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CC10-1 ZOMETA ® in Breast Cancer and Multiple Myeloma: Pamidronate-Controlled Trial (010) James Berenson, MD Cedars-Sinai Medical Center Los Angeles, California.

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Presentation on theme: "CC10-1 ZOMETA ® in Breast Cancer and Multiple Myeloma: Pamidronate-Controlled Trial (010) James Berenson, MD Cedars-Sinai Medical Center Los Angeles, California."— Presentation transcript:

1 CC10-1 ZOMETA ® in Breast Cancer and Multiple Myeloma: Pamidronate-Controlled Trial (010) James Berenson, MD Cedars-Sinai Medical Center Los Angeles, California C

2 CC10-2 Breast Cancer and Multiple Myeloma Trial 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 µmol/L) C Stage IV breast cancer with  1 osteolytic, osteoblastic, or mixed lesion

3 CC10-3 Breast Cancer and Multiple Myeloma Trial 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 C

4 CC10-4 Breast Cancer and Multiple Myeloma Study 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 3 §Margin of 8% with 2-sided 95% confidence intervals based on the results of pamidronate bone metastases registration trials.

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

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 C

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) C

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 §Skeletal events occurring within 21 days counted as a single occurrence. C

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 C

10 CC10-10815 N = 1,648 Clinical Trial History Breast Cancer and Multiple Myeloma (010) 29 6/9812/986/996/0012/0012/99 Accrual 1/01 Treatment and follow-up833 Renal amendment 2 (8 mg  4 mg dose) Renal amendment 1 (5  15 min infusion)

11 CC10-11 Breast Cancer and Multiple Myeloma Demographics and Prognostic Factors ZOMETA ® ZOMETAPam 4 mg8/4 mg 90 mg Demographic factorN = 561N = 524N = 555 Mean age, yr59.758.958.8 Gender, % female81.581.783.5 Race, % Caucasian87.984.487.1 Performance status ECOG 0 - 1, %84.581.978.6 Breast cancer Chemotherapy, n 178172181 Hormonal therapy, n 200192207 Multiple myeloma, n 183160167 31  Treatment groups were generally well balanced for prior skeletal complications, prognostic factors, and prior therapy

12 CC10-12 Breast Cancer and Multiple Myeloma Patient Disposition ZOMETA ® ZOMETAPam Disposition4 mg8/4 mg90 mg Intent-to-treat, N561524555 Completed study therapy (13 mo) n353313337 % 62.959.760.7 8 ISE T2-27, 28

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 prematurely37.140.339.3 Death10.710.711.5 Adverse events10.213.4 9.2 Withdrew consent 8.4 8.610.1 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 8 ISE T2-27, 28

14 CC10-14 Breast Cancer and Multiple Myeloma Proportion (%) of Patients With an SRE N =561524555  ZOMETA 4 mg versus pamidronate 90 mg: 95% CI (–7.9%, 3.7%). The noninferiority criterion, the upper boundary of the 95% CI, is below 8%

15 CC10-15 Noninferiority Margin for Study 010 (Using Pamidronate 12, 18, and 19) % with SRE Placebo vs Pam 90 mg PatientsPlaceboPamDiff95% CImargin All52.038.913.1(7.3, 18.9)3.65 32 Pt 91-2AR1 Conservative 12, 18, 19: (Placebo – Pam) 010: (ZOMETA – Pam) 0 0 ( ( ) ) * * 3.657.313.118.9 0 0 ( ( ) ) –7.93.7–2.0 PAM Placebo ZOM

16 CC10-16 Breast Cancer and Multiple Myeloma Components of SRE by Month 13 8 ISE T 2-40; CSR 010 T9-7 N 561 524 555

17 CC10-17 Breast Cancer and Multiple Myeloma Time to First SRE ZOMETA 4 mg56135427918511 ZOMETA 8/4 mg52433423815412 Pam 90 mg5553612391535 ZOMETA ® 4 mg3730.915 (0.786, 1.090) ZOMETA 8/4 mg3530.994 (0.834, 1.185) Pam 90 mg363 010 PTF 9.2-1p4; CSR 010 T9-3 14 Median time, days Hazard ratio § (95% CI) §ZOMETA 4 mg, ZOMETA 8/4 mg versus pamidronate 90 mg.

18 CC10-18 Breast Cancer and Multiple Myeloma Mean SMR 561524555N =

19 CC10-19 Breast Cancer and Multiple Myeloma Andersen-Gill Multiple Event Analysis Time to SRE up to Month 13 ZOMETA ® 4 mg ZOMETA 8/4 mg Hazard95% CI forHazard95% CI for ratiohazard ratioratiohazard ratio Pam 90 mg0.885(0.748, 1.047)0.910(0.768, 1.079) ZOMETA 4 mg1.025(0.863, 1.218) C

20 CC10-20 Breast Cancer (010) Proportion of Patients With an SRE Patients With Different Types of Bone Lesions 57 N =190176117143716416212483

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 C

22 CC10-22 Breast Cancer and Multiple Myeloma Disease-Related Endpoints Median time, days ZOMETA ® ZOMETA Pam 4 mg 8/4 mg 90 mg EndpointN = 561 N = 524 N = 555 Time to progression of bone lesion, days179.0175.0171.0 Time to progression of disease, days 134.0 125.0 111.0 CSR 010 T9-14 C

