ZOMETA in Breast Cancer and Multiple Myeloma: Pamidronate-Controlled Trial 010

1. ZOMETA� in Breast Cancer and Multiple Myeloma: Pamidronate-Controlled Trial (010) James Berenson, MDCedars-Sinai Medical CenterLos Angeles, California

2. CC10-2 Breast Cancer and Multiple MyelomaTrial Design (1) Double-blind, double-dummy Stratification Durie-Salmon Stage III multiple myeloma with? 1 osteolytic lesion Chemotherapy Hormonal therapy Appropriate antineoplastic therapy at baseline and during the course of the trial ECOG performance status 0, 1, 2 Serum creatinine ? 3.0 mg/dL (265 �mol/L)

3. CC10-3 Breast Cancer and Multiple MyelomaTrial Design (2) 12-mo dosing regimen Pamidronate 90 mg every 3 to 4 wk/120-min infusion ZOMETA� 4 mg and 8/4 mg every 3 to 4 wk/5-min amended to 15-min infusion Study duration of 13 mo Patients received oral vitamin D 400 IU and calcium 500 mg

4. CC10-4 Breast Cancer and Multiple MyelomaStudy Objectives Primary objective Demonstrate the effectiveness of ZOMETA� through the noninferiority� comparison to pamidronate for the treatment of bone metastases Demonstrate safety profile of ZOMETA comparable to pamidronate

5. CC10-5 Breast Cancer and Multiple MyelomaStudy Endpoints (1) Primary endpoint Proportion (%) of patients experiencing any skeletal-related event (SRE) not including hypercalcemia of malignancy (HCM)

6. CC10-6 Breast Cancer and Multiple Myeloma Study Endpoints (2) Secondary endpoints Time to first SRE Skeletal morbidity rate (SMR) Andersen-Gill multiple event analysis Time to first SRE, SMR, and proportion (%) of patients with any SRE (+HCM) Pain/analgesic scores Bone lesion response Time to progression of disease Safety (including survival) Additional 6 mo of survival and serum creatinine data

7. CC10-7 Breast Cancer and Multiple Myeloma Skeletal-Related Events (SREs) Pathologic fractures Spinal cord compression Radiation for bone pain or to treat or prevent pathologic fractures or spinal cord compression Surgery to bone Hypercalcemia of malignancy (HCM)

8. CC10-8 Breast Cancer and Multiple Myeloma Preplanned SRE Analysis Proportion (%) of patients with an SRE Number of patients with SRE divided by number of patients in each treatment group Time to first SRE Time from randomization to first SRE (days) Skeletal morbidity rate (SMR)� Number of SREs divided by time at risk on trial (yr) Andersen-Gill multiple event analysis� Time from randomization to each occurrence of the events

9. CC10-9 Clinical Trial History Original study design ZOMETA� (4 mg or 8 mg) via 5-min infusion versus pamidronate 90 mg infused over 120 min every 3 to 4 wk for 12 mo Renal amendment 1 (June 1999) Infusion time for ZOMETA increased from 5 min to 15 min Infusion volume increased from 50 mL to 100 mL Renal amendment 2 (June 2000) 8 mg switched to 4 mg (8/4-mg group) Renal function monitoring within 2 wk prior to each dose Statistical amendment Primary efficacy analysis based on ZOMETA 4 mg versus pamidronate 90 mg

10. CC10-10 Clinical Trial History Breast Cancer and Multiple Myeloma (010)

11. CC10-11 Breast Cancer and Multiple Myeloma Demographics and Prognostic Factors ZOMETA� ZOMETA Pam 4 mg 8/4 mg 90 mg Demographic factor N = 561 N = 524 N = 555 Mean age, yr 59.7 58.9 58.8 Gender, % female 81.5 81.7 83.5 Race, % Caucasian 87.9 84.4 87.1 Performance status ECOG 0 - 1, % 84.5 81.9 78.6 Breast cancer Chemotherapy, n 178 172 181 Hormonal therapy, n 200 192 207 Multiple myeloma, n 183 160 167

12. CC10-12 Breast Cancer and Multiple Myeloma Patient Disposition ZOMETA� ZOMETA Pam Disposition 4 mg 8/4 mg 90 mg Intent-to-treat, N 561 524 555 Completed studytherapy (13 mo) n 353 313 337 % 62.9 59.7 60.7

13. CC10-13 Breast Cancer and Multiple Myeloma Reasons for Early Discontinuation Patients, % ZOMETA� ZOMETA Pam  4 mg 8/4 mg 90 mg Reason for discontinuation N = 561 N = 524 N = 555 Total discontinued prematurely 37.1 40.3 39.3 Death 10.7 10.7 11.5 Adverse events 10.2 13.4 9.2 Withdrew consent 8.4 8.6 10.1 Unsatisfactory therapeutic effect 3.2 3.4 4.0 Condition no longer required study drug 1.1 1.3 1.4 Protocol violation 1.1 0.8 0.7 Others 2.5 2.2 2.3

