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19 th Annual NOCR Meeting

19 th Annual NOCR Meeting. Session I: Breast Cancer Bone Directed Therapy in Breast Cancer Christy A Russell, MD Keck School of Medicine University of Southern California. Indications: Bisphosphonates vs RANK-Ligand inhibitor.

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19 th Annual NOCR Meeting

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  1. 19th Annual NOCR Meeting Session I: Breast Cancer Bone Directed Therapy in Breast Cancer Christy A Russell, MD Keck School of Medicine University of Southern California

  2. Indications: Bisphosphonates vs RANK-Ligand inhibitor •Zoledronic acid is indicated for the treatment of HCM and patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. •Denosumab is indicated for the prevention of skeletal related events in patients with bone metastases from solid tumors.

  3. Pathogenesis of Osteolytic Bone Metastases Tumor Cells in Bone • Tumor-derived osteoclast activating factors • Parathyroid hormone-related protein • Interleukins -6, -8, -11 • Tumor necrosis factor • Macrophage colony-stimulating factor • Bone-derived tumorgrowth factors • Transforming growth factor  • Insulin-like growth factors • Fibroblast growth factors • Platelet-derived growth factor • Bone morphogenic proteins (+) (+) Osteoclast Bone Derived from Roodman GD. N Engl J Med. 2004;350:1655-1664.

  4. Pathogenesis of Osteoblastic Bone Metastases Tumor Cells Bone-derived growth factors Osteoblast-derived signals • Tumor-derived osteoclast activating • factors • PTH-RP • IL-6 • Tumor-derived osteoblast growth factors • ET-1 • TGF- • FGF • BMPs • IGFs (+) (+) Osteoclast Osteoblasts Bone Adapted with permission from Saad F et al. Eur Urol. 2004;45:26-34.

  5. Mechanism of Bisphosphonate Inhibition of Osteoclast Activity Bisphosphonates may modulate signaling from osteoblasts to osteoclasts X Bisphosphonates inhibit osteoclast activity, and promote osteoclast apoptosis1 • Increased OPG production2 • Decreased RANKL expression3 New bone Bone Bisphosphonates are released locally during bone resorption1 Bisphosphonates are concentrated under osteoclasts1 1. Reszka AA, Rodan GA. Curr Rheumatol Rep. 2003;5:65-74. 2. Viereck V et al. Biochem Biophys Res Commun. 2002;291:680-686. 3. Pan B et al. J Bone Miner Res. 2004;19:147-154.

  6. Parathyroid hormone/ Parathyroid hormone–related protein 1,25D3 RANKL PGE2 Interleukin-11 Receptor Activator of Nuclear Factor kB Ligand (RANKL) and Osteoprotegerin (OPG) Stromal cell/Osteoblast OPG RANK Osteoclast Precursor Osteoclast Derived from Roodman GD. N Engl J Med. 2004;350:1655-1664.

  7. Breast Cancer

  8. 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 Lipton A. Cancer.2003;97:848-853.

  9. Untreated Patients Experience Multiple SREs 4.5 Skeletal Morbidity Rate* 4.00 4.0 3.70 3.5 3.0 2.71 2.5 2.0 1.47 1.5 1.0 0.5 0 SRE SRE + HCM Prostate CA[2] NSCLC + Other Solid Tumors[3] Breast Cancer[1] *Mean number of SRE per patient per yr. 1. Lipton A, et al. Cancer. 2000;88:1082-1090. 2. Saad F. Clin Prostate Cancer. 2005;4:31-37. 3. Rosen LS, et al. Cancer. 2004;100:2613-2621.

  10. FDA-Approved Agents for Prevention of SREs in Metastatic Breast Cancer • Both ASCO and NCCN recommend all 3 agents[1,2] • No agent recommended over another 1. Van Poznak CH, et al. J Clin Oncol. 2011;29:1221-1227. 2. NCCN. Clinical practice guidelines in oncology: breast cancer. v.2.2011.

  11. Proportion of Breast Cancer Patients Having Skeletal-Related Events (SREs) With Pamidronate 12 Months1 24 Months2 P=0.005 P=0.002 P=0.49*P=0.001† P≤0.001 P<0.001 P=0.002 *P=0.49 for nonvertebral fracture; †P=0.001 for vertebral fracture. 1. Hortobagyi GN et al. N Engl J Med. 1996;335:1785-1791. 2. Lipton A et al. Cancer. 2000;88:1082-1090.

