Managing Skeletal Metastases

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1 Managing Skeletal Metastases Alison Stopeck, M.D. Professor of Medicine Director, Breast Cancer Program University of Arizona Cancer Center Tucson, AZ Disclosures: Consulting, research funding, and honoraria from Amgen

2 The Natural History of Bone Metastases in Breast Cancer Pathologic fracture is the most common SRE in patients with breast cancer Median onset is 11 mos from initial diagnosis of bone metastases ~ 20% develop hypercalcemia after a median of 14 mos ~ 10% develop cord compression after a median of 17 mos Over 60% of patients develop SRE within 2 years of diagnosis if untreated with a bone-modifying agent Lipton A. Cancer. 2003;97:

$Complications of Bone Metastases Skeletal Related Events Fracture Need for radiation to bone PAIN Need for surgery to bone Impending fracture Spinal cord compression Hypercalcemia$

3 Complications of Bone Metastases Skeletal Related Events Fracture Need for radiation to bone PAIN Need for surgery to bone Impending fracture Spinal cord compression Hypercalcemia Skeletal complications account for 63% of hospital costs in patients with advanced breast cancer Coleman RE. Cancer. 1997;80: Biermann WA, et al. Bone. 1991;12(suppl 1):S37-S42

4 RANK Ligand Is a Key Mediator in the Vicious Cycle of Bone Destruction RANKL Cancer Cells in Bone Cytokines and Growth Factors (IL-6, IL-8, IL-1b, PGE-2, TNF-, CSF-1, PTHrP) Direct effects on tumor? Growth Factors (TGF-b, IGFs, FGFs, PDGFs, BMPs) Osteoclast Bone Resorption RANKL RANK Bone Adapted from Roodman GD. N Engl J Med. 2004;350:

5 Optimal Management of Patients with Bone Metastases: Treat the Disease and Prevent SREs Fracture Bone Metastasis Bone pain Spinal cord compression Primary treatment 1 Yong M et al. Breast Cancer Res Treat 2011; 129(2): Sathiakum N et al. Prostate Cancer Prostatic Dis (2): Hypercalcemia Patients with SREs have worse OS than Prevent those with the bone consequences mets alone 1,2

6 Preventing Skeletal Related Events

7 FDA-Approved Agents for Prevention of SREs in Patients with Solid Tumors Agent Drug Class Recommended Dose and Schedule Zoledronic acid Bisphosphonate 4 mg IV q3-4w Pamidronate Bisphosphonate 90 mg IV q3-4w Denosumab RANKL-targeted MAb 120 mg SQ q4w Both ASCO and NCCN recommend all 3 agents [1,2] No agent recommended over another Agents Approved Outside US Drug Class Recommended Dose and Schedule Clodronate Bisphosphonate mg IV or mg po daily 1. Van Poznak CH, et al. J Clin Oncol. 2011;29: NCCN. Clinical practice guidelines in oncology: Ibandronate breast cancer. v Bisphosphonate 6mg IV or 50mg po daily

8 Differences in Bone-Modifying Agents Efficacy Toxicity Administration Cost Patient Characteristics and Preferences Risks Benefits

9 Bisphosphonates Reduce Skeletal Related Events in Breast Cancer % pts with SRE Placebo 65% 24 months 1 Pamidronate 46% Pamidronate 49% 24 months 2 Zoledronic Acid 46% (p = ns) Placebo 50% 12 months 3 Zoledronic Acid 30% 1 Lipton A et al, Cancer, 2000; 2 Rosen LS et al, Cancer, 2003; 3 Kohno N et al, J Clin Oncol 23, 2005

10 Zoledronic Acid vs. Placebo in Stage IV Breast Cancer Pain Scores (Brief Pain Inventory) Kohno N et al, J Clin Oncol 23, 2005

11 Bisphosphonates: Side Effects Oral administration: Poorly absorbed from the GI tract (0.5-4%) Non-nitrogen-containing: diarrhea Nitrogen-containing: esophagitis, nausea IV administration: Fever, flu symptoms, arthralgias/myalgias, hypocalcemia Renal insufficiency (related to dose, volume, rate) Potential for interference with mineralization Skeletal ½-life several years Osteonecrosis of the jaw Atypical femoral fractures