14. CC10-14 Breast Cancer and Multiple Myeloma Proportion (%) of Patients With an SRE

15. CC10-15 Noninferiority Margin for Study 010(Using Pamidronate 12, 18, and 19) % with SRE Placebo vs Pam 90 mg Patients Placebo Pam Diff 95% CI margin All 52.0 38.9 13.1 (7.3, 18.9) 3.65

16. CC10-16 Breast Cancer and Multiple Myeloma Components of SRE by Month 13

17. CC10-17 Breast Cancer and Multiple Myeloma Time to First SRE

18. CC10-18 Breast Cancer and Multiple Myeloma Mean SMR

19. CC10-19 Breast Cancer and Multiple MyelomaAndersen-Gill Multiple Event Analysis Time to SRE up to Month 13 ZOMETA� 4 mg ZOMETA 8/4 mg Hazard 95% CI for Hazard 95% CI for ratio hazard ratio ratio hazard ratio Pam 90 mg 0.885 (0.748, 1.047) 0.910 (0.768, 1.079) ZOMETA 4 mg 1.025 (0.863, 1.218)

20. CC10-20 Breast Cancer (010)Proportion of Patients With an SRE Patients With Different Types of Bone Lesions

21. CC10-21 Breast Cancer and Multiple Myeloma Disease- and QOL-Related Endpoints Comparable disease and QOL-related measures were demonstrated for the ZOMETA� and pamidronate arms Time to progression of bone metastases Time to overall progression of disease Pain and analgesic scores ECOG performance status Global quality of life

22. CC10-22 Breast Cancer and Multiple Myeloma Disease-Related Endpoints

23. CC10-23 Breast Cancer and Multiple Myeloma Quality-of-Life Endpoints

24. CC10-24 Breast Cancer and Multiple Myeloma Efficacy Summary ZOMETA demonstrated comparable efficacy to pamidronate (noninferiority) in preventing skeletal-related events

25. ZOMETA� in Breast Cancer and Multiple Myeloma:Pamidronate-Controlled Trial (010) Safety

26. CC10-26 Primary Cause of Death During theTrial or Within 28 Days After Study Drug Termination� Patients, n (%) ZOMETA� ZOMETA Pam 4 mg 8/4 mg 90 mgCause of death N = 563 N = 524 N = 556

27. CC10-27 Breast Cancer and Multiple Myeloma Survival � All Patients�

28. CC10-28 Breast Cancer and Multiple Myeloma Incidence of Adverse Events (? 15%)Regardless of Study Drug Relationship

29. CC10-29 Breast Cancer and Multiple MyelomaNCI Grade 3/4 HematologyElectrolyte and Mineral Changes Anemia Incidence < 6% for all treatment groups No differences between treatment groups Use of red blood cells and erythropoietin was similar for all treatment groups Electrolyte and mineral adverse events Incidence < 10% in all treatment groups Most common events in the ZOMETA� 4 mg treatment group were hypophosphatemia, hypokalemia, and hyperkalemia

30. CC10-30 Breast Cancer and Multiple MyelomaDefinition of Serum Creatinine Increase Serum creatinine normal (< 1.4 mg/dL) and an increase of 0.5 mg/dL Serum creatinine abnormal (? 1.4 mg/dL) and an increase of 1.0 mg/dL Doubling of serum creatinine baseline value If serum creatinine was increased, dose was held until within 10% of the baseline serum level

31. CC10-31 Breast Cancer and Multiple Myeloma Kaplan-Meier Estimates of First Serum Creatinine Increase�

32. CC10-32 Breast Cancer and Multiple MyelomaPatients Enrolling After the 15-min Amendment NCI Grade 3/4 Serum Creatinine Changes� Patients, n (%) N = 803 ZOMETA� ZOMETA Pam  4 mg 8/4 mg 90 mg N = 272 N = 263 N = 268 Grade 3 1 (0.4) 6 (2.3) 4 (1.5) Grade 4 0 (0.0) 1 (0.4) 1 (0.4)

33. CC10-33 Breast Cancer and Multiple Myeloma Safety Summary ZOMETA� (4 mg via 15-min infusion) has a safety profile, including renal effects, comparable to i.v. pamidronate (90 mg over 120 min) dosed every 3 to 4 weeks

34. CC10-34 Breast Cancer and Multiple Myeloma Overall Summary ZOMETA� 4 mg via 15-min infusion every 3 to 4 weeks demonstrated comparable safety and efficacy (noninferiority) to pamidronate 90 mg over 120 min in treating bone metastases in breast cancer and osteolytic lesions in multiple myeloma