  12. Bisphosphonates Reduce SREs in Breast Cancer *Includes HCM. 1. Lipton A, et al. Cancer. 2000;88:1082-1090. 2. Rosen LS, et al. Cancer. 2003;98:1735-1744. 3. Kohno N, et al. J Clin Oncol. 2005;23:3314-3321.

  13. Zoledronic Acid Significantly Delays Time to First SRE Compared With Placebo 1.0 0.9 0.8 P = .004 0.7 0.6 Proportion of Patients With Bone Metastases Without an SRE 0.5 0.4 Zoledronic acid 4 mg 0.3 Placebo 0.2 0.1 0 0 50 100 150 200 250 300 350 400 Days After Start of Study Drug Kohno N, et al. SABCS2004. Abstract 3060. Kohno N, et al. J Clin Oncol. 2005;23:3314-3321. Reprinted with permission.

  14. Zoledronic Acid vs Placebo in Stage IV Breast Cancer With Bone Metastases 100 90 Zoledronic acid 4 mg (n = 114) Placebo (n = 113) 80 70 60 52.2 50 Patients (%) 38.9 40 30.7 30 25.4 17.7 20 11.5 8.8 8.8 10 2.6 3.5 0 All SREs Radiation to bone Fractures Spinal cord compression HCM Events at 12 Mos Kohno N, et al. J Clin Oncol. 2005;23:3314-3321.

  15. Zoledronic Acid and Pamidronate in Breast Cancer and Multiple Myeloma Patients With Bone Metastases: 13-Month Data Median time (days) Zoledronic acid: 373 Pamidronate: 363 SREs=skeletal-related events.Adapted with permission from Rosen LS et al. Cancer J. 2001;7:377-387.

  16. Zoledronic Acid vs Pamidronate in Breast Cancer and Multiple Myeloma: 25-Month Data *Hypercalcemia of malignancy is included as an SRE.Rosen LS et al. Cancer. 2003;98:1735-1744.

  17. Multiple myeloma Breastcancer Total Zoledronic acid is More Effective than Pamidronate In Reducing the Risk of Skeletal Complications Multiple Event Analysis: Breast Cancer and Multiple Myeloma Riskreduction P value 0.932 7% .593 0.799 20% .025 0.841 16% .030 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 Risk ratio (zoledronic acid 4 mg versus pam) In favor of pamidronate In favor of zoledronic acid Rosen LS, et al. Cancer. 2003;98:1735-1744.

  18. Renal Profile of Pamidronate and Zoledronic Acid in Patients With Metastatic Breast Cancer or Multiple Myeloma Zoledronic acid 4 mg 272 226 197 152 81 68 30Pamidronate 90 mg 268 213 182 138 73 59 27 *Post–15-minute infusion amendment. Adapted with permission from Berenson JR. The Oncologist. 2005;10:52-62.

  19. 3 Identical International, Randomized, Double-Blind, Active-Controlled Trials • Enrollment Criteria • Adults with breast, prostate, or other solid tumors and bone metastases or multiple myeloma • No current or previous IV bisphosphonate administration for treatment of bone metastases Denosumab 120 mg SC and PlaceboIV* q4w (n = 2862) Supplemental Calcium and Vitamin D Recommended Zoledronic Acid 4 mg IV* and PlaceboSC q4w (n = 2861) *Per protocol and zoledronic acid label, IV product dose adjusted for baseline creatinine.

  20. 1. Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139. 2. Fizazi K, et al. Lancet. 2011;377:813-822. 3. Henry DH, et al. J Clin Oncol. 2011;29:1125-1132. Denosumab vs Zoledronic Acid Pivotal Phase III SRE Prevention Trials In total, > 5700 patients with bone metastases R A N D O M I Z A T I O N Study 136[1] Breast cancer (N = 2049) Denosumab 120 mg SC q4w + PlaceboIV q4w† Study 103[2] Prostate cancer (N = 1904) Supplemental calcium and vitamin D Zoledronic Acid 4 mg IV q4w† + Placebo SC q4w Study 244[3] Other solid tumors/MM (N = 1779)

  21. SRE Rate: Denosumab vs ZA in Breast Cancer Patients With Bone Metastases 1.2 1.0 0.8 -22% (P = .004) 0.58 SREs per Patient per Yr 0.6 0.45 0.4 0.2 0 ZA Denosumab Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.