12 RANKL Inhibition as a Target for the Prevention of Skeletal Complications of Metastases RANKL is the primary mediator of osteoclast formation, function, and survival and plays a vital role in physiologic and cancer-induced bone resorption Metastatic tumour cells stimulate RANKL activity, leading to a self-reinforcing cycle of bone resorption ( vicious cycle hypothesis) 1 The fully human monoclonal antibody, denosumab, binds and inhibits RANKL thereby preventing bone destruction In phase 2 trials, denosumab significantly lowered bone turnover markers and reduced SREs, including in pts with elevated untx levels despite IV bisphosphonate therapy 2,3 1 Roodman GD. N Engl J Med 2004;350: , 2 Fizazi K, et al. J Clin Oncol 2009;27: Lipton A, et al. J Clin Oncol 2007;25:

13 Denosumab vs Zoledronic Acid in the Pivotal Phase III SRE Prevention Trials In total > 5700 patients with bone metastases Study Breast cancer (N = 2049) Study Prostate cancer (N = 1904) Study Other solid tumours/mm (N = 1779) R A N D O M I z A T I O N Denosumab 120 mg SC Q4W + Placebo IV Q4W Supplemental calcium and vitamin D Zoledronic acid 4 mg IV Q4W + Placebo SC Q4W 1. Stopeck AT, et al. J Clin Oncol 2010;28: Fizazi K, et al. Lancet 2011;377: Henry DH, et al. J Clin Oncol 2011;29:

14 Proportion of Subjects Without SRE Time to First On-Study SRE HR 0.82 (95% CI: 0.71, 0.95) P < (Noninferiority) P = 0.01 (Superiority)* 18% Risk Reduction Subjects at risk: Denosumab Zoledronic Acid KM Estimate of Median Months Not reached Months Zoledronic Acid Denosumab * Adjusted for multiplicity Stopeck et al. JCO 2010: 28: 5132

15 Proportion of Patients Without SRE or Hypercalcemia Time to First On-Study SRE or Hypercalcemia: Extended Analysis HR: 0.82 (95% CI: ; P =.0076) 18% Risk Reduction Patients at Risk, n KM Estimate of Median Mos Denosumab 32.4 Zoledronic acid Study Mo Zoledronic acid Denosumab Stopeck A, et al. SABCS Abstract P

16 Cumulative Mean Number of SRE Time to First-and-Subsequent On-Study SRE* (Multiple Event Analysis) 1.5 Rate Ratio 0.77 (95% CI: 0.66, 0.89) P = % Risk Reduction Denosumab Zoledronic acid Total # of Events Months *Events that occurred at least 21 days apart; Adjusted for multiplicity Stopeck et al. JCO 2010: 28: 5132

17 Proportion of subjects (%) Types of SREs in Each Treatment Group 30.0 P = Zoledronic acid Denosumab P = Pathologic fracture Radiation to bone Surgery to bone Spinal cord compression

18 Risk of First On-study SRE by Solid Tumor Types Richardson G et al. COSA November 2011

19 Percent Decrease in untx Levels With Therapy Trial Denosumab Zoledronic Acid Breast cancer 80% 68% Prostate cancer 40% 28% Solid tumor/mm 76% 65% Comparing baseline to Wk 13 values Stopeck A, et al. SABCS Abstract P

20 Overall Adverse Events Toxicity Patient incidence, n (%) ZA (N = 2744) Denosumab (N = 2755) All adverse events (AEs) 2654 (96.7) 2650 (96.2) CTCAE Grade 3, 4, or 5 AEs 1941 (70.7) 1934 (70.2) Serious AEs 1573 (57.3) 1549 (56.2) AEs leading to study discontinuation 270 (9.8) 261 (9.5) Adverse events of interest Acute phase reactions (first 3 days) 561 (20.4) 241 (8.7) ONJ (adjudicated) 35 (1.3) 48 (1.7) Hypocalcemia* 131 (4.8) 261 (9.5) N = the number of patients who received at least one dose of active drug. *Includes hypocalcemia, blood calcium decreased, calcium deficiency, and calcium ionized decreased. Richardson G et al. COSA November 2011

