95% CI, 9 to 86 days) for the BP cohort. In the 180 mg every 12 weeks denosumab cohort, 30 patients (70%) had a more than 65% reduction in untx/cr; the median time to more than 65% reduction in untx/cr in this cohort was 33 days (95% CI, 29 to 89 days). Suppression of untx/cr was sustained through week 13 in patients who received denosumab every 4 weeks, but not in all patients on the every 12 weeks dosing schedule. For example, a patient in the denosumab 180 mg every 12 weeks group had a baseline untx/cr of 93.6 nmol/l BCE/mM Cr. That patient s untx/cr was suppressed to 26.2 nmol/l BCE/mM Cr at week 4, increased to 45.0 nmol/l at week 9, and then rose to 550 nmol/l BCE/mM Cr at week 13. The Kaplan-Meier curves of time to first on-study SRE were similar for denosumab- and -treated cohorts (Fig 2). At data cutoff, the percentage of patients experiencing a first on-study SRE was 9% for denosumab-treated patients (20 of 211) versus 16% for -treated patients (seven of 43). The most common SRE was fracture. Safety Laboratory parameters. No unexpected changes were observed in laboratory values for calcium, serum creatinine, liver enzymes, or electrolytes in the denosumab cohorts. Sixteen denosumab-treated patients (8%) and two -treated patients (5%) experienced transient, asymptomatic decreases in serum calcium levels to less than 2 mmol/l. Among patients whose serum calcium levels decreased to less than 2 mmol/l, 14 denosumab-treated patients (88%) and one BPtreated patient (50%) were receiving supplementary calcium. The calcium decreases occurred within the first 2 weeks after initial dosing for the 10 denosumab-treated patients (63%) and the one treated patient (50%). Values returned to more than 2 mmol/l within 30 days for the 10 denosumab-treated patients (63%) and the one IV BP-treated patient (50%). Clinical parameters. The incidence of serious adverse events appeared to be similar for all denosumab and cohorts, with no serious adverse events attributed to denosumab or s (Table 2). No apparent increases in cardiovascular events or infections were observed in denosumab-treated patients compared with treated patients. Osteonecrosis of the jaw was not reported in this study. At data cutoff (September 2005), eight denosumab-treated patients (4%) and four -treated patients (9%) had died while on study. The investigators determined that these deaths were unrelated to either product. Treatment-related adverse events were experienced by 41 denosumab-treated patients (19%) and 13 -treated patients (30%). Two -treated patients experienced treatment-related adverse events that were considered severe; no treatment-related adverse events experienced by denosumab patients were considered severe, serious, life threatening, or fatal. The adverse events experienced by more than 10% of patients, whether treatment related or not, are presented in Table 2. No apparent dose-dependent increase in adverse events occurred in the denosumab arms. No binding or neutralizing antidenosumab antibodies were detected in any patients tested at week 13 (n 197). Injection-site reactions (local swelling, injection-site pain, and injection-site hemorrhage) were reported in seven denosumab-treated patients (3%) and no IV BP-treated patients. PK/PD Modeling and Simulation At the dose regimens tested, denosumab exposure increased in an approximately dose-proportionate manner. Denosumab profiles were biphasic, with rapid, sustained absorption followed by slow elimination. For the every 4 weeks dosing regimen, an approximately 2.4-fold accumulation was observed after the third dose. Population PK/PD modeling was conducted to characterize the variability in the PK and PD of denosumab among patients in this study; results were utilized in simulations of the exposure-response over a range of doses. Denosumab serum concentrations were well described by a two-compartment PK model with dual Michaelis- Menten (concentration dependent) and linear (concentration independent) clearances from the central compartment. For PD, an

4 Lipton et al Table 1. Baseline Demographic and Disease Characteristics of Study Population 30 mg Q4W 120 mg Q4W Characteristic No. % No. % No. % No. % No. % No. % Race/ethnicity White Hispanic Other Age, years Mean Min Max ECOG status at screening Unknown Hormone receptor status Negative Positive Unknown Time since original diagnosis, years Median Min Max Time since bone metastases, months Median Min Max Bone metastases Total No. of previous SREs egfr Median Min Max nmol/l BCE/mM Cr Median Min Max Antineoplastic therapy at baseline Chemotherapy Hormone therapy Cohort Dose of Denosumab 180 mg Q4W 60 mg Q12W 180 mg Q12W Abbreviations,, intravenous bisphosphonate; Q4W, every 4 weeks; Q12W, every 12 