1. Julie R. Gralow, MD Professor, Medical Oncology University of Washington School of Medicine Director, Breast Medical Oncology Seattle Cancer Care Alliance Member, Clinical Research Division Fred Hutchinson Cancer Research Center Seattle, Washington Current Therapeutic Approaches to Treat Bone Metastases in Women with Breast Cancer This program is supported by an educational donation from

2. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer About These Slides  Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Disclosure Julie R. Gralow, MD, has disclosed that she has received fees for contracted research from Amgen, Genentech, Novartis, and Roche.

4. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Case 1  60-yr-old woman with history of T2N1 breast cancer, diagnosed 7 yrs ago; treatment: –Lumpectomy and radiation therapy –Anthracycline/taxane chemotherapy –5 yrs of aromatase inhibitor therapy, completed 1 yr ago  At a routine follow-up clinic visit, complains of 1 mo of increasing right hip pain, somewhat responsive to ibuprofen –Bone scan shows multiple areas of uptake suspicious for metastases, including right hip –CA27.29 is elevated (350 U/mL; ULN: 37 U/mL) –CT shows no evidence of lung or liver recurrence  Patient is started on fulvestrant

5. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Which of the following approaches would you recommend? A.Pamidronate 90 mg IV every 4 wks B.Zoledronic acid 4 mg every 4 wks C.Denosumab 120 mg SQ every 4 wks D.Ibandronate 50 mg/day PO or 6 mg IV every 4 wks E.Other treatment

6. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer FDA-Approved Antiosteoclast Agents for Reduction of SREs in MBC  Both ASCO and NCCN recommend all 3 agents  No agent recommended over another AgentDrug ClassRecommended Dose and Schedule Zoledronic acidBisphosphonate4 mg IV q3-4w PamidronateBisphosphonate90 mg IV q3-4w DenosumabRANKL-targeted MAb120 mg SQ q4w 1. Van Poznak CH, et al. J Clin Oncol. 2011;29:1221-1227. 2. National Comprehensive Cancer Network. Clinical practice guidelines in oncology: breast cancer. v.1.2012.

7. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Osteoclast-Targeted Therapy Reduces SREs in Breast Cancer 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. 4. Stopeck A, et al. J Clin Oncol. 2010;28:5132-5139. StudyTreatment Duration, MosPatients With SRE, %P Value Lipton et al* [1] 24  Placebo 64 <.001  Pamidronate 51 Rosen et al [2] 24  Pamidronate 49 NS  Zoledronic acid 46 Kohno et al [3] 12  Placebo 50.003  Zoledronic acid 30 Stopeck et al [4] 17  Zoledronic acid 37N/A  Denosumab 31 *Includes HCM.

8. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Phase III Study: Denosumab vs Zoledronic Acid for Prevention of SREs Zoledronic Acid 4 mg IV* and Placebo SC q4w (n = 1020) Denosumab 120 mg SC and Placebo IV* q4w (n = 1026) Patients with advanced breast cancer and confirmed bone metastases, with no previous bisphosphonate exposure (N = 2046) *Per protocol and zoledronic acid label, IV product dose adjusted for baseline creatinine clearance. Supplemental calcium and vitamin D recommended 1° Endpoint  Time to first on-study SRE (noninferiority) 2° Endpoints  Time to first on-study SRE (superiority)  Time to first and subsequent on-study SRE (superiority) Stopeck A, et al. J Clin Oncol. 2010;28:5132-5139.

9. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Denosumab vs Zoledronic Acid: Time to First On-Study SRE Zoledronic acid10208296765844984272961919429 Denosumab10268396976025144373061899926 Patients at Risk, n *Adjusted for multiplicity. KM Estimate of Median Mos Denosumab Zoledronic acid Not reached 26.4 HR: 0.82 (95% CI: 0.71-0.95; P <.001 noninferiority; P =.01 superiority*) Mos 0 1.00 Proportion of Subjects Without SRE 036912151821242730 0.25 0.50 0.75 Stopeck AT, et al. J Clin Oncol. 2010;28:5132-5139.

10. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer 40 20 0 Mo 12 Mo 18At Time of Analysis Denosumab (n = 1026)Zoledronic acid (n = 1020) Percent of Subjects With SREs (95% CI) 4.5% relative reduction 11.4% relative reduction 15.4% relative reduction 10 30 28.8%32.5%32.9%38.9%25.4%26.6% Stopeck A, et al. SABCS 2010. Abstract P6-14-01. Denosumab vs Zoledronic Acid: Proportion Experiencing ≥ 1 SRE

11. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer *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. Event, n (%)Zoledronic Acid (n = 1013) Denosumab (n = 1020) All adverse events987 (97.4)961 (96.2) Serious adverse events509 (50.2)489 (47.9) Adverse events related to renal toxicity95 (9.4)55 (5.4) Osteonecrosis of the jaw*18 (1.8)26 (2.5) Hypocalcemia (any)37 (3.7)62 (6.1)  Hypocalcemia of grade 3 or 4 † 12 (1.2)18 (1.8) Acute-phase reactions ‡ 286 (28.2)109 (10.7) Denosumab vs Zoledronic Acid: Adverse Events

12. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Case 2  51-yr-old postmenopausal female with metastatic breast cancer involving bone, lymph nodes, and lungs –Started on daily aromatase inhibitor and zoledronic acid every 4 wks –Good response to treatment –Well tolerated  Staging studies after 2.5 yrs of therapy show minimal residual uptake in the bone, no other evidence of disease

13. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer What would be your recommendation for further treatment? A.Stop all therapy B.Continue AI, stop zoledronic acid C.Continue AI, switch zoledronic acid to 8- to 12-wk dosing intervals D.Continue AI and zoledronic acid unchanged E.Other

14. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer 2009 NCCN Task Force Report: Bone Health in Cancer Care  Reconsider bisphosphonate therapy at 2 yrs –Continued bisphosphonate treatment should be considered in patients with active cancer –Discontinuation should be considered in patients who have no active bone disease or who have experienced significant deterioration of renal function –If a clear indication for initiation of bisphosphonate therapy exists at the onset, and those indications continue to exist, continued therapy may be appropriate  Unknown potential additional benefit from continuing bisphosphonates must be weighed against potential toxicities of long-term administration Gralow JR, et al. J Natl Compr Canc Netw. 2009;7(suppl):S1-S32.

15. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer 2011 ASCO Guideline on Bone-Modifying Agents in Breast Cancer  Once initiated, bone-modifying agents should be continued until evidence of substantial decline in performance score  Clinical judgment must guide what constitutes a substantial decline  No evidence addressing consequences of stopping bone- modifying agents after 1 or more adverse skeletal-related events Van Poznak C, et al. J Clin Oncol. 2011;29:1221-1227.

16. How to Dose Bisphosphonates

17. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Patients with breast cancer and bone metastases who received zoledronic acid (9-12 doses) in previous yr (N = 1638) Arm 2 Zoledronic Acid q12w (placebo for interim infusions) (n = 655) Treat for 52 wks Arm 1 Zoledronic Acid q4w (n = 655) 2:2:1 randomization; stratified by duration of previous bisphosphonate treatment (10-15 vs > 15 mos) and elevated uNTx (> 100) at study entry (yes vs no) Arm 3 Placebo q12w (+ zoledronic acid rescue q4w after first SRE) (n = 328) ClinicalTrials.gov. NCT00320710. OPTIMIZE-2 Phase III Study: Zoledronic Acid Dosing Intervals Primary efficacy endpoint: time to first SRE

18. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer ZOOM: ZA q4 vs q12 Wks for Bone Mets After 1 Year of Standard Treatment  Primary endpoint: skeletal morbidity rate (#SREs/patient/year) Zoledronic acid 4 mg IV 12 wkly n = 209 Zoledronic acid 4 mg IV 4 wkly n = 216 Patients with advanced breast cancer and bone metastases, s/p 9-12 prior doses of zoledronic acid in past 15 months (N = 425) Amadori D, et al. ASCO 2012. Abstract 9005. To be presented Monday, June 4 th.

19. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Phase III ZOOM Trial: Results, Safety  Non-inferiority of q12 vs q 4 weekly remains statistically significant”  Safety: –Renal AEs similar in both arms –7 cases of ONJ (1.65% overall) –q12 weekly: n = 4 –q4 weekly: n = 3  Conclusions: Limitations in study design suggest need to confirm non- inferiority of ZOL q12 wk in other ongoing phase III trials ResultsZOL q4 weekly (n = 216) ZOL q12 weekly (n = 209) SMR (95% CI)0.22 (0.14, 0.29)0.26 (0.15, 0.37) Amadori D, et al. ASCO 2012. Abstract 9005.

20. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer BISMARK Phase III Trial: Use of Bone Resorption Markers to Direct Therapy  Primary endpoint: skeletal events *Marker directed schedule  NTx > 100 nmol/mmol creatinine: zoledronic acid 4 mg q3-4 wks  NTx 50-100 nmol/mmol creatinine: zoledronic acid 4 mg q8-9 wks  NTx < 50 nmol/mmol creatinine: zoledronic acid 4 mg q15-16 wks Zoledronic acid, dosed using bone marker (NTx)–directed therapy* (measured q15-16w) Zoledronic acid 4 mg IV 3-4 wkly Patients with advanced breast cancer and bone metastases, WHO or ECOG PS 0-2 (N = 1400) ClinicalTrials.gov. NCT00458796.

21. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Patients with metastatic breast or prostate cancer, or myeloma with bone involvement; no previous IV bisphosphonates (N = 1540) Activated 3/09 Zoledronic acid 4 mg q4w Zoledronic acid 4 mg q12w ClinicalTrials.gov. NCT00869206. CALGB 70604 Phase III Trial: Standard vs Longer Dosing Interval of Zoledronic Acid  Primary endpoint: proportion of patients with ≥ 1 SRE within 2 yrs of randomization

22. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Case 3  A 45-yr-old female with metastatic recurrence of ER- negative and HER2-negative breast cancer –Staging shows inflammatory involvement of skin on chest wall, axillary and supraclavicular nodes, thoracic and lumbar spine, and right femur  First-line treatment: taxane and zoledronic acid, radiation to chest/nodes –Partial response on chest/nodes, stable bone metastases at 3- and 6-mo evaluations

23. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Case 3  At 9-mo evaluation, progression in bone with several new sites of bone metastases including left hip, but otherwise stable chest/node disease –Patient reports increasing pain in left hip over past mo  Patient is switched to capecitabine chemotherapy  MRI of left hip documents lytic lesion in femoral head with < 20% cortical destruction

24. Small Group Discussion

25. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer How would you manage her antiosteoclast-targeted therapy? A.Continue zoledronic acid B.Switch to pamidronate C.Switch to denosumab D.Discontinue antiosteoclast therapy

26. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Denosumab in Pts With Bone Mets and Excess Bone Resorption Despite IV BP  Randomized phase II study  N = 111 cancer patients with bone metastases receiving IV bisphosphonate (mostly breast or prostate) –Elevated uNTx (> 50 nmol/mmol creatinine)  Treatment –Continue IV bisphosphonate q4w –Switch to denosumab 180 mg SQ q4w –Switch to denosumab 180 mg SQ q12w  Primary endpoint: % patients with uNTx < 50 nmol/mmol at 13 wks Fizazi K, et al. J Clin Oncol. 2009;27:1564-1571.

27. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Denosumab in Pts With Bone Mets and Excess Bone Resorption Despite IV BP Fizazi K, et al. J Clin Oncol. 2009;27:1564-1571. ResultIV Bisphosphonate Denosumab (Combined Arms) Patients with uNTx < 50 nmol/mmol at Wk 13, % 2971 Time to uNTx < 50 nmol/mmol, days 659 Duration of uNTx < 50 nmol/mmol, days 24160 SREs, % 178

28. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Denosumab in Pts With Bone Mets and Excess Bone Resorption Despite IV BP 100 020139212517 Visit Wk Median Change From Baseline in uNTx Corrected by Creatine (%) 80 60 40 20 0 -20 -40 -60 -80 -100 IV BP q4w Denosumab 180 mg q12w Denosumab 180 mg q4w Pooled denosumab group Fizazi K, et al. J Clin Oncol. 2009;27:1564-1571.

29. clinicaloptions.com/oncology Maximizing Skeletal Integrity in Patients With Cancer Treatment of Bone Metastases With Bone- Targeted Therapy in Breast Cancer  Which drugs? –Bisphosphonates vs denosumab –Concerns: renal monitoring, route of administration, first infusion effect, ONJ, cost  Dosing interval, duration? –Ongoing studies

30. Go Online for More Education on Bone Health Interactive Decision Support Tools: Experts make treatment recommendations for patients with prostate or breast cancer Optimizing Bone Health in Patients With Cancer: Proceedings of an Independent Expert Panel Downloadable slides clinicaloptions.com/oncology