  22. Time to First On-Study SRE: Extended Analysis 1.0 HR: 0.82 (95% CI: 0.71-0.95; P = .0096, superiority) 0.8 0.6 Subjects Without SRE (%) 0.4 KM Estimate ofMedian Mos 32.7 Denosumab 0.2 27.4 Zoledronic acid 0 0 3 6 9 12 15 18 21 24 27 30 33 Study Mo Patients at Risk, n Stopeck A, et al. SABCS 2010. Abstract P6-14-01.

  23. Time to First and Subsequent On-Study SRE* (Multiple Event Analysis) Rate ratio: 0.77 (95% CI: 0.66-0.89; P = .001†) 1.5 1.0 Cumulative Mean Number of SRE 0.5 Total No. of Events 474 Denosumab 608 Zoledronic acid 0 0 3 6 9 12 15 18 21 24 27 30 Mos *Events that occurred at least 21 days apart. †Adjusted for multiplicity. Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.

  24. Pooled Analysis: Time to First On-Study SRE by Previous SRE History With Previous SRE Without Previous SRE Overall Zoledronic acid (n = 1091)Denosumab (n = 1094) Zoledronic acid (n = 819)Denosumab (n = 818) Zoledronic acid (n = 1910)Denosumab (n = 1912) 1.0 0.8 0.6 Proportion of Patients Without On-Study SRE 0.4 0.2 HR: 0.82 (95% CI: 0.70-0.96;P = .015) HR: 0.83 (95% CI: 0.74-0.92; P < .001) HR: 0.83 (95% CI: 0.72-0.97;P = .021) 0 0 6 12 18 24 30 0 6 12 18 24 30 0 6 12 18 24 30 Study Mo Risk Set, n ZADmab 10911094 627673 426450 237258 7879 43 19101912 819818 10521084 425411 266266 692716 145144 382402 3648 114127 44 01 n = number of patients randomized Lipton A, et al. ASCO 2010. Abstract 9015.

  25. Skeletal Complication Risk: Incremental Benefits in Breast Cancer No bisphosphonate 64% risk at 2 yrs Pamidronate~ 20% risk reduction Zoledronic acid Additional ~ 20% risk reduction Denosumab Additional 18% risk reduction 34% 64% 27% 51% Lipton A, et al. Cancer. 2000;88:3033-3037. Rosen LS, et al. Cancer. 2003;100:36-43. Stopeck A, et al. ECCO/ESMO 2009. Abstract 2LBA. Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.

  26. Between-Group Differences in AEs With Unadjusted P < .05 Denosumab, Zoledronic Acid, n (%) (n = 1020) n (%) (n = 1013) Pyrexia 170 (16.7) 247 (24.4) Bone pain 186 (18.2) 238 (23.5) Arthralgia 250 (24.5) 291 (28.7) Anemia 192 (18.8) 232 (22.9) Chills 29 (2.8) 58 (5.7) Pain 72 (7.1) 97 (9.6) Renal failure 2 (0.2) 25 (2.5) Dyspepsia 52 (5.1) 74 (7.3) Lumbar vertebral fracture 35 (3.4) 56 (5.5) Alanine aminotransferase increased 28 (2.7) 47 (4.6) Edema 22 (2.2) 40 (3.9) Hypercalcemia 17 (1.7) 35 (3.5) Metastases to spine 9 (0.9) 21 (2.1) Skin hyperpigmentation 7 (0.7) 19 (1.9) Hyperthermia 4 (0.4) 15 (1.5) Bronchospasm 2 (0.2) 10 (1.0) Blood urea increased 0 (0.0) 8 (0.8) Renal failure acute 1 (0.1) 7 (0.7) Toothache 57 (5.6) 37 (3.7) -10 -5 0 5 10 Hypocalcemia 56 (5.5) 34 (3.4) Risk Difference Favors denosumab Favors zoledronic acid Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.

  27. Adverse Events: From Extended Analysis *P = .2861 †No cases of hypocalcemia were grade 5 (fatal). ‡In the first 3 days after initial treatment. Stopeck A, et al. SABCS 2010. Abstract P6-14-01.

  28. Saad F, et al. Ann Oncol. 2012;23:1341-1347. ONJ Associated With Bone-Targeted Therapy in Patients With Bone Metastases All patients (N = 5723) Potential ONJ(n = 276) Positively adjudicatedfor ONJ(n = 89) Integrated analysis of pivotal denosumab SRE prevention trials Zoledronic acid (n = 37) 1.3% Denosumab (n = 52) 1.8% No significant difference between groups (P = .13)

  29. Associated Oral Events Location of ONJ Saad F, et al. Ann Oncol. 2012;23:1341-1347.

  30. Systemic Risk Factors Saad F, et al. Ann Oncol. 2012;23:1341-1347.

  31. Denosumab. EPAR and summary of product characteristics; Amgen. Zoledronic acid. Summary of product characteristics; Novartis. Preventing and Managing ONJ

  32. Incidence of Hypocalcemia in the 3 Pivotal Phase III Trials *CTCAE grading, grade 3 < 7 mg/dL, grade 4 < 6 mg/dL; No fatal events of hypocalcemia were reported Body JJ, et al. Presentation from the 12th International Conference on Cancer-Induced Bone Disease, November 15-17, 2012, Lyon, France.

  33. Hypocalcemia in Relation to Calcium/Vit D Supplementation With Denosumab *All AEs of hypocalcemia. • Median time to hypocalcemia was 2.8 mos • Most common in the first 6 mos of initiation of denosumab therapy Body JJ, et al. Presentation from the 12th International Conference on Cancer-Induced Bone Disease, November 15-17, 2012, Lyon, France.

  34. Hypocalcemia in Relation to Tumor Type With Denosumab Treatment Body JJ, et al. Presentation from the 12th International Conference on Cancer-Induced Bone Disease, November 15-17, 2012, Lyon, France.

  35. Denosumab. Summary of product characteristics; Amgen. Zoledronic acid. Summary of product characteristics; Novartis. Block G, et al. Poster presentation at the National Kidney Foundation spring clinical meeting 2010. Preventing and Managing Hypocalcaemia

  36. Question: What is the Maximum Time You Provide Bone-Modifying Therapy

  37. Guidelines and Duration of Bone-Targeted Therapy 1. Cardoso F, et al. Ann Oncol. 2011;22(suppl 6) vi 25-30. 2. NCCN. Clinical practice guidelines in oncology: breast cancer. v3.2012. 3. Van Poznak CH, et al. J Clin Oncol. 2011;29:1221-1227.

  38. 2-Yr Open-Label Extension Phase Dmab 120 mg SC q4w 2 yrs (n = 652) Dmab 120 mg SC + Placebo IV q4w (n = 1026) Yes (89%) Superiority of Dmab over ZA positive risk:benefit profile † A n a l y s i s P r i m a r y Adults with advanced breast cancer and confirmed bone metastases Patient choice for open-label Dmab (n = 752) ZA 4 mg IV + Placebo SC q4w (n = 1020)) 2-yr survival follow-up q12w • Among patients previously receiving denosumab or zoledronic acid, 89% in each treatment group chose to receive open-label denosumab • Cumulative median exposure to denosumab for the entire study (including blinded and open-label treatment phases) was 19.1 mos (range: 0.1-59.8 mos, ie, ~ 5 yrs) • 216 patients received denosumab for ≥ 3 yrs • 76 patients received denosumab for ≥ 4 yrs Stopeck AT, et al. SABCS 2011. Abstract P3-16-07.

  39. AEs During Open-Label Treatment Phase • No new safety signals were observed with up to ~ 5 yrs of monthly denosumab therapy • Incidence and pattern of AEs in patients who switched from zoledronic acid to denosumabwere similar to those observed in pts who continued with denosumab • Cumulative incidence of positively adjudicated ONJ was 4.7% for denosumab/ denosumabpts when administered for up to ~ 5 yrs and 3.5% for pts who switched from zoledronic acid to denosumab • No neutralizing anti-denosumab antibodies were detected in either group Stopeck AT, et al. SABCS 2011. Abstract P3-16-07.

  40. BMA Optimal Interval

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  45. Management Summary • Patients with bone metastases from breast cancer should be offered therapy with a bone modifying agent in the absence of contraindications • BMA should be used as an adjunct to systemic therapy for the underlying malignancy • Appropriate bone modifying agents include subcutaneous denosumab, IV pamidronate, and IV zoledronic acid • For patients receiving a bisphosphonate, creatinine clearance must be monitored and dose adjustments should be made as necessary • The use of calcium and vitamin D supplements should be explored in patients receiving bone modifying agents particularly with denosumab use • Routine dental care should be performed prior to initiation of a bone modifying agent • Continuation of the bone modifying agent for up to 2 years is certainly acceptable though the optimal duration of therapy remains unclear

  46. Conclusions • Bisphosphonates and denosumab are both effective at • Preventing SREs and HCM • Palliating pain from bone mets • Preventing the development of pain • 2 distinct choices • Different toxicity profiles • Zoledronic acid: flulike symptoms, fevers, bone pains, renal toxicity • Denosumab: hypocalcemia • Subcutaneous vs intravenous administration

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