weeks; SD, standard deviation; ECOG, Eastern Cooperative Oncology Group; SRE, skeletal-related event; egfr, estimated glomerular filtration rate; untx/cr, urine N-telopeptide corrected for urine creatinine level. Other includes patients who self-identified as Asian, Native Hawaiian or Pacific Islander, or other. Tumors were screened for expression of the estrogen receptor or progesterone receptor. egfr 170 serum creatinine ( 0.999) age ( 0.176) (0.762 if patient is female) (1.180 if patient is black) BUN ( 0.17) serum albumin (0.318) Patients receiving both chemotherapy and hormone therapy were assigned to the chemotherapy arm. indirect, inhibition-of-synthesis, sigmoidal E max model provided an adequate fit to untx/cr levels from denosumab-treated patients. Parameter estimates, relative SEs, interpatient variabilities, and other relevant metrics are provided in Appendix Tables A1 and A2 (online only). Model parameters were estimated with acceptable precision and during predictive checks the model performed well. Therefore, the resulting model and parameters were used to perform simulations of interest. Monte Carlo simulations of 2,000 simulated patients per dose (every 4 weeks doses of 30, 60, 120, 150, and 180 mg for 12 doses) were performed. The denosumab serum level that would produce 90% of the maximum achievable inhibition of untx/cr (IC 90 )in 4434 JOURNAL OF CLINICAL ONCOLOGY

5 Denosumab Efficacy and Safety in Breast Cancer A Median Percentage (Q1, Q3) Change in untx/cr B Median Percentage (Q1, Q3) Change in untx/cr * Study Week * Study Week each simulated patient was determined, and the proportion of simulated patients with serum denosumab levels above their individual IC 90 before each subsequent dose (trough level) was calculated and plotted for each dose group. Simulations suggested that the 120 mg every 4 weeks dose would result in approximately 95% of patients achieving more than 90% suppression of untx/cr, while 30 mg every 4 weeks would only provide approximately 87% of patients a similar level of untx/cr suppression (Appendix Fig A3, online only). Doses above 120 mg every 4 weeks would not be expected to appreciably improve the proportion of patients achieving the desired level of untx/cr suppression. DISCUSSION Q4W Denosumab 30 mg Q4W Denosumab 120 mg Q4W Denosumab 180 mg Q4W Denosumab 60 mg Q12W Denosumab 180 mg Q12W Q4W Fig 1. Median (Q1, Q3) percentage reduction in urine N-telopeptide corrected for urine creatinine level (untx/cr) from baseline through study week 13. All denosumab versus intravenous bisphosphonate () and denosumab dose groups versus. * Study week 1 baseline. Q4W, every 4 weeks; Q12W, every 12 weeks. Elevated levels of bone turnover markers correlate with disease progression and poorer prognosis. 6-8,27 Inhibition of osteoclast function, as measured by decreases in bone resorption, may result in fewer skeletal complications and a more favorable prognosis. In this study, A Proportion of Patients (%) Study Day No. of patients at risk Q4W Denosumab 30 mg Q4W mg Q4W mg Q4W mg Q12W mg Q12W B Proportion of Patients (%) Q4W Denosumab 30 mg Q4W Denosumab 120 mg Q4W Denosumab 180 mg Q4W Denosumab 60 mg Q12W Denosumab 180 mg Q12W No. of patients at risk Q4W Study Day Q4W Fig 2. Kaplan-Meier curve of estimated time to first on-study skeletal-related event (SRE). The number of patients at risk for experiencing a first on-study SRE at the study day indicated on the x-axis for each cohort is indicated. One patient in the 120 mg every 4 weeks (Q4W) arm did not receive treatment, was considered not to have experienced an on-study SRE, and time to SRE was censored at day 0., intravenous bisphosphonate; Q12W, every 12 weeks. suppression of untx/cr appeared to be similar among patients treated with all doses of denosumab compared with. Suppression of untx/cr was rapid and untx/cr levels reached the nadir by the first visit after the initial dose. Previous studies in healthy postmenopausal women treated with denosumab showed that reduction in untx/cr can be detected as soon as 12 hours postdose. 20 Suppression of untx/cr in this study was sustained through 12 weeks in patients dosed every 4 weeks with denosumab, but not in all patients on the every 12 weeks dosing schedule; evidence of escape from suppression was noted at week 13. More patients in all denosumab cohorts than in the cohort achieved a more than 65% reduction in untx/cr, demonstrating the biologic activity of denosumab. These data suggest that denosumab can suppress markers of bone turnover to a level similar to that previously reported for s in patients with breast cancer-related bone metastases. 24,

6 Lipton et al Table 2. Adverse Events Reported by 10% of Patients Cohort Dosage of Denosumab All Denosumab (n 211) 30 mg Q4W 120 mg Q4W (n 41) 180 mg Q4W 60 mg Q12W 180 mg Q12W Event No. % No. % No. % No. % No. % No. % No. % Patients reporting serious adverse events Patients reporting treatment-related adverse events Patients reporting adverse events Event Pyrexia Arthralgia Asthenia Bone pain Headache Vomiting Constipation Cough Diarrhea Myalgia Pain in extremity Nausea Fatigue Abbreviations:, intravenous bisphosphonate; Q4W, every 4 weeks; Q12W, every 12 weeks. SREs are a common complication of metastatic bone disease, causing pain and reduced quality of life for patients. The s administered in this study reduced SRE incidence and pain in patients with breast cancer related bone metastases compared with placebo. 14,15,18,28 While no comparison with placebo was done in this study and the study was not powered to detect differences in SRE rates, the time to first on-study SRE appeared to be similar for patients in the denosumab and cohorts. However, larger studies are needed to provide a more accurate estimate of the effect of denosumab treatment on the risk of SREs. No flu-like syndrome was attributed to denosumab administration and few injection-site reactions to denosumab were reported. Overall, the safety results are consistent with an adverse event pattern expected in an advanced cancer population receiving systemic antineoplastic therapy. The incidence of adverse events was similar among the and denosumab cohorts. Pyrexia, arthralgia, and asthenia were more common in the cohort; nausea and fatigue were more common in the denosumab cohorts. The data from this study support further investigation of targeted inhibition of RANKL by denosumab as a potential treatment for bone destruction in metastatic cancer. The choice of dose for subsequent study in this population must consider both efficacy and safety measures. Based on the interim data and results of PK/PD modeling and simulations, a denosumab dose was selected for use in phase III clinical trials in cancer patients with bone metastases. In this study, administration of denosumab every 4 weeks resulted in a numerically greater extent of suppression of untx/cr than every 12 weeks administration, with the 120 mg every 4 weeks cohort showing the greatest overall median suppression of untx/cr at study week 13. Phase III trials evaluating the efficacy of denosumab in preventing and treating complications caused by bone metastases are in progress. AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a U are those for which no compensation was received; those relationships marked with a C were compensated. For a detailed description of the disclosure categories, or for more information about ASCO s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Mark C. Peterson, Amgen Inc (C); Michelle Fan, Amgen Inc (C); Amy Kinsey, Amgen Inc (C); Susie Jun, Amgen Inc (C) Consultant or Advisory Role: Allan Lipton, Amgen Inc (C); Jean-Jacques Body, Amgen Inc (C), Novartis (C); Richard de Boer, Amgen Inc (C); Robert E. Coleman, Novartis (C), Amgen Inc (C) Stock Ownership: Mark C. Peterson, Amgen Inc; Michelle Fan, Amgen Inc; Amy Kinsey, Amgen Inc; Susie Jun, Amgen Inc Honoraria: Allan Lipton, Amgen Inc; Guenther G. Steger, Amgen Inc; Jean-Jacques Body, Amgen Inc, Novartis; Richard de Boer, Amgen Inc; Pere Gascon, Janssen-Cilag, Roche Pharma, Amgen Inc; Robert E. Coleman, Amgen Inc, Novartis Research Funding: Philippe Solal-Celigny, Amgen Inc; Richard de Boer, Amgen Inc; Katia S. Tonkin, Amgen Inc; Robert E. Coleman, Novartis; Alexander H.G. Paterson, Amgen Inc Expert Testimony: Robert E. Coleman, Novartis (C) Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Allan Lipton, Mark C. Peterson, Michelle Fan, Amy Kinsey, Susie Jun Provision of study materials or patients: Allan Lipton, Guenther G. Steger, Jazmin Figueroa, Cristina Alvarado, Philippe Solal-Celigny, Jean-Jacques Body, Richard de Boer, Rossana Berardi, Pere Gascon, 4436 JOURNAL OF CLINICAL ONCOLOGY

7 Denosumab Efficacy and Safety in Breast Cancer Katia S. Tonkin, Robert E. Coleman, Alexander H.G. Paterson, Amy Kinsey, Susie Jun Collection and assembly of data: Allan Lipton, Guenther G. Steger, Philippe Solal-Celigny, Richard de Boer, Mark C. Peterson, Amy Kinsey, Susie Jun Data analysis and interpretation: Allan Lipton, Guenther G. Steger, Jean-Jacques Body, Richard de Boer, Mark C. Peterson, Michelle Fan, Amy Kinsey, Susie Jun Manuscript writing: Allan Lipton, Guenther G. Steger, Jean-Jacques Body, Richard de Boer, Katia S. Tonkin, Robert E. Coleman, Mark C. Peterson, Michelle Fan, Amy Kinsey, Susie Jun Final approval of manuscript: Allan Lipton, Guenther G. Steger, Jazmin Figueroa, Cristina Alvarado, Philippe Solal-Celigny, Jean-Jacques Body, Richard de Boer, Rossana Berardi, Pere Gascon, Katia S. Tonkin, Robert E. Coleman, Alexander H.G. Paterson, Mark C. Peterson, Michelle Fan, Amy Kinsey, Susie Jun REFERENCES 1. Coleman RE: Skeletal complications of malignancy. Cancer 80: , Lipton A: Biochemical bone markers in breast cancer. Cancer Treat Rev 32:20-22, 2006 (suppl 1) 3. Palma MA, Body JJ: Usefulness of bone formation markers in breast cancer. Int J Biol Markers 20: , Mundy GR: Metastasis to bone: Causes, consequences and therapeutic opportunities. Nat Rev Cancer 2: , Coleman RE, Smith P, Rubens RD: Clinical course and prognostic factors following bone recurrence from breast cancer. Br J Cancer 77: , Brown JE, Cook RJ, Major P, et al: Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst 97:59-69, Brown JE, Thomson CS, Ellis SP, et al: Bone resorption predicts for skeletal complications in metastatic bone disease. Br J Cancer 89: , Costa L, Demers LM, Gouveia-Oliveira A, et al: Prospective evaluation of the peptide-bound collagen type I cross-links N-telopeptide and C-telopeptide in predicting bone metastases status. J Clin Oncol 20: , Fuller K, Wong B, Fox S, et al: TRANCE is necessary and sufficient for osteoblast-mediated activation of bone resorption in osteoclasts. J Exp Med 188: , Lacey DL, Tan HL, Lu J, et al: Osteoprotegerin ligand modulates murine osteoclast survival in vitro and in vivo. Am J Pathol 157: , Lacey DL, Timms E, Tan HL, et al: Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93: , Roodman GD: Mechanisms of bone metastasis. N Engl J Med 350: , Jones DH, Nakashima T, Sanchez OH, et al: Regulation of cancer cell migration and bone metastasis by RANKL. Nature 440: , Hortobagyi GN, Theriault RL, Lipton A, et al: Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate: Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol 16: , Hortobagyi GN, Theriault RL, Porter L, et al: Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases: Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med 335: , Saad F, Gleason DM, Murray R, et al: A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 94: , Wardley A, Davidson N, Barrett-Lee P, et al: Zoledronic acid significantly improves pain scores and quality of life in breast cancer patients with bone metastases: A randomised, crossover study of community vs hospital bisphosphonate administration. Br J Cancer 92: , Hultborn R, Gundersen S, Ryden S, et al: Efficacy of pamidronate in breast cancer with bone metastases: A randomized, double-blind placebocontrolled multicenter study. Anticancer Res 19: , Theriault RL, Lipton A, Hortobagyi GN, et al: Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: A randomized, placebo-controlled trial: Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol 17: , Bekker PJ, Holloway DL, Rasmussen AS, et al: A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res 19: , Body JJ, Facon T, Coleman RE, et al: A study of the biological receptor activator of nuclear factorkappab ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin Cancer Res 12: , Berenson JR, Vescio R, Henick K, et al: A phase I, open label, dose ranging trial of intravenous bolus zoledronic acid, a novel bisphosphonate, in cancer patients with metastatic bone disease. Cancer 91: , Berruti A, Dogliotti L, Tucci M, et al: Metabolic effects of single-dose pamidronate administration in prostate cancer patients with bone metastases. Int J Biol Markers 17: , Chen T, Berenson J, Vescio R, et al: Pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with bone metastases. J Clin Pharmacol 42: , Cremers SC, Papapoulos SE, Gelderblom H, et al: Skeletal retention of bisphosphonate (pamidronate) and its relation to the rate of bone resorption in patients with breast cancer and bone metastases. J Bone Miner Res 20: , Peterson MC, Jang G, Kim W, et al: Selection of a phase 3 dose regimen for denosumab based on pharmacokinetic (PK), pharmacodynamic (PD), and safety data from multiple subcutaneous (SC) dosing regimens in breast cancer patients (pts) with bone metastases (BM). ASCO Virtual Meeting, Coleman RE, Major P, Lipton A, et al: Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol 23: , Tripathy AD, Diel I, Body JJ: Ibandronate reduces skeletal morbidity in patients with breast cancer. Semin Oncol 31:64-66, 2004 Acknowledgment We thank Cristoph Zielinski, MD, and Christoph Wiltschke, MD, from the Universitätsklinik für Innere Medizin, Wien, Austria, and our fellow study investigators; Amy Foreman-Wykert, Kendle International Inc, and Sue Hudson for providing medical writing assistance; and Sumra Khaja, Kendle International Inc, for providing graphics assistance. Appendix The Appendix is included in the full-text version of this article, available online at It is not included in the PDF version (via Adobe Reader )