21 Stopeck et al. JCO 2010: 28: 5132 Between-Group Differences in Adverse Events With Unadjusted P < 0.05 Pyrexia Bone pain Arthralgia Anemia Chills Pain Renal failure Dyspepsia Lumbar vertebral fracture Alanine aminotransferase increased Edema Hypercalcemia Metastases to spine Skin hyperpigmentation Hyperthermia Bronchospasm Blood urea increased Renal failure acute Toothache Hypocalcemia Risk Difference Favors Denosumab Denosumab (N=1020) n (%) 170 (16.7) 186 (18.2) 250 (24.5) 192 (18.8) 29 (2.8) 72 (7.1) 2 (0.2) 52 (5.1) 35 (3.4) 28 (2.7) 22 (2.2) 17 (1.7) 9 (0.9) 7 (0.7) 4 (0.4) 2 (0.2) 0 (0.0) 1 (0.1) 57 (5.6) 56 (5.5) Favors Zoledronic Acid Zoledronic Acid (N=1013) n (%) 247 (24.4) 238 (23.5) 291 (28.7) 232 (22.9) 58 (5.7) 97 (9.6) 25 (2.5) 74 (7.3) 56 (5.5) 47 (4.6) 40 (3.9) 35 (3.5) 21 (2.1) 19 (1.9) 15 (1.5) 10 (1.0) 8 (0.8) 7 (0.7) 37 (3.7) 34 (3.4)

22 Overall Incidence Of Hypocalcemia from the 3 Pivotal Trials Ref: Body JJ et al. ASCO 2013 abstract

23 Risk Factors for Hypocalcemia Diagnosed with metastatic prostate cancer (20.5%) vs Breast Cancer (8.4%) Taking Calcium/Vit D Supplements (12% vs 15.1%) Renal Insufficiency (11% vs 15.3%) First 6 months of therapy (7.7%) vs next 6 months of therapy (3.2%) Median time to hypocalcemia: 3.8 months with Dmab vs 6.5 months with ZA Ref: Body JJ et al. ASCO 2013 abs

24 Preventing and Managing Hypocalcemia Situation Pre-existing hypocalcemia or vitamin D deficiency Start of bone-targeted therapy Severe renal impairment (creatinine clearance < 30 ml/min) or dialysis Hypocalcemia on therapy Action Correct before starting bone-targeted therapy Start daily oral supplements of 500 mg calcium and 400 IU vitamin D Counsel patients on symptoms of hypocalcemia Monitor calcium levels more frequently Additional short-term calcium supplementation may be necessary

25 First prospective study of ONJ in cancer patients with bone metastases First prospective study to Zoledronic acid (n = 37) 1.3%* All patients (N = 5723) Potential ONJ (n = 276) Positive for ONJ (n = 89) P = 0.13* 1. Saad F et al. Annal. Oncol 2011; 23: Browb JE et al. ECC 2013 (abstract) Denosumab (n = 52) 1.8%* assess the incidence, risk factors, and outcomes of ONJ through an integrated analysis comparing denosumab with zoledronic acid in three blinded activecontrolled phase III trials in cancer patients with bone metastases 1 Recently updated with results from open label extension phases in breast and prostate cancer 2. Now 63 (1.9%) cases (Dmab) vs 44 (1.3%) ZA (P=0.08)

26 Associated Oral Events n (%) Zoledronic Acid (n = 37) Denosumab (n = 52) All (N = 89) Tooth extraction 24 (65) 30 (58) 54 (61) Jaw pain 25 (68) 46 (88) 71 (80) Local infection 17 (46) 26 (50) 43 (48) Location of ONJ n (%) Zoledronic Acid (n = 37) Denosumab (n = 52) All (N = 89) Mandible 31 (84) 34 (65) 65 (73) Maxilla 5 (14) 15 (29) 20 (22) Both 1 (3) 3 (6) 4 (4) Saad F et al. Annal. Oncol 2011, doi: /annonc/mdr435

27 Systemic Risk Factors Subjects With ONJ Subjects Without ONJ* ZA Denosumab All ZA Denosumab All n (%) (n = 37) (n = 52) (N = 89) (n = 2824) (n = 2810) (N = 5634) Diabetes 11 (30) 9 (17) 20 (22) 431 (15) 443 (16) 874 (16) Anemia (Hg <10) 17 (46) 23 (44) 40 (45) 1185 (42) 1119 (40) 2304 (41) Chemotherapy agents 27 (73) 36 (69) 63 (71) 1950 (69) 1921 (68) 3871 (69) Antiangiogenics 8 (22) 6 (12) 14 (16) 236 (8) 214 (8) 450 (8) Corticosteroids 28 (76) 39 (75) 67 (75) 1786 (63) 1762 (63) 3548 (63) Ref: Saad F et al. Annal. Oncol 2011, doi: /annonc/mdr435

28 Treatment n (%) Zoledronic Acid (n = 37) Denosumab (n = 52) All (N = 89) Limited surgery 16 (43) 21 (40) 37 (42) Bone resection 1 (3) 3 (6) 4 (4) Outcomes Median or n (%) Zoledronic Acid (n = 37) Denosumab (n = 52) All (N = 89) Resolved* 11 (30) 21 (40) 32 (36) Time to resolution, mos Ongoing, present at time of death, or unknown 26 (70) 31 (60) 57 (64) * Complete mucosal coverage of exposed bone; Among subjects with ONJ resolution

29 Majority of Breast Cancer Patients with Bone Metastases Report Pain Characteristic Proportion of patients (%) Pain status (n = 1926) No pain 15 Mild pain 39 Moderate pain 22 Severe pain 24 Analgesic use (n = 2046) No analgesic use 84 Opioid-based analgesic use 16 46% Typically bone pain is not adequately managed Cleeland CS, et al. Cancer 2013;119: Data are baseline data from the pivotal Phase III denosumab SRE prevention study in breast cancer patients. Based on observed data.

30 Proportion of Subjects Time to Experiencing Pain Improvement ( 2-Point Decrease in Worst Pain Score of Brief Pain Inventory) Denosumab Zoledronic acid KM Estimate of Median Days HR 1.02 (95% CI: 0.91, 1.15) P = Subjects at risk: Months Zoledronic Acid Denosumab Stopeck A, et al. ASCO Abstract 1024

31 Proportion of Subjects Time to Worsening Pain in Patients With No or Mild Pain (0-4) at Baseline KM Estimate of Median Mos Denosumab 9.7 Zoledronic acid 5.8 HR: 0.78 (95% CI: ; P =.0024) BL Mos Pts at Risk, n Denosumab Zoledronic acid Stopeck A, et al. ASCO Abstract 1024.

32 Proportion of patients (%) A lower proportion of breast cancer patients on denosumab progressed from no or low analgesic use to strong opioid use vs zoledronic acid 14 Denosumab (n = 863) 12 Zoledronic acid (n = 848) * * * * Study month Cleeland CS, et al. SABCS 2010 [abstract P and poster]. *P < 0.05; not adjusted for multiplicity

Zoledronic acid improves QoL in breast cancer patients 1 Phase IIIb, multicentre, randomised, open-label, crossover study Zoledronic acid administered in the community setting vs the hospital 101

33 Zoledronic acid improves QoL in breast cancer patients 1 Phase IIIb, multicentre, randomised, open-label, crossover study Zoledronic acid administered in the community setting vs the hospital 101 breast cancer patients with bone metastasis receiving hormonal therapy Quality of life assessed by EORTC QLQ-C30 Administration Preferences *P<0.05; P< Adapted from Wardley, A. Br J Cancer 2005; 92: QoL = quality of life

34 Issues with Adherence and Administration Patient preferences (perceived inconveniences) Prefer oral to IV Prefer home to clinic administration Prefer shortest time of administration i.e. 15 vs 120 minute infusion time Health state utility study in UK Subcutaneous injections preferred over intravenous Allows for home administration Ref: Matza LS et al. ASCO 2012

35 Costs of Bone-Targeted Treatment Costs vary by country and health-care systems Most cost-effectiveness analysis limited: Generally do not take into account costs that may be important to the patient: Lost time for patient or caregivers to receive therapy Time and QOL lost for treatment of SRE Controversial assessments on number of expected SRE Cost of drug acquisition and SRE rates determine cost effectiveness of therapy

36 Cost-Effectiveness of Denosumab versus Zoledronic Acid Prostate cancer Breast cancer NSCLC Dmab ZA Diff Dmab ZA Diff Dmab ZA Diff Total lifetime number of SREs Total lifetime costs ($) Cost/QALY gained ($) Cost/SRE avoided ($) ,486 69,577 6, ,538 95,087 13,451 49,068 44,993 4,076 49,405 78,915 67,931 8,567 13,557 10,513 Other studies: Cost/QALY estimated 192,000 to 1.3 million, and cost/sre avoided estimated at up to 50,000 Ref: Stopeck A et al. J Med Econ 2012

37 Costs of Therapy: Metastatic Breast Cancer Average life expectancy after bone mets = 3.1 years Costs of Dmab for 3.1 yrs x $1650/mo = $59,400 Costs of Zoledronic acid for 3.1 yrs x $900/mo = $32,400 Difference = $27,000 SRE prevented = 1 (cost per SRE ~ 13,000) Cost per SRE = $14,000 Costs of Pamidronate for 3.1 yrs = $1860 Cost per SRE ~ $44,500

38 Cost-Effectiveness of Denosumab versus ZA Relative to Other Select Oncology Therapies Erbitux vs supportive care adv CRC* Zometa vs PBO in mpc Armidex vs Tamoxifen in ER+ BC Herceptin vs no Herceptin in HER-2 +ve denosumab vs zoledronic acid in BC Tamoxifen vs no tamoxifen, BC risk >=3% denosumab vs zoledronic acid in mnsclc Gleevec vs IFN+Cyt in CML denosumab vs zoledronic acid in CRPC Radiotherapy vs Pain meds rpc WHO Definition of U.S Threshold Mean Implied Oncology Threshold in US $180,000 $159,200 $130,000 $110,000 $78,915 $74,000 $67,931 $62,000 $49,405 $44,000 $142,200 $320,000 $0 $100,000 $200,000 $300,000 Cost /QALY Gained ($) Chung K, et al. HOPA 2012.

39 Incremental Benefits in Breast Cancer 64% risk of skeletal complication with no bisphosphonate at 2 yrs Approx 33% risk reduction with pamidronate Further 20% risk reduction with zoledronic acid Additional 18% risk reduction with denosumab 64% 43% 34% 27% Lipton A, et al. Cancer. 2000;88: Rosen LS, et al. Cancer. 2003;100: Stopeck A, et al. JCO 2010;28:

40 Surgical Considerations for Preventing and Treating SREs

41 Metastatic Epidural Spinal Cord Compression -Effects up to 5% of cancer patients -Most common symptom is pain -Medical emergency -Diagnosis best made with MRI -Steroids, radiation therapy, and decompressive surgery Ref: Cole and Patchell. The Lancet Neurology. 2008; &:

42 Spinal Cord Compression: Randomized Trial: Radiation +/- Surgery Able to walk after treatment: Surgical & RT: 42/50, (84%) Radiation: 29/51, (57%) OR 6 2 [95% CI ] p=0 001 Surgery + RT RT Duration of ability to walk: Surgical & RT: 122 D Radiation: 13 D p=0.003 Continence & functionally better with surgery & RT Patchell et al. The Lancet 2005: 366: 643.

43 Does age makes a difference? P= 0.002) -Younger patients do better with combined therapy compared to older patients -In pts < 65 yrs, odds of ambulating in surgical + XRT 5.14 times higher than in XRT alone (P=0.002) Ref: Chi et al. Spine 2009; 34:

$5 cm Lesion: 50% bone diameter Lesion is a Lesser trochanter avulsion Patient has 6 weeks life expectancy Lesion At risk For Fracture Scoring system to predict pathologic fractures: clinically not$

44 To Operate, Most Surgeons Consider: Consider surgery: Size of lesion: 2.5 cm Lesion: 50% bone diameter Lesion is a Lesser trochanter avulsion Patient has 6 weeks life expectancy Lesion At risk For Fracture Scoring system to predict pathologic fractures: clinically not used Limited outcomes data: surgery for impending fracture vs. surgery for completed fracture (favors pre-fracture tx) Shorter hospital stays (7 vs. 11 days) Greater likelihood of discharge home (vs. extended care) (79% vs 56%) Greater likelihood of support-free ambulation (35% vs. 12%) Mirels Clin Ortho 2003 Ward CORR 2003

45 Guidelines and Duration of Bone-Targeted Therapy 1. Cardoso F, et al., Ann Oncol 2011;22(Suppl 6) vi NCCN Clinical Practice Guidelines Oncology: Breast Cancer v Van Poznak CH, et al., J Clin Oncol 2011;29:

46 Study Design and Treatment Schema Adults with advanced breast cancer and confirmed bone metastases Denosumab 120 mg SC + Placebo IV Q4W N = 1026 Placebo SC + Zoled r onic acid 4 mg IV* Q4W N = 1020 P r i m a r y A n a l y s i s Superiority of Denosumab over Zoledronic Acid Positive risk: benefit profile Patient choice for open label denosumab (N = 752) Yes (89%) Denosumab 120 mg SC Q4 W f o r 2 y ea r s (N = 652) 2-Year Survival Fo l low - up (Q12W) Among patients previously receiving denosumab or zoledronic acid, 89% in each treatment group chose to receive open-label denosumab. Ref: Stopeck et al SABCS 2011

47 Open label extension Breast cancer (n = 652 ) 1 Zoledronic acid denosumab Denosumab denosumab Cumulative median exposure to denosumab, months (range) NR 19.1 ( ) Denosumab 3 years, n Denosumab 4 years, n - 76 Prostate cancer (n = 281 ) 2 Cumulative median exposure to denosumab, months (range) NR 12.0 ( ) No neutralizing anti-denosumab antibodies were detected and no new safety signals were observed The cumulative incidence of positively adjudicated ONJ was 4.7% for denosumab/denosumab patients when administered for up to ~5-years and 3.5% for patients who switched from zoledronic acid to denosumab. 1. Stopeck AT, et al. Poster presented at SABCS 2011 [Abstract P ]; 2. Fizazi K, et al. ESMO 2012 Patients who chose to receive open-label denosumab; Entire study including double-blind and open-label treatment phases.

48 Dosing of IV Bisphosphonate by Markers of Bone Turnover Coleman ASCO 2012 AB # 511 BISMARK Met Breast Cancer to bone R A N D O M I Z E Zoledronic Acid Every 4 weeks Zoledronic Acid Dosed by Markers of Bone Resorption Planned N= 1500 Study closed early due to poor accrual with N <300 Follow For SREs

49 BISMARK: untx Directed Therapy Time to First SRE Coleman ASCO 2012 AB # 511 Larger number of SREs in M-Zol 150 vs 109 in S-Zol HR 1.41 (CI ) P=.12 More patients on M-Zol experienced multiple SREs NTX levels were higher in M-Zol group at all time points Trial underpowered but results suggest NTX based schedule may represent sub-optimal management

50 Study of the Interval of Zoledronic Acid Dosing: New Start of Therapy CALGB Bone Metastases Breast Prostate Multiple Myeloma No prior treatment with IV BP R A N D O M I Z E Zoledronic Acid Every 4 weeks Zoledronic Acid Every 12 weeks Follow For SREs & Toxicity Open Label N= approx 1500 Await Results ClinicalTrials.gov # NCT

51 Conclusions Management of skeletal metastases often requires a multidisciplinary approach SREs cause significant morbidity and decrease mortality Pain Control RX: NSAIDs and Opiates Osteoclast inhibition External beam radiation and radiopharmaceuticals Reduce fracture risk Surgery and/or radiation Osteoclast inhibition

52 Bone Targeted Therapies: Prevent SRE and hypercalcemia Palliate and Prevent Pain Decrease use of narcotics and improve QOL Do not improve overall survival or PFS Important differences in efficacy, toxicity, mode of administration and cost among the available agents Patient preference, convenience, characteristics, and treatment plan should be considered when deciding on the most appropriate therapy Still questions on optimal dose and schedule, role in preventing development of metastases/breast cancer

53 Thank you for your attention

Managing Skeletal Metastases

School of Breast Oncology 2012 Managing Skeletal Metastases Cathy Van Poznak, MD Assistant Professor University of Michigan Comprehensive Cancer Center Saturday, November 3, 2012 Learning Objectives: Define