23 CC10-23 §Increased score = decline. ||Increased score = improvement. Breast Cancer and Multiple Myeloma Quality-of-Life Endpoints Change from baseline, mean  SD ZOMETA ® ZOMETA Pam 4 mg 8/4 mg90 mg Endpoint (13 mo) N = 561N = 524N = 555 Brief pain inventory score § –0.5  2.06–0.6  2.20–0.4  2.13 Analgesic score § –0.1  1.41–0.1  1.44–0.1  1.41 Performance status (ECOG) § 0.3  1.04 0.3  1.05 0.4  1.09 FACT-G total score || 0.5  14.9 3.1  14.9 2.1  15.6 CSR 010 T9-10, 9-11, 9-12, 9-13 C

24 CC10-24 Breast Cancer and Multiple Myeloma Efficacy Summary  ZOMETA demonstrated comparable efficacy to pamidronate (noninferiority) in preventing skeletal-related events C Time to Multiple Proportionfirst SREMean skeletalevent analysis with SRE, %(hazard ratio)morbidity ratehazard ratio ZOMETA ® 4 mg440.9151.130.885 ZOMETA 8/4 mg460.9941.080.910 Pam 90 mg46—1.40—

25 CC10-25 ZOMETA ® in Breast Cancer and Multiple Myeloma: Pamidronate-Controlled Trial (010) Safety

26 CC10-26 Primary Cause of Death During the Trial or Within 28 Days After Study Drug Termination § Patients, n (%) ZOMETA ® ZOMETAPam 4 mg8/4 mg90 mg Cause of deathN = 563N = 524N = 556 8 Neoplasms benign/ malignant 54(9.6)40(7.6)47(8.5) Respiratory/thoracic/ mediastinal4(0.7)6(1.1)9(1.6) Cardiac7(1.2)6(1.1)9(1.6) General disorders/ administration site 3(0.5)1(0.2)5(0.9) Infections/infestations11(2.0)8(1.5)10(1.8) Renal/urinary0(0.0)4(0.8)0(0.0) Hepato-biliary disorders3(0.5)1(0.2)0(0.0) ISS T5-12 §6 mo additional data.

27 CC10-27 Breast Cancer and Multiple Myeloma Survival – All Patients § ZOMETA 4 mg56351947943537930816061 ZOMETA 8/4 mg52448643839633827015464 Pam 90 mg55652646641636330917558 Median time, days ZOMETA ® 4 mg838P =.843 ZOMETA 8/4 mg830P =.516 Pam 90 mg811 010E1 PTF 10.5-1p4 35 §6 mo additional data.

28 CC10-28 Safety-evaluable patients, n (%) ZOMETA ® 4 mg ZOMETA 8/4 mgPam 90 mg Preferred termN = 563N = 524N = 556 Bone pain312 (55.4)276 (52.7)302 (54.5) Nausea250 (44.4)240 (45.8)245 (44.1) Fatigue217 (38.5)192 (36.6)212 (38.1) Pyrexia200 (35.5)180 (34.4)160 (28.8) Vomiting NOS166 (29.5)158 (30.2)164 (29.5) Anemia NOS153 (27.2)155 (29.6)155 (27.9) Myalgia144 (25.6)119 (22.7)130 (23.4) Diarrhea NOS141 (25.0)138 (26.3)139 (25.0) Dyspnea NOS138 (24.5)110 (21.0)134 (24.1) Cough135 (24.0)101 (19.3)114 (20.5) Constipation134 (23.8)130 (24.8)132 (23.7) Arthralgia125 (22.2) 98 (18.7) 95 (17.1) Weakness113 (20.1) 93 (17.7) 91 (16.4) Headache NOS106 (18.8)113 (21.6)131 (23.6) Anorexia105 (18.7) 83 (15.8) 70 (12.6) Edema lower limb 92 (16.3) 83 (15.8)108 (19.4) Alopecia 89 (15.8) 73 (13.9) 72 (12.9) Neutropenia 84 (14.9) 80 (15.3) 77 (13.8) Insomnia NEC 80 (14.2) 78 (14.9) 94 (16.9) Back pain 60 (10.7) 82 (15.6) 72 (12.9) Breast Cancer and Multiple Myeloma Incidence of Adverse Events (  15%) Regardless of Study Drug Relationship NOS = Not otherwise specified. NEC = Not elsewhere classified. C

29 CC10-29 Breast Cancer and Multiple Myeloma NCI Grade 3/4 Hematology Electrolyte 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 8 Vol 166 ISS PTT 5.1-5

30 CC10-30 Breast Cancer and Multiple Myeloma Definition 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 48

31 CC10-31 Breast Cancer and Multiple Myeloma Kaplan-Meier Estimates of First Serum Creatinine Increase § n Hazard ratioP-value ZOMETA ® 4 mg2722.338.003 ZOMETA 8/4 mg || 2403.580.001 Pam 90 mg270 010E1 PTF 10.6-2p1 35 nHazard ratioP-value ZOMETA 4 mg2721.012.965 ZOMETA 8/4 mg ¶ 2632.191.001 Pam 90 mg268 Percent of patients without increase (randomized prior to 15-min infusion amendment) Percent of patients without increase (randomized after 15-min infusion amendment) §6 mo additional data. ||46% of patients received only 8-mg. ¶21% of patients received only 8 mg.

32 CC10-32 Breast Cancer and Multiple Myeloma Patients Enrolling After the 15-min Amendment NCI Grade 3/4 Serum Creatinine Changes § Patients, n (%) N = 803 ZOMETA ® ZOMETA Pam 4 mg 8/4 mg90 mg N = 272N = 263N = 268 Grade 3 1 (0.4)6 (2.3)4 (1.5) Grade 4 0 (0.0)1 (0.4)1 (0.4) C §6 mo additional data.

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 C

